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Santos F, Sum H, Yan DCL, Brewer AC. Metaboloepigenetics: Role in the Regulation of Flow-Mediated Endothelial (Dys)Function and Atherosclerosis. Cells 2025; 14:378. [PMID: 40072106 PMCID: PMC11898952 DOI: 10.3390/cells14050378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 02/26/2025] [Accepted: 03/03/2025] [Indexed: 03/15/2025] Open
Abstract
Endothelial dysfunction is the main initiating factor in atherosclerosis. Through mechanotransduction, shear stress regulates endothelial cell function in both homeostatic and diseased states. Accumulating evidence reveals that epigenetic changes play critical roles in the etiology of cardiovascular diseases, including atherosclerosis. The metabolic regulation of epigenetics has emerged as an important factor in the control of gene expression in diseased states, but to the best of our knowledge, this connection remains largely unexplored in endothelial dysfunction and atherosclerosis. In this review, we (1) summarize how shear stress (or flow) regulates endothelial (dys)function; (2) explore the epigenetic alterations that occur in the endothelium in response to disturbed flow; (3) review endothelial cell metabolism under different shear stress conditions; and (4) suggest mechanisms which may link this altered metabolism to the regulation of the endothelial epigenome by modulations in metabolite availability. We believe that metabolic regulation plays an important role in endothelial epigenetic reprogramming and could pave the way for novel metabolism-based therapeutic strategies.
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Affiliation(s)
- Francisco Santos
- School of Cardiovascular and Metabolic Medicine & Sciences, British Heart Foundation Centre of Research Excellence, Faculty of Life Sciences & Medicine, King’s College London, London SE5 9NU, UK; (F.S.); (H.S.)
| | - Hashum Sum
- School of Cardiovascular and Metabolic Medicine & Sciences, British Heart Foundation Centre of Research Excellence, Faculty of Life Sciences & Medicine, King’s College London, London SE5 9NU, UK; (F.S.); (H.S.)
| | | | - Alison C. Brewer
- School of Cardiovascular and Metabolic Medicine & Sciences, British Heart Foundation Centre of Research Excellence, Faculty of Life Sciences & Medicine, King’s College London, London SE5 9NU, UK; (F.S.); (H.S.)
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Kurhaluk N, Tkaczenko H. L-Arginine and Nitric Oxide in Vascular Regulation-Experimental Findings in the Context of Blood Donation. Nutrients 2025; 17:665. [PMID: 40004994 PMCID: PMC11858268 DOI: 10.3390/nu17040665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/08/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
This narrative review provides an analysis of the role of nitric oxide (NO) and its precursors, particularly L-arginine, in vascular regulation and health, with an emphasis on findings from our experimental research in animal models. NO serves as a critical mediator of vascular function, contributing to vasodilation, the regulation of blood flow, and the prevention of thrombosis. As a primary precursor of NO, L-arginine is essential for maintaining endothelial integrity, modulating mitochondrial function, and reducing oxidative damage. This review synthesises the data and contextualises these findings within the physiological challenges faced by blood donors, such as repeated blood donation and associated oxidative stress. It examines the effects of L-arginine supplementation on mitochondrial respiration, lipid peroxidation, and microsomal oxidation in different conditions, including differences in age, gender, and dietary interventions. The mechanisms by which L-arginine enhances NO production, improves vascular elasticity, and alleviates endothelial dysfunction caused by reduced NO bioavailability are also investigated. By integrating experimental findings with insights from the existing literature, this review provides a perspective on the potential of L-arginine supplementation to address the specific physiological needs of blood donors. It highlights the importance of personalised nutritional approaches in enhancing donor recovery and vascular resilience. In addition, this review assesses the wider implications of L-arginine supplementation in mitigating oxidative stress and preserving vascular function. The interplay between NO bioavailability, dietary factors, and physiological adaptation in blood donors is highlighted, along with the identification of current knowledge gaps and recommendations for future research. By presenting both original experimental evidence and a critical synthesis of the literature, this article highlights the therapeutic potential of NO precursors, particularly L-arginine, in promoting vascular health in the context of blood donation.
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Affiliation(s)
- Natalia Kurhaluk
- Institute of Biology, Pomeranian University in Słupsk, Arciszewski St. 22b, 76-200 Słupsk, Poland;
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Polhemus D, Almodiel D, Harb T, Ziogos E, Amat-Codina N, Ranek M, Santhanam L, Gerstenblith G, Leucker TM. Vericiguat prevents high glucose-mediated impaired vascular smooth muscle cGMP production and vasorelaxation. Sci Rep 2025; 15:4939. [PMID: 39929946 PMCID: PMC11811225 DOI: 10.1038/s41598-025-88938-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 01/31/2025] [Indexed: 02/13/2025] Open
Abstract
Normal endothelial cell dependent vascular smooth muscle cell function is mediated by nitric oxide (NO), which stimulates soluble guanylyl cyclase (sGC) production of the second messenger cyclic guanosine monophosphate (cGMP) leading to increased protein kinase G (PKG) activity and vascular smooth muscle relaxation. NO bioavailability is impaired in high glucose (HG). We tested the hypothesis that the sGC sensitizer vericiguat reverses HG-mediated decreased sGC activity in two experimental models, human aortic vascular smooth muscle cells (HVSMCs) and isolated mouse aortic rings. HVSMCs were exposed to normal glucose (NG) or to HG with or without 1 μm vericiguat for 24 h and cGMP and PKG activity were measured. Murine aortic rings were incubated in NG or HG for 24 h. Following incubation, the aortic rings were placed in an organ chamber bath containing the same NG or HG concentration used during the incubation. Dose-response curves to increasing concentrations of acetylcholine (ACh) and sodium nitroprusside were constructed for four groups: control (NG), NG + vericiguat, HG, and HG + vericiguat. As compared with the results in the NG group, cGMP production and PKG activity were significantly impaired in the HG cells incubated without, but not in those incubated with, vericiguat. In isolated aortic rings, ACh-mediated relaxation was impaired following treatment with HG, but not when a HG group was treated with vericiguat. The findings suggest clinical studies are warranted to investigate the potential of sGC sensitization as a therapeutic intervention to improve vascular NO-cGMP signaling endothelium -dependent function that is impaired in HG settings such as diabetes and the metabolic syndrome.
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Affiliation(s)
- David Polhemus
- Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Diego Almodiel
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Tarek Harb
- Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Efthymios Ziogos
- Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Nuria Amat-Codina
- Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Mark Ranek
- Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Lakshmi Santhanam
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Gary Gerstenblith
- Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Thorsten M Leucker
- Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
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Aggarwal H, Gautam J, Gupta SK, Das B, Kumar Y, Jagavelu K, Dikshit M. Improved metabolic stability in iNOS knockout mice with Lactobacillus supplementation. Nutr Res 2024; 132:95-111. [PMID: 39532058 DOI: 10.1016/j.nutres.2024.09.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 09/25/2024] [Accepted: 09/25/2024] [Indexed: 11/16/2024]
Abstract
Oxidative and nitrosative stress play pivotal roles in normal physiological processes and the pathogenesis of metabolic disorders. Previous studies from our lab demonstrated insulin resistance (IR), and dyslipidemia in iNOS-/- mice, emphasizing the importance of maintaining optimal redox balance. These mice exhibited altered gut microbiota with decreased Lactobacillus. Therefore, we hypothesized that Lactobacillus supplementation could mitigate metabolic disturbances in iNOS-/- mice. To test this hypothesis, iNOS-/- mice and wild-type (WT) mice were divided into four groups: iNOS-/- with or without Lactobacillus supplementation, WT with or without Lactobacillus supplementation and glucose tolerance, insulin resistance, gluconeogenesis, lipids, gene expression related to glucose and lipid metabolism (qPCR), fecal gut microbiota (16S rRNA sequencing), and serum and caecum metabolomics (LC-MS) were monitored. IR and dyslipidemic iNOS-/- mice exhibited reduced microbial diversity, diminished presence of Lactobacillus, and altered serum metabolites, indicating metabolic dysregulation. Lactobacillus supplementation in iNOS-/- mice effectively reversed glucose intolerance, IR, dyslipidemia, and associated metabolic irregularities compared to WT. These improvements correlated with changes in gene expression related to fatty acid synthesis in liver and adipose tissue, lipid oxidation in liver, and lipid efflux in intestinal tissue as compared to untreated iNOS-/- mice. Despite the positive effects on metabolic markers, Lactobacillus supplementation did not reduce body weight or rectify disrupted energy balance, as evidenced by reduced VCO2 production, heat generation, and metabolic rates in iNOS-/- mice. The results suggest that Lactobacillus supplementation ameliorates metabolic disturbances but did not fully restore disrupted energy balance, highlighting complex interactions between the gut microbiome and metabolism.
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Affiliation(s)
- Hobby Aggarwal
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India; Non-communicable Diseases Division, Translational Health Science and Technology Institute, Faridabad, Haryana 121001, India
| | - Jyoti Gautam
- Non-communicable Diseases Division, Translational Health Science and Technology Institute, Faridabad, Haryana 121001, India; Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India
| | - Sonu Kumar Gupta
- Non-communicable Diseases Division, Translational Health Science and Technology Institute, Faridabad, Haryana 121001, India
| | - Bhabatosh Das
- Molecular Genetics Laboratory, Infection and Immunology Division, Translational Health Science and Technology Institute, Faridabad, Haryana 121001, India
| | - Yashwant Kumar
- Non-communicable Diseases Division, Translational Health Science and Technology Institute, Faridabad, Haryana 121001, India
| | - Kumaravelu Jagavelu
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India
| | - Madhu Dikshit
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India; Non-communicable Diseases Division, Translational Health Science and Technology Institute, Faridabad, Haryana 121001, India.
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Prasad K. Atherogenic Effect of Homocysteine, a Biomarker of Inflammation and Its Treatment. Int J Angiol 2024; 33:262-270. [PMID: 39502352 PMCID: PMC11534477 DOI: 10.1055/s-0044-1788280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2024] Open
Abstract
Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis. Ischemic stroke and heart disease, coronary heart disease, and cardiovascular disease are events resulting from long-lasting and silent atherosclerosis. This paper deals with the synthesis of homocysteine (Hcy), causes of HHcy, mechanism of HHcy-induced atherosclerosis, and treatment of HHcy. Synthesis and metabolism of Hcy involves demethylation, transmethylation, and transsulfuration, and these processes require vitamin B 6 and vitamin B 12 folic acid (vitamin B 9 ). Causes of HHcy include deficiency of vitamins B 6 , B 9 , and B 12 , genetic defects, use of smokeless tobacco, cigarette smoking, alcohol consumption, diabetes, rheumatoid arthritis, low thyroid hormone, consumption of caffeine, folic acid antagonist, cholesterol-lowering drugs (niacin), folic acid antagonist (phenytoin), prolonged use of proton pump inhibitors, metformin, and hypertension. HHcy-induced atherosclerosis may be mediated through oxidative stress, decreased availability of nitric oxide (NO), increased expression of monocyte chemoattractant protein-1, smooth muscle cell proliferation, increased thrombogenicity, and induction of arterial connective tissue. HHcy increases the generation of atherogenic biomolecules such as nuclear factor-kappa B, proinflammatory cytokines (IL-1β, IL-6, and IL-8), cell adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selection), growth factors (IGF-1 and TGF-β), and monocyte colony-stimulating factor which lead to the development of atherosclerosis. NO which is protective against the development of atherosclerosis is reduced by HHcy. Therapy with folic acid, vitamin B 6 , and vitamin B 12 lowers the levels of Hcy, with folic acid being the most effective. Dietary sources of folic acid, vitamin B 6 , vitamin B 12 , omega-3 fatty acid, and green coffee extract reduce Hcy. Abstaining from drinking coffee and alcohol, and smoking also reduces blood levels of Hcy. In conclusion, HHcy induces atherosclerosis by generating atherogenic biomolecules, and treatment of atherosclerosis-induced diseases may be by reducing the levels of Hcy.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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Evanoff NG, Dengel DR, Stockelman KA, Fandl H, DeSouza NM, Greiner JJ, Dufresne SR, Kotlyar M, Garcia VP. Circulating extracellular microvesicles associated with electronic cigarette use increase endothelial cell inflammation and reduce nitric oxide production. Exp Physiol 2024; 109:1593-1603. [PMID: 39092897 PMCID: PMC11363099 DOI: 10.1113/ep091715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Accepted: 07/05/2024] [Indexed: 08/04/2024]
Abstract
The purpose of this study was to determine the effect of circulating microvesicles isolated from chronic electronic (e-)cigarette users on cultured human umbilical vein endothelial cell (HUVEC) expression of nuclear factor-κB (NF-κB), cellular cytokine release, phosphorylation of endothelial nitric oxide synthase (eNOS) and NO production. The HUVECs were treated with microvesicles isolated via flow cytometry from nine non-tobacco users (five male and four female; 22 ± 2 years of age) and 10 e-cigarette users (six male and four female; 22 ± 2 years of age). Microvesicles from e-cigarette users induced significantly greater release of interleukin-6 (183.4 ± 23.6 vs. 150.6 ± 15.4 pg/mL; P = 0.002) and interleukin-8 (160.0 ± 31.6 vs. 129.4 ± 11.2 pg/mL; P = 0.01), in addition to expression of p-NF-κB p65 (Ser536) (18.8 ± 3.4 vs. 15.6 ± 1.5 a.u.; P = 0.02) from HUVECs compared with microvesicles from non-tobacco users. Nuclear factor-κB p65 was not significantly different between microvesicles from the non-tobacco users and from the e-cigarette users (87.6 ± 8.7 vs. 90.4 ± 24.6 a.u.; P = 0.701). Neither total eNOS (71.4 ± 21.8 vs. 80.4 ± 24.5 a.u.; P = 0.413) nor p-eNOS (Thr495) (229.2 ± 26.5 vs. 222.1 ± 22.7 a.u.; P = 0.542) was significantly different between microvesicle-treated HUVECs from non-tobacco users and e-cigarette users. However, p-eNOS (Ser1177) (28.9 ± 6.2 vs. 45.8 ± 9.0 a.u.; P < 0.001) expression was significantly lower from e-cigarette users compared with non-tobacco users. Nitric oxide production was significantly lower (8.2 ± 0.6 vs. 9.7 ± 0.9 μmol/L; P = 0.001) in HUVECs treated with microvesicles from e-cigarette users compared with microvesicles from non-tobacco users. This study demonstrated increased NF-κB activation and inflammatory cytokine production, in addition to diminished eNOS activity and NO production resulting from e-cigarette use. HIGHLIGHTS: What is the central question of this study? Circulating microvesicles contribute to cardiovascular health and disease via their effects on the vascular endothelium. The impact of electronic (e-)cigarette use on circulating microvesicle phenotype is not well understood. What is the main finding and its importance? Circulating microvesicles from e-cigarette users increase endothelial cell inflammation and impair endothelial nitric oxide production. Endothelial inflammation and diminished nitric oxide bioavailability are central factors underlying endothelial dysfunction and, in turn, cardiovascular disease risk. Deleterious changes in the functional phenotype of circulating microvesicles might contribute to the reported adverse effects of e-cigarette use on cardiovascular health.
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Affiliation(s)
- Nicholas G. Evanoff
- School of KinesiologyUniversity of MinnesotaMinneapolisMinnesotaUSA
- Center for Pediatric Obesity MedicineUniversity of Minnesota Medical SchoolMinneapolisMinnesotaUSA
| | - Donald R. Dengel
- School of KinesiologyUniversity of MinnesotaMinneapolisMinnesotaUSA
- Center for Pediatric Obesity MedicineUniversity of Minnesota Medical SchoolMinneapolisMinnesotaUSA
| | - Kelly A. Stockelman
- Department of Integrative PhysiologyUniversity of ColoradoBoulderColoradoUSA
| | - Hannah Fandl
- Department of Integrative PhysiologyUniversity of ColoradoBoulderColoradoUSA
| | - Noah M. DeSouza
- Department of Integrative PhysiologyUniversity of ColoradoBoulderColoradoUSA
| | - Jared J. Greiner
- Department of Integrative PhysiologyUniversity of ColoradoBoulderColoradoUSA
| | - Sheena R. Dufresne
- Department of Experimental and Clinical PharmacologyUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Michael Kotlyar
- Department of Experimental and Clinical PharmacologyUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Vinicius P. Garcia
- Department of Integrative PhysiologyUniversity of ColoradoBoulderColoradoUSA
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Polhemus D, Almodiel D, Harb T, Ziogos E, Amat-Codina N, Ranek M, Santhanam L, Gerstenblith G, Leucker T. VERICIGUAT RESCUES CYCLIC GUANOSINE MONOPHOSPHATE PRODUCTION IN HUMAN AORTIC VASCULAR SMOOTH MUSCLE CELLS AND AUGMENTS VASORELAXATION IN AORTIC RINGS EXPOSED TO HIGH GLUCOSE. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.21.600154. [PMID: 38948704 PMCID: PMC11213137 DOI: 10.1101/2024.06.21.600154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Background Normal endothelial cell dependent vascular smooth muscle cell function is mediated by nitric oxide (NO), which stimulates soluble guanylyl cyclase (sGC) production of the second messenger, cyclic guanosine monophosphate (cGMP) leading to increased protein kinase G (PKG) activity and vascular smooth muscle relaxation. NO bioavailability is impaired in inflammatory settings, such as high glucose (HG). We examined whether the direct sGC sensitizer/stimulator vericiguat, augments cGMP production in human vascular smooth muscle cells (HVSMC) exposed to high glucose and explored its effect on vasorelaxation. Methods Aortic HVSMCs were exposed to HG for 24h. In the treatment group, cells also received 1uM vericiguat for 24h. After incubation, cGMP and PKG activity were measured. Additionally, thoracic murine aortas were exposed to HG or to normal glucose (NG) control. The rings were then placed in an organ chamber bath and dose response curves to increasing doses of acetylcholine (Ach) and sodium nitroprusside were constructed for three groups: control (normal glucose), HG alone, and HG + vericiguat. Results HVSMCs exposed to HG produced significantly less cGMP than those exposed to NG. cGMP production in the presence of HG was rescued when treated with 1uM vericiguat. Additionally, PKG activity was impaired in the presence of HG and enzyme activity was restored with vericiguat. In isolated mouse aortic rings, ACh mediated relaxation was impaired following treatment with HG, but was improved when a HG group was treated with vericiguat. Conclusions The sGC sensitizer/stimulator vericiguat restored cGMP production and PKG activity in the setting of HG. Vericiguat enhanced ACh-mediated vasorelaxation in the setting of HG. The findings suggest clinical studies are warranted to investigate the potential of sGC sensitization/stimulation as a therapeutic intervention to improve vascular endothelial-dependent function that is impaired in pro-inflammatory settings that are associated with the development of atherosclerotic disease.
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Sharma H, Mossman K, Austin RC. Fatal attractions that trigger inflammation and drive atherosclerotic disease. Eur J Clin Invest 2024; 54:e14169. [PMID: 38287209 DOI: 10.1111/eci.14169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 12/14/2023] [Accepted: 01/09/2024] [Indexed: 01/31/2024]
Abstract
BACKGROUND Atherosclerosis is the salient, underlying cause of cardiovascular diseases, such as arrhythmia, coronary artery disease, cardiomyopathy, pulmonary embolism and myocardial infarction. In recent years, atherosclerosis pathophysiology has evolved from a lipid-based to an inflammation-centric ideology. METHODS This narrative review is comprised of review and original articles that were found through the PubMed search engine. The following search terms or amalgamation of terms were used: "cardiovascular disease," "atherosclerosis," "inflammation," "GRP78," "Hsp60," "oxidative low-density lipoproteins," "aldehyde dehydrogenase," "β2-glycoprotein," "lipoprotein lipase A," "human cytomegalovirus." "SARS-CoV-2," "chlamydia pneumonia," "autophagy," "thrombosis" and "therapeutics." RESULTS Emerging evidence supports the concept that atherosclerosis is associated with the interaction between cell surface expression of stress response chaperones, including GRP78 and Hsp60, and their respective autoantibodies. Moreover, various other autoantigens and their autoantibodies have displayed a compelling connection with the development of atherosclerosis, including oxidative low-density lipoproteins, aldehyde dehydrogenase, β2-glycoprotein and lipoprotein lipase A. Atherosclerosis progression is also concurrent with viral and bacterial activators of various diseases. This narrative review will focus on the contributions of human cytomegalovirus as well as SARS-CoV-2 and chlamydia pneumonia in atherosclerosis development. Notably, the interaction of an autoantigen with their respective autoantibodies or the presence of a foreign antigen can enhance inflammation development, which leads to atherosclerotic lesion progression. CONCLUSION We will highlight and discuss the complex role of the interaction between autoantigens and autoantibodies, and the presence of foreign antigens in the development of atherosclerotic lesions in relationship to pro-inflammatory responses.
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Affiliation(s)
- Hitesh Sharma
- Division of Nephrology, Department of Medicine, McMaster University, The Research Institute of St. Joe's Hamilton and the Hamilton Centre for Kidney Research, Hamilton, Ontario, Canada
| | - Karen Mossman
- Department of Medicine, Michael DeGroote Institute for Infectious Disease Research and the McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Richard C Austin
- Division of Nephrology, Department of Medicine, McMaster University, The Research Institute of St. Joe's Hamilton and the Hamilton Centre for Kidney Research, Hamilton, Ontario, Canada
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Lee H, Koh GY, Lee H, Alves P, Yokoyama W, Wang Y. Discovery of a Novel Bioactive Compound in Orange Peel Polar Fraction on the Inhibition of Trimethylamine and Trimethylamine N-Oxide through Metabolomics Approaches and In Vitro and In Vivo Assays: Feruloylputrescine Inhibits Trimethylamine via Suppressing cntA/B Enzyme. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:7870-7881. [PMID: 38562057 DOI: 10.1021/acs.jafc.3c09005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
This study compares the inhibitory effects of orange peel polar fraction (OPP) and orange peel nonpolar fraction (OPNP) on trimethylamine (TMA) and trimethylamine N-oxide (TMAO) production in response to l-carnitine treatment in vivo and in vitro. Metabolomics is used to identify bioactive compounds. The research demonstrates that the OPP effectively regulates atherosclerosis-related markers, TMA and TMAO in plasma and urine, compared to the OPNP. Our investigation reveals that these inhibitory effects are independent of changes in gut microbiota composition. The effects are attributed to the modulation of cntA/B enzyme activity and FMO3 mRNA expression in vitro. Moreover, OPP exhibits stronger inhibitory effects on TMA production than OPNP, potentially due to its higher content of feruloylputrescine, which displays the highest inhibitory activity on the cntA/B enzyme and TMA production. These findings suggest that the OPP containing feruloylputrescine has the potential to alleviate cardiovascular diseases by modulating cntA/B and FMO3 enzymes without directly influencing gut microbiota composition.
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Affiliation(s)
- Hana Lee
- Department of Food Science and Human Nutrition, Citrus Research and Education Center, University of Florida, Lake Alfred, Florida 33850, United States
| | - Gar Yee Koh
- Department of Food Science and Human Nutrition, Citrus Research and Education Center, University of Florida, Lake Alfred, Florida 33850, United States
- Nutrition and Foods Program, School of Family and Consumer Sciences, Texas State University, San Marcos, Texas 78666, United States
| | - Hanna Lee
- Healthy Processed Foods Research Unit, Agricultural Research Service, United States Department of Agricultural, Albany, California 94710, United States
| | - Priscila Alves
- Healthy Processed Foods Research Unit, Agricultural Research Service, United States Department of Agricultural, Albany, California 94710, United States
| | - Wallace Yokoyama
- Healthy Processed Foods Research Unit, Agricultural Research Service, United States Department of Agricultural, Albany, California 94710, United States
| | - Yu Wang
- Department of Food Science and Human Nutrition, Citrus Research and Education Center, University of Florida, Lake Alfred, Florida 33850, United States
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Ramírez-Carracedo R, Hernández I, Moreno-Gómez-Toledano R, Díez-Mata J, Tesoro L, González-Cucharero C, Jiménez-Guirado B, Alcharani N, Botana L, Saura M, Zamorano JL, Zaragoza C. NOS3 prevents MMP-9, and MMP-13 induced extracellular matrix proteolytic degradation through specific microRNA-targeted expression of extracellular matrix metalloproteinase inducer in hypertension-related atherosclerosis. J Hypertens 2024; 42:685-693. [PMID: 38406874 PMCID: PMC10906209 DOI: 10.1097/hjh.0000000000003679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 01/08/2024] [Accepted: 01/22/2024] [Indexed: 02/27/2024]
Abstract
BACKGROUND Endothelial nitric oxide synthase (NOS3) elicits atheroprotection by preventing extracellular matrix (ECM) proteolytic degradation through inhibition of extracellular matrix metalloproteinase inducer (EMMPRIN) and collagenase MMP-13 by still unknown mechanisms. METHODS C57BL/6 mice lacking ApoE , NOS3, and/or MMP13 were fed with a high-fat diet for 6 weeks. Entire aortas were extracted and frozen to analyze protein and nucleic acid expression. Atherosclerotic plaques were detected by ultrasound imaging, Oil Red O (ORO) staining, and Western Blot. RNA-seq and RT-qPCR were performed to evaluate EMMPRIN, MMP-9, and EMMPRIN-targeting miRNAs. Mouse aortic endothelial cells (MAEC) were incubated to assess the role of active MMP-13 over MMP-9. One-way ANOVA or Kruskal-Wallis tests were performed to determine statistical differences. RESULTS Lack of NOS3 in ApoE null mice fed with a high-fat diet increased severe plaque accumulation, vessel wall widening, and high mortality, along with EMMPRIN-induced expression by upregulation of miRNAs 46a-5p and 486-5p. However, knocking out MMP-13 in ApoE/NOS3 -deficient mice was sufficient to prevent mortality (66.6 vs. 26.6%), plaque progression (23.1 vs. 8.8%), and MMP-9 expression, as confirmed in murine aortic endothelial cell (MAEC) cultures, in which MMP-9 was upregulated by incubation with active recombinant MMP-13, suggesting MMP-9 as a new target of MMP-13 in atherosclerosis. CONCLUSION We describe a novel mechanism by which the absence of NOS3 may worsen atherosclerosis through EMMPRIN-induced ECM proteolytic degradation by targeting the expression of miRNAs 146a-5p and 485-5p. Focusing on NOS3 regulation of ECM degradation could be a promising approach in the management of atherosclerosis.
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Affiliation(s)
- Rafael Ramírez-Carracedo
- Unidad Mixta de Investigación Cardiovascular, Departamento de Cardiología, Universidad Francisco de Vitoria, Hospital Ramón y Cajal (IRYCIS)
| | - Ignacio Hernández
- Unidad Mixta de Investigación Cardiovascular, Departamento de Cardiología, Universidad Francisco de Vitoria, Hospital Ramón y Cajal (IRYCIS)
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Av. Monforte de Lemos
| | - Rafael Moreno-Gómez-Toledano
- Unidad Mixta de Investigación Cardiovascular, Departamento de Cardiología, Universidad Francisco de Vitoria, Hospital Ramón y Cajal (IRYCIS)
- Universidad de Alcalá, Unidad de Fisiología, Departamento de Biología de Sistemas, Alcalá de Henares
| | - Javier Díez-Mata
- Unidad Mixta de Investigación Cardiovascular, Departamento de Cardiología, Universidad Francisco de Vitoria, Hospital Ramón y Cajal (IRYCIS)
| | - Laura Tesoro
- Unidad Mixta de Investigación Cardiovascular, Departamento de Cardiología, Universidad Francisco de Vitoria, Hospital Ramón y Cajal (IRYCIS)
| | - Claudia González-Cucharero
- Unidad Mixta de Investigación Cardiovascular, Departamento de Cardiología, Universidad Francisco de Vitoria, Hospital Ramón y Cajal (IRYCIS)
| | - Beatriz Jiménez-Guirado
- Unidad Mixta de Investigación Cardiovascular, Departamento de Cardiología, Universidad Francisco de Vitoria, Hospital Ramón y Cajal (IRYCIS)
| | - Nunzio Alcharani
- Unidad Mixta de Investigación Cardiovascular, Departamento de Cardiología, Universidad Francisco de Vitoria, Hospital Ramón y Cajal (IRYCIS)
| | - Laura Botana
- Unidad Mixta de Investigación Cardiovascular, Departamento de Cardiología, Universidad Francisco de Vitoria, Hospital Ramón y Cajal (IRYCIS)
| | - Marta Saura
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Av. Monforte de Lemos
- Universidad de Alcalá, Unidad de Fisiología, Departamento de Biología de Sistemas, Alcalá de Henares
| | - Jose L. Zamorano
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Av. Monforte de Lemos
- Departamento de Cardiología, Hospital Universitario Ramón y Cajal (IRYCIS), Madrid, Spain
| | - Carlos Zaragoza
- Unidad Mixta de Investigación Cardiovascular, Departamento de Cardiología, Universidad Francisco de Vitoria, Hospital Ramón y Cajal (IRYCIS)
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Av. Monforte de Lemos
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11
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Garcia VP, Fandl HK, Hijmans JG, Berry AR, Cardenas HL, Stockelman KA, DeSouza NM, Treuth JW, Greiner JJ, Park AJ, Stauffer BL, DeSouza CA. Effects of circulating endothelial microvesicles isolated from adults with obesity on endothelial cell inflammation, apoptosis, and nitric oxide production. Am J Physiol Endocrinol Metab 2024; 326:E38-E49. [PMID: 37991453 PMCID: PMC11193534 DOI: 10.1152/ajpendo.00139.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 10/27/2023] [Accepted: 11/14/2023] [Indexed: 11/23/2023]
Abstract
Circulating endothelial cell-derived microvesicles (EMVs) have been shown to be elevated with obesity and associated with endothelial dysfunction; however, their direct effect on endothelial cells is unknown. The experimental aim of this study was to determine the effect of EMVs isolated from adults with obesity on endothelial cell inflammation, apoptosis, and nitric oxide (NO) production. EMVs (CD144+ microvesicles) were identified, enumerated, and isolated from plasma by flow cytometry from 24 sedentary adults: 12 normal-weight adults [8 M/4 F; age: 55 ± 6 yr; body mass index (BMI): 24.3 ± 0.7 kg/m2; EMV: 144 ± 53 EMVs/µL] and 12 adults with obesity (6 M/6 F; 59 ± 7 yr; BMI: 31.0 ± 1.1 kg/m2; EMV: 245 ± 89 EMVs/µL). Human umbilical vein endothelial cells were cultured and treated with EMVs from either normal-weight adults or adults with obesity. EMVs from obese adults induced significantly higher release of interleukin (IL)-6 (108.2 ± 7.7 vs. 90.9 ± 10.0 pg/mL) and IL-8 (75.4 ± 9.8 vs. 59.5 ± 11.5 pg/mL) from endothelial cells vs. EMVs from normal-weight adults, concordant with greater intracellular expression of phosphorylated NF-κB p65 (Ser536; active NF-κB) [145.0 ± 34.1 vs. 114.5 ± 30.4 arbitrary units (AU)]. Expression of phosphorylated p38-MAPK (15.4 ± 5.7 vs. 9.2 ± 2.5 AU) and active caspase-3 (168.2 ± 65.5 vs. 107.8 ± 40.5 AU), markers of cell apoptosis, was higher in cells treated with obesity-related EMVs. Phosphorylated endothelial nitric oxide synthase (eNOS) (Ser1177) expression (23.5 ± 7.2 vs. 34.7 ± 9.7 AU) and NO production (6.9 ± 1.4 vs. 8.7 ± 0.7 µmol/L) were significantly lower in the cells treated with EMVs from obese adults. These data indicate that circulating EMVs from adults with obesity promote a proinflammatory, proapoptotic, and NO-compromised endothelial phenotype. Circulating EMVs are a potential mediator of obesity-related endothelial dysfunction.NEW & NOTEWORTHY In the present study, we determined the effect of circulating endothelial cell-derived microvesicles (EMVs) isolated from adults with obesity on endothelial cell inflammation, apoptosis, and nitric oxide (NO) production in vitro. Circulating EMVs harvested from adults with obesity promoted a proinflammatory, proapoptotic, and NO-compromised endothelial phenotype. Elevated circulating EMVs in adults with obesity, independent of other cardiometabolic risk factors, are a potential novel systemic mediator of obesity-related endothelial dysfunction and vascular risk.
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Affiliation(s)
- Vinicius P Garcia
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado, United States
| | - Hannah K Fandl
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado, United States
| | - Jamie G Hijmans
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado, United States
| | - Auburn R Berry
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado, United States
| | - Hannah L Cardenas
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado, United States
| | - Kelly A Stockelman
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado, United States
| | - Noah M DeSouza
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado, United States
| | - J William Treuth
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado, United States
| | - Jared J Greiner
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado, United States
| | - Andrew J Park
- Rocky Mountain Regional Spinal Injury System, Craig Hospital, Englewood, Colorado, United States
- Department of Medicine, University of Colorado Anschutz Medical Center, Denver, Colorado, United States
| | - Brian L Stauffer
- Department of Medicine, University of Colorado Anschutz Medical Center, Denver, Colorado, United States
- Denver Health Medical Center, Denver, Colorado, United States
| | - Christopher A DeSouza
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado, United States
- Department of Medicine, University of Colorado Anschutz Medical Center, Denver, Colorado, United States
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12
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Roberts R, Huckstepp RT. Innate Sleep Apnea in Spontaneously Hypertensive Rats Is Associated With Microvascular Rarefaction and Neuronal Loss in the preBötzinger Complex. Stroke 2023; 54:3141-3152. [PMID: 38011231 PMCID: PMC10769171 DOI: 10.1161/strokeaha.123.044732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 10/13/2023] [Accepted: 10/18/2023] [Indexed: 11/29/2023]
Abstract
BACKGROUND Sleep apnea (SA) is a major threat to physical health and carries a significant economic burden. These impacts are worsened by its interaction with, and induction of, its comorbidities. SA holds a bidirectional relationship with hypertension, which drives atherosclerosis/arteriolosclerosis, ultimately culminating in vascular dementia. METHODS To enable a better understanding of these sequelae of events, we investigated innate SA and its effects on cognition in adult-aged spontaneously hypertensive rats, which have a range of cardiovascular disorders: plethysmography and electroencephalographic/electromyographic recordings were used to assess sleep-wake state, breathing parameters, and sleep-disordered breathing; immunocytochemistry was used to assess vascular and neural health; the forced alteration Y maze and Barnes maze were used to assess short- and long-term memories, respectively; and an anesthetized preparation was used to assess baroreflex sensitivity. RESULTS Spontaneously hypertensive rats displayed a higher degree of sleep-disordered breathing, which emanates from poor vascular health leading to a loss of preBötzinger Complex neurons. These rats also display small vessel white matter disease, a form of vascular dementia, which may be exacerbated by the SA-induced neuroinflammation in the hippocampus to worsen the related deficits in both long- and short-term memories. CONCLUSIONS Therefore, we postulate that hypertension induces SA through vascular damage in the respiratory column, culminating in neuronal loss in the inspiratory oscillator. This induction of SA, which, in turn, will independently exacerbate hypertension and neural inflammation, increases the rate of vascular dementia.
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Affiliation(s)
- Reno Roberts
- School of Life Sciences, University of Warwick, Coventry, United Kingdom
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13
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Mthembu SXH, Orlando P, Silvestri S, Ziqubu K, Mazibuko-Mbeje SE, Mabhida SE, Nyambuya TM, Nkambule BB, Muller CJF, Basson AK, Tiano L, Dludla PV. Impact of dyslipidemia in the development of cardiovascular complications: Delineating the potential therapeutic role of coenzyme Q 10. Biochimie 2023; 204:33-40. [PMID: 36067903 DOI: 10.1016/j.biochi.2022.08.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 08/23/2022] [Accepted: 08/29/2022] [Indexed: 01/12/2023]
Abstract
Dyslipidemia is one of the major risk factors for the development of cardiovascular disease (CVD) in patients with type 2 diabetes (T2D). This metabolic anomality is implicated in the generation of oxidative stress, an inevitable process involved in destructive mechanisms leading to myocardial damage. Fortunately, commonly used drugs like statins can counteract the detrimental effects of dyslipidemia by lowering cholesterol to reduce CVD-risk in patients with T2D. Statins mainly function by blocking the production of cholesterol by targeting the mevalonate pathway. However, by blocking cholesterol synthesis, statins coincidently inhibit the synthesis of other essential isoprenoid intermediates of the mevalonate pathway like farnesyl pyrophosphate and coenzyme Q10 (CoQ10). The latter is by far the most important co-factor and co-enzyme required for efficient mitochondrial oxidative capacity, in addition to its robust antioxidant properties. In fact, supplementation with CoQ10 has been found to be beneficial in ameliorating oxidative stress and improving blood flow in subjects with mild dyslipidemia.. Beyond discussing the destructive effects of oxidative stress in dyslipidemia-induced CVD-related complications, the current review brings a unique perspective in exploring the mevalonate pathway to block cholesterol synthesis while enhancing or maintaining CoQ10 levels in conditions of dyslipidemia. Furthermore, this review disscusses the therapeutic potential of bioactive compounds in targeting the downstream of the mevalonate pathway, more importantly, their ability to block cholesterol while maintaining CoQ10 biosynthesis to protect against the destructive complications of dyslipidemia.
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Affiliation(s)
- Sinenhlanhla X H Mthembu
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, 7505, South Africa; Department of Biochemistry, Mafikeng Campus, Northwest University, Mmabatho, 2735, South Africa
| | - Patrick Orlando
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, 60131, Italy
| | - Sonia Silvestri
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, 60131, Italy
| | - Khanyisani Ziqubu
- Department of Biochemistry, Mafikeng Campus, Northwest University, Mmabatho, 2735, South Africa
| | | | - Sihle E Mabhida
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, 7505, South Africa
| | - Tawanda M Nyambuya
- Department of Health Sciences, Namibia University of Science and Technology, Windhoek, 9000, Namibia
| | - Bongani B Nkambule
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa
| | - Christo J F Muller
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, 7505, South Africa; Centre for Cardiometabolic Research Africa (CARMA), Division of Medical Physiology, Stellenbosch University, Tygerberg, 7505, South Africa; Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, 3886, South Africa
| | - Albertus K Basson
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, 3886, South Africa
| | - Luca Tiano
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, 60131, Italy
| | - Phiwayinkosi V Dludla
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, 7505, South Africa.
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14
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Lew LA, Ethier TS, Pyke KE. The impact of exercise training on endothelial function in postmenopausal women: a systematic review. Exp Physiol 2022; 107:1388-1421. [PMID: 36288824 DOI: 10.1113/ep090702] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 09/27/2022] [Indexed: 12/14/2022]
Abstract
NEW FINDINGS What is the topic of this review? The aim of this systematic review was to evaluate and summarize all published literature examining the impact of various exercise training interventions on endothelial function in postmenopausal women. What advances does it highlight? There was a moderate effect of training on macrovascular and microvascular endothelial function and just under two-thirds of studies demonstrated a significant increase in at least one measure of endothelial function in postmenopausal women. Factors including exercise intensity and duration, vessel type, clinical status, hormone therapy, and menopausal status may influence the effects of training on endothelial function in postmenopausal women. ABSTRACT Women experience a rapid decline in endothelial function during menopause. Therefore, it is important to explore interventions, such as exercise training, that may prevent endothelial dysfunction in postmenopausal women. The aim of this systematic review was to evaluate and summarize all published literature examining the impact of various exercise training interventions on endothelial function in postmenopausal women. Three electronic databases (MEDLINE, EMBASE and Web of Science) were used to systematically select studies related to exercise training, endothelial function and postmenopausal women. The major initial and secondary update systematic searches yielded 502 unique articles that were screened for eligibility. Thirty-five studies were included in the systematic review. Two-thirds of all studies demonstrated a group-level increase in at least one measure of endothelial function with training. Most studies investigating biomarkers of endothelial function showed improvement in at least one measured biomarker post-training. There was a moderate effect of training on both macrovascular and microvascular endothelial function in observational and randomized intervention studies. Variability in study designs, training protocols and participant characteristics make it difficult to directly compare studies. Factors including exercise intensity and duration, vessel type, clinical status, hormone therapy, and menopausal status may contribute to the inconsistent effects of training on endothelial function in postmenopausal women. Future research is needed in this population to understand the mechanisms driving inter-study and inter-individual differences in training-induced changes in endothelial function.
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Affiliation(s)
- Lindsay A Lew
- Cardiovascular Stress Response Lab, School of Kinesiology and Health Studies, Queen's University, Kingston, Ontario, Canada
| | - Tarrah S Ethier
- Cardiovascular Stress Response Lab, School of Kinesiology and Health Studies, Queen's University, Kingston, Ontario, Canada
| | - Kyra E Pyke
- Cardiovascular Stress Response Lab, School of Kinesiology and Health Studies, Queen's University, Kingston, Ontario, Canada
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15
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Zhou L, Liu C, Zheng Y, Huang Z, Zhang X, Xiao Y. Bio-orthogonal Toolbox for Monitoring Nitric Oxide in Targeted Organelles of Live Cells and Zebrafishes. Anal Chem 2022; 94:15678-15685. [DOI: 10.1021/acs.analchem.2c02768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Lin Zhou
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
| | - Chuanhao Liu
- School of Medicine, Engineering Research Centre of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Huaqiao University, Quanzhou 362021, China
| | - Ying Zheng
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
| | - Zhenlong Huang
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
| | - Xinfu Zhang
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
| | - Yi Xiao
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
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16
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Bu S, Nguyen HC, Nikfarjam S, Michels DCR, Rasheed B, Maheshkumar S, Singh S, Singh KK. Endothelial cell-specific loss of eNOS differentially affects endothelial function. PLoS One 2022; 17:e0274487. [PMID: 36149900 PMCID: PMC9506615 DOI: 10.1371/journal.pone.0274487] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 08/29/2022] [Indexed: 12/01/2022] Open
Abstract
The endothelium maintains and regulates vascular homeostasis mainly by balancing interplay between vasorelaxation and vasoconstriction via regulating Nitric Oxide (NO) availability. Endothelial nitric oxide synthase (eNOS) is one of three NOS isoforms that catalyses the synthesis of NO to regulate endothelial function. However, eNOS’s role in the regulation of endothelial function, such as cell proliferation and migration remain unclear. To gain a better understanding, we genetically knocked down eNOS in cultured endothelial cells using sieNOS and evaluated cell proliferation, migration and also tube forming potential in vitro. To our surprise, loss of eNOS significantly induced endothelial cell proliferation, which was associated with significant downregulation of both cell cycle inhibitor p21 and cell proliferation antigen Ki-67. Knockdown of eNOS induced cell migration but inhibited formation of tube-like structures in vitro. Mechanistically, loss of eNOS was associated with activation of MAPK/ERK and inhibition of PI3-K/AKT signaling pathway. On the contrary, pharmacologic inhibition of eNOS by inhibitors L-NAME or L-NMMA, inhibited cell proliferation. Genetic and pharmacologic inhibition of eNOS, both promoted endothelial cell migration but inhibited tube-forming potential. Our findings confirm that eNOS regulate endothelial function by inversely controlling endothelial cell proliferation and migration, and by directly regulating its tube-forming potential. Differential results obtained following pharmacologic versus genetic inhibition of eNOS indicates a more complex mechanism behind eNOS regulation and activity in endothelial cells, warranting further investigation.
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Affiliation(s)
- Shuhan Bu
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Hien C. Nguyen
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
- Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Sepideh Nikfarjam
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
- Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - David C. R. Michels
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Berk Rasheed
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
- Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Sauraish Maheshkumar
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Shweta Singh
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Krishna K. Singh
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
- Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
- * E-mail:
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17
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Karnewar S, Pulipaka S, Katta S, Panuganti D, Neeli PK, Thennati R, Jerald MK, Kotamraju S. Mitochondria-targeted esculetin mitigates atherosclerosis in the setting of aging via the modulation of SIRT1-mediated vascular cell senescence and mitochondrial function in Apoe mice. Atherosclerosis 2022; 356:28-40. [DOI: 10.1016/j.atherosclerosis.2022.07.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 07/11/2022] [Accepted: 07/15/2022] [Indexed: 11/25/2022]
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18
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Madonna R. Angiocrine endothelium: From physiology to atherosclerosis and cardiac repair. Vascul Pharmacol 2022; 144:106993. [DOI: 10.1016/j.vph.2022.106993] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 03/25/2022] [Accepted: 03/30/2022] [Indexed: 02/08/2023]
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19
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Ataie Z, Fatehi-Hassanabad Z, Nakhaee S, Foadoddini M, Farrokhfall K. Sex-specific endothelial dysfunction induced by high-cholesterol diet in rats: The role of protein tyrosine kinase and nitric oxide. Nutr Metab Cardiovasc Dis 2022; 32:745-754. [PMID: 35144857 DOI: 10.1016/j.numecd.2021.11.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 10/28/2021] [Accepted: 11/15/2021] [Indexed: 12/01/2022]
Abstract
BACKGROUND AND AIMS Atherosclerosis is a chronic process playing a crucial role in the pathogenesis of cardiovascular disease. Sex-specific differences in the incidence of atherosclerosis indicate that estrogen has a protective effect on the cardiovascular disease. However, the role of sex on endothelium responses in animal models of high cholesterol (HC) diet-induced atherosclerosis has not been fully investigated. This study was aimed to investigate vascular responses in HC-fed rats. METHODS AND RESULTS Male and female Sprague rats (12-week-old) were treated with either a standard diet (n = 12 of each sex) or an HC enriched diet (n = 12 of each sex) containing 2% cholesterol for 24 weeks. HC treated animals (both sexes) showed increased levels of total cholesterol, LDL-cholesterol, triglyceride and blood pressure (BP) compared to control rats. While the BP of control rats (both sexes) was increased following aminoguanidine administration (AG, 100 mg/kg i.p.), it was not changed in HC animals (both sexes). The hypotensive effect of acetylcholine was significantly impaired in male HC-treated rats. In vitro experiments demonstrated that aortic rings from HC group (both sexes) had an increased contractile response to phenylephrine and a decreased vasodilatory response to acetylcholine. The vasorelaxant effect of acetylcholine in HC rats (only male) was improved by applying 10-5 M genistein (tyrosine kinase inhibitor) or AG. CONCLUSION HC diet alters endothelium function through Nitric oxide (NO) and tyrosine kinase pathways in male rats.
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Affiliation(s)
- Zomorrod Ataie
- Health Clinical Science Research Center, Zahedan Branch, Islamic Azad University, Zahedan, Iran; Student Research Committee, Islamic Azad University, Zahedan Branch, Zahedan, Iran
| | | | - Samaneh Nakhaee
- Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sciences (BUMS), Birjand, Iran
| | - Mohsen Foadoddini
- Cardiovascular Disease Research Center, Department of Physiology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Khadijeh Farrokhfall
- Cardiovascular Disease Research Center, Department of Physiology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran.
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20
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Aggarwal H, Pathak P, Kumar Y, Jagavelu K, Dikshit M. Modulation of Insulin Resistance, Dyslipidemia and Serum Metabolome in iNOS Knockout Mice following Treatment with Nitrite, Metformin, Pioglitazone, and a Combination of Ampicillin and Neomycin. Int J Mol Sci 2021; 23:195. [PMID: 35008623 PMCID: PMC8745663 DOI: 10.3390/ijms23010195] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/28/2021] [Accepted: 12/01/2021] [Indexed: 12/27/2022] Open
Abstract
Oxidative and nitrosative stress plays a pivotal role in the incidence of metabolic disorders. Studies from this lab and others in iNOS-/- mice have demonstrated occurrence of insulin resistance (IR), hyperglycemia and dyslipidemia highlighting the importance of optimal redox balance. The present study evaluates role of nitrite, L-arginine, antidiabetics (metformin, pioglitazone) and antibiotics (ampicillin-neomycin combination, metronidazole) on metabolic perturbations observed in iNOS-/- mice. The animals were monitored for glucose tolerance (IPGTT), IR (insulin, HOMA-IR, QUICKI), circulating lipids and serum metabolomics (LC-MS). Hyperglycemia, hyperinsulinemia and IR were rescued by nitrite, antidiabetics, and antibiotics treatments in iNOS-/- mice. Glucose intolerance was improved with nitrite, metformin and pioglitazone treatment, while ampicillin-neomycin combination normalised the glucose utilization in iNOS-/- mice. Increased serum phosphatidylethanolamine lipids in iNOS-/- mice were reversed by metformin, pioglitazone and ampicillin-neomycin; dyslipidemia was however marginally improved by nitrite treatment. The metabolic improvements were associated with changes in selected serum metabolites-purines, ceramide, 10-hydroxydecanoate, glucosaminate, diosmetin, sebacic acid, 3-nitrotyrosine and cysteamine. Bacterial metabolites-hippurate, indole-3-ethanol; IR marker-aminoadipate and oxidative stress marker-ophthalmate were reduced by pioglitazone and ampicillin-neomycin, but not by nitrite and metformin treatment. Results obtained in the present study suggest a crucial role of gut microbiota in the metabolic perturbations observed in iNOS-/- mice.
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Affiliation(s)
- Hobby Aggarwal
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; (H.A.); (P.P.); (K.J.)
| | - Priya Pathak
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; (H.A.); (P.P.); (K.J.)
| | - Yashwant Kumar
- Non-Communicable Diseases Division, Translational Health Science and Technology Institute, Faridabad 121001, India;
| | - Kumaravelu Jagavelu
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; (H.A.); (P.P.); (K.J.)
| | - Madhu Dikshit
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; (H.A.); (P.P.); (K.J.)
- Non-Communicable Diseases Division, Translational Health Science and Technology Institute, Faridabad 121001, India;
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21
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Kumar SK, Mani KP. Endocan alters nitric oxide production in endothelial cells by targeting AKT/eNOS and NFkB/iNOS signaling. Nitric Oxide 2021; 117:26-33. [PMID: 34592471 DOI: 10.1016/j.niox.2021.09.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 09/13/2021] [Accepted: 09/23/2021] [Indexed: 01/08/2023]
Abstract
Endocan, a secretary proteoglycan, known to induce vascular inflammation. Nitric oxide (NO) produced by endothelial cells is an important signaling molecule in maintaining the vascular homeostasis. However, the precise effect of endocan in regulating NO pathway is not known. The present study explores the effect of endocan on eNOS-iNOS-NO and ROS production in cultured endothelial cells. Results showed that recombinant endocan treatment in HUVEC could increase NO and nitrite levels. However, pharmacological inhibition of iNOS using 1400W significantly decreased these effects. Furthermore, protein expression analysis showed that endocan could inhibit AKT/eNOS pathway and activate NF-κB/iNOS pathway. The production of superoxide, hydrogen peroxide, peroxynitrite and total ROS were also significantly increased with endocan treatment supported by decreased activity of superoxide dismutase and catalase. Moreover, selective inhibition of NOX reduced the ROS formation. In addition, mRNA expression analysis demonstrated that endocan can upregulate the expression of NOX1, NOX2 and NOX4. These findings suggest that endocan alters the NO production and their by enhances oxidative stress in endothelial cells. Thus, inhibition of endocan-NO signaling could be a one of the strategy to reduce oxidative stress in vascular disease.
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Affiliation(s)
- Sarwareddy Kartik Kumar
- Vascular Research Laboratory, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur, 613 401, Tamil Nadu, India
| | - Krishna Priya Mani
- Vascular Research Laboratory, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur, 613 401, Tamil Nadu, India.
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22
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Metwalli O, Hashem E, Ajabnoor MA, Alama N, Banjar ZM. Study of Some Inflammatory Mediators in the Serum of Patients With Atherosclerosis and Acute Myocardial Infarction. Cureus 2021; 13:e18450. [PMID: 34745775 PMCID: PMC8561326 DOI: 10.7759/cureus.18450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/03/2021] [Indexed: 11/21/2022] Open
Abstract
Background and aim of the study The aim of this study is to evaluate the changes in the inflammatory mediator's serum amyloid A (SAA), adiponectin, and resistin in the serum of patients with stable angina and acute myocardial infarction. Subjects and methods The study was done on 60 subjects divided into three groups: 20 healthy normal individuals as a control group, 20 patients with stable angina (atherosclerotic plaque), and 20 patients with myocardial infarction. Fasting blood samples were withdrawn from all subjects and serum was prepared. SAA, resistin, and adiponectin levels were quantitatively measured by enzyme-linked immunosorbent assay (ELISA). Results The SAA level was significantly higher in both stable angina and the acute myocardial infarction group than the control group (2.7179 ± 0.44501 mg/L) and the serum resistin level was significantly higher (p-value = 0.0) in the stable angina (8.368 ± 1.633 ng/ml) and the acute myocardial infarction (13.606 ± 2.067 ng/ml) groups (p-value= 0.0) than the control group. (2.4272±1.25210 ng/ml). Moreover, resistin levels in stable angina when compared to the AMI showed a significant difference between them (p-value = 0.0) while adiponectin was significantly lower in the acute myocardial infarction group. (6.641±2.6011 µg/mL, p-value = 0.019) than its level in the control group (11.873±1.798 µg/mL). While the adiponectin level showed no significant differences between stable angina in comparison to the AMI. Conclusion SAA can be used as a confirmatory marker for stable angina and a diagnostic tool for AMI patients. Both SAA and resistin may participate in the atherosclerosis process as an effectors molecule of inflammatory reactions. For adiponectin, we concluded that it has the antiatherogenic property and its levels were lower in both the stable angina and acute myocardial infarction groups.
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Affiliation(s)
- Ohoud Metwalli
- Pathology, Department of Laboratory, King Abdulaziz University Hospital, Jeddah, SAU
| | - Enayat Hashem
- Clinical Biochemistry, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
| | | | - Nabil Alama
- Cardiology, Department of Medicine, King Abdulaziz University Hospital, Jeddah, SAU
| | - Zainy M Banjar
- Clinical Biochemistry, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
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23
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De Lorenzis E, Di Giorgio A, Natalello G, Nesci A, Tanti G, Rubortone P, Lucchetti D, Magurano MR, Di Mario C, Tolusso B, Peluso G, Santoliquido A, Gremese E. Depression and Endothelial Dysfunction in Psoriatic Arthritis: Is There Any Possible Relationship? Front Med (Lausanne) 2021; 8:669397. [PMID: 34513861 PMCID: PMC8429609 DOI: 10.3389/fmed.2021.669397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 08/02/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Cardiovascular events (CVEs) are the first cause of death in patients with psoriatic arthritis (PsA). Depression is a recognized risk factor in cardiovascular events and is frequently associated with PsA. Flow-mediated dilatation (FMD) is a widely used method for assessing endothelial dysfunction, a parameter with strong prognostic implications for CVEs. The study aims to explore the relationship between FMD, depressive symptoms and serum cytokines in a cohort of patients with PsA. Patients and Methods: FMD was assessed in 50 consecutive PsA patients aged between 30 and 75 years without known cerebrovascular and coronary heart disease or diabetes. Depressive symptoms were reported using the related subscale of the Hospital Anxiety and Depression Scale (HDS). Disease features, activity indexes, and adjusted Framingham risk score (aFRS) were calculated. Serum level of IL-6, TNF-α, and IL-17A were also assessed. Results: In PsA patients (age 50.7 ± 10.2 years, male 42%, disease duration 5.9 ± 3.3 years, Disease Activity in PSoriatic Arthritis (DAPSA) score 14.0 ± 9.4) FMD inversely correlated with the severity of depressive symptoms according to HDS (ρ = -0.339, p = 0.016), age (ρ = -0.507, p = 0.001), aFRS (rs = -0.453, p < 0.001), duration of PsA (ρ = -0.507, p = 0.001), intensity of pain (ρ = -0.507, p = 0.001), and DAPSA (ρ = -0.507, p = 0.001). No statistically significant correlation was found between FMD or HDS and serum cytokines concentrations. HDS predicted FMD in a model adjusted for age, aFRS, PsA duration, and pain intensity (β = -0.271, p = 0.008), with depressive symptoms contributing directly to 6.4% of the variance. Conclusions: Depressive symptoms correlate with endothelial dysfunction with an exposure-response pattern in our cohort of PsA patients.
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Affiliation(s)
- Enrico De Lorenzis
- Institute of Rheumatology, Catholic University of the Sacred Heart, Rome, Italy.,PhD Program in Biomolecular Medicine - Cycle XXXV, University of Verona, Verona, Italy
| | - Angela Di Giorgio
- Department of Internal Medicine, Angiology Unit, Catholic University of the Sacred Heart, Rome, Italy
| | - Gerlando Natalello
- Institute of Rheumatology, Catholic University of the Sacred Heart, Rome, Italy
| | - Antonio Nesci
- Department of Internal Medicine, Angiology Unit, Catholic University of the Sacred Heart, Rome, Italy
| | - Giacomo Tanti
- Institute of Rheumatology, Catholic University of the Sacred Heart, Rome, Italy
| | - Pietro Rubortone
- Institute of Rheumatology, Catholic University of the Sacred Heart, Rome, Italy
| | - Donatella Lucchetti
- Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, Rome, Italy
| | - Maria Rosaria Magurano
- Unit of Clinical Psychology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Clara Di Mario
- Institute of Rheumatology, Catholic University of the Sacred Heart, Rome, Italy
| | - Barbara Tolusso
- Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Giusy Peluso
- Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Angelo Santoliquido
- Department of Internal Medicine, Angiology Unit, Catholic University of the Sacred Heart, Rome, Italy
| | - Elisa Gremese
- Institute of Rheumatology, Catholic University of the Sacred Heart, Rome, Italy.,Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
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24
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Ng YH, Okolo CA, Erickson JR, Baldi JC, Jones PP. Protein O-GlcNAcylation in the heart. Acta Physiol (Oxf) 2021; 233:e13696. [PMID: 34057811 DOI: 10.1111/apha.13696] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/25/2021] [Accepted: 05/27/2021] [Indexed: 12/30/2022]
Abstract
O-GlcNAcylation is a ubiquitous post-translational modification that is extremely labile and plays a significant role in physiology, including the heart. Sustained activation of cardiac O-GlcNAcylation is frequently associated with alterations in cellular metabolism, leading to detrimental effects on cardiovascular function. This is particularly true during conditions such as diabetes, hypertension, cardiac remodelling, heart failure and arrhythmogenesis. Paradoxically, transient elevation of cardiac protein O-GlcNAcylation can also exert beneficial effects in the heart. There is compelling evidence to suggest that a complex interaction between O-GlcNAcylation and phosphorylation also exists in the heart. Beyond direct functional consequences on cardiomyocytes, O-GlcNAcylation also acts indirectly by altering the function of transcription factors that affect downstream signalling. This review focuses on the potential cardioprotective role of protein O-GlcNAcylation during ischaemia-reperfusion injury, the deleterious consequences of chronically elevated O-GlcNAc levels, the interplay between O-GlcNAcylation and phosphorylation in the cardiomyocytes and the effects of O-GlcNAcylation on other major non-myocyte cell types in the heart.
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Affiliation(s)
- Yann Huey Ng
- Department of Medicine and HeartOtago University of Otago Dunedin New Zealand
| | - Chidinma A. Okolo
- Department of Physiology and HeartOtago University of Otago Dunedin New Zealand
- Life Sciences Division Diamond Light Source LtdHarwell Science and Innovation Campus Didcot UK
| | - Jeffrey R. Erickson
- Department of Physiology and HeartOtago University of Otago Dunedin New Zealand
| | - James C. Baldi
- Department of Medicine and HeartOtago University of Otago Dunedin New Zealand
| | - Peter P. Jones
- Department of Physiology and HeartOtago University of Otago Dunedin New Zealand
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25
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Caravà E, Moretto P, Caon I, Parnigoni A, Passi A, Karousou E, Vigetti D, Canino J, Canobbio I, Viola M. HA and HS Changes in Endothelial Inflammatory Activation. Biomolecules 2021; 11:biom11060809. [PMID: 34072476 PMCID: PMC8229641 DOI: 10.3390/biom11060809] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 05/10/2021] [Accepted: 05/25/2021] [Indexed: 12/28/2022] Open
Abstract
Cardiovascular diseases are a group of disorders caused by the presence of a combination of risk factors, such as tobacco use, unhealthy diet and obesity, physical inactivity, etc., which cause the modification of the composition of the vessel’s matrix and lead to the alteration of blood flow, matched with an inflammation condition. Nevertheless, it is not clear if the inflammation is a permissive condition or a consequent one. In order to investigate the effect of inflammation on the onset of vascular disease, we treated endothelial cells with the cytokine TNF-α that is increased in obese patients and is reported to induce cardiometabolic diseases. The inflammation induced a large change in the extracellular matrix, increasing the pericellular hyaluronan and altering the heparan sulfate Syndecans sets, which seems to be related to layer permeability but does not influence cell proliferation or migration nor induce blood cell recruitment or activation.
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Affiliation(s)
- Elena Caravà
- Quantix Italia S.r.l., 20121 Milano, Italy;
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (P.M.); (I.C.); (A.P.); (A.P.); (E.K.); (D.V.)
| | - Paola Moretto
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (P.M.); (I.C.); (A.P.); (A.P.); (E.K.); (D.V.)
| | - Ilaria Caon
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (P.M.); (I.C.); (A.P.); (A.P.); (E.K.); (D.V.)
| | - Arianna Parnigoni
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (P.M.); (I.C.); (A.P.); (A.P.); (E.K.); (D.V.)
| | - Alberto Passi
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (P.M.); (I.C.); (A.P.); (A.P.); (E.K.); (D.V.)
| | - Evgenia Karousou
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (P.M.); (I.C.); (A.P.); (A.P.); (E.K.); (D.V.)
| | - Davide Vigetti
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (P.M.); (I.C.); (A.P.); (A.P.); (E.K.); (D.V.)
| | - Jessica Canino
- Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy; (J.C.); (I.C.)
| | - Ilaria Canobbio
- Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy; (J.C.); (I.C.)
| | - Manuela Viola
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (P.M.); (I.C.); (A.P.); (A.P.); (E.K.); (D.V.)
- Correspondence: ; Tel.: +39-0332-397143
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26
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Abstract
The endothelium is a crucial regulator of vascular homeostasis by controlling barrier integrity as well acting as an important signal transducer, thereby illustrating that endothelial cells are not inert cells. In the context of atherosclerosis, this barrier function is impaired and endothelial cells become activated, resulting in the upregulation of adhesion molecules, secretion of cytokines and chemokines and internalization of integrins. Finally, this leads to increased vessel permeability, thereby facilitating leukocyte extravasation as well as fostering a pro-inflammatory environment. Additionally, activated endothelial cells can form migrating tip cells and proliferative stalk cells, resulting in the formation of new blood vessels. Emerging evidence has accumulated indicating that cellular metabolism is crucial in fueling these pro-atherosclerotic processes, including neovascularization and inflammation, thereby contributing to plaque progression and altering plaque stability. Therefore, further research is necessary to unravel the complex mechanisms underlying endothelial cell metabolic changes, and exploit this knowledge for finding and developing potential future therapeutic strategies. In this review we discuss the metabolic alterations endothelial cells undergo in the context of inflammation and atherosclerosis and how this relates to changes in endothelial functioning. Finally, we will describe several metabolic targets that are currently being used for therapeutic interventions.
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27
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Brewster LM, Bain AR, Garcia VP, Fandl HK, Stone R, DeSouza NM, Greiner JJ, Tymko MM, Vizcardo-Galindo GA, Figueroa-Mujica RJ, Villafuerte FC, Ainslie PN, DeSouza CA. Global REACH 2018: dysfunctional extracellular microvesicles in Andean highlander males with excessive erythrocytosis. Am J Physiol Heart Circ Physiol 2021; 320:H1851-H1861. [PMID: 33710927 DOI: 10.1152/ajpheart.00016.2021] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
High altitude-related excessive erythrocytosis (EE) is associated with increased cardiovascular risk. The experimental aim of this study was to determine the effects of microvesicles isolated from Andean highlanders with EE on endothelial cell inflammation, oxidative stress, apoptosis, and nitric oxide (NO) production. Twenty-six male residents of Cerro de Pasco, Peru (4,340 m), were studied: 12 highlanders without EE (age: 40 ± 4 yr; BMI: 26.4 ± 1.7; Hb: 17.4 ± 0.5 g/dL, Spo2: 86.9 ± 1.0%) and 14 highlanders with EE (43 ± 4 yr; 26.2 ± 0.9; 24.4 ± 0.4 g/dL; 79.7 ± 1.6%). Microvesicles were isolated, enumerated, and collected from plasma by flow cytometry. Human umbilical vein endothelial cells were cultured and treated with microvesicles from highlanders without and with EE. Microvesicles from highlanders with EE induced significantly higher release of interleukin (IL)-6 (89.8 ± 2.7 vs. 77.1 ± 1.9 pg/mL) and IL-8 (62.0 ± 2.7 vs. 53.3 ± 2.2 pg/mL) compared with microvesicles from healthy highlanders. Although intracellular expression of total NF-κB p65 (65.3 ± 6.0 vs. 74.9 ± 7.8.9 AU) was not significantly affected in cells treated with microvesicles from highlanders without versus with EE, microvesicles from highlanders with EE resulted in an ∼25% higher (P < 0.05) expression of p-NF-κB p65 (173.6 ± 14.3 vs. 132.8 ± 12.2 AU). Cell reactive oxygen species production was significantly higher (76.4.7 ± 5.4 vs. 56.7 ± 1.7% of control) and endothelial nitric oxide synthase (p-eNOS) activation (231.3 ± 15.5 vs. 286.6 ± 23.0 AU) and NO production (8.3 ± 0.6 vs. 10.7 ± 0.7 μM/L) were significantly lower in cells treated with microvesicles from highlanders with versus without EE. Cell apoptotic susceptibility was not significantly affected by EE-related microvesicles. Circulating microvesicles from Andean highlanders with EE increased endothelial cell inflammation and oxidative stress and reduced NO production.NEW & NOTEWORTHY In this study, we determined the effects of microvesicles isolated from Andean highlanders with excessive erythrocytosis (EE) on endothelial cell inflammation, oxidative stress, apoptosis, and NO production. Microvesicles from highlanders with EE induced a dysfunctional response from endothelial cells characterized by increased cytokine release and expression of active nuclear factor-κB and reduced nitric oxide production. Andean highlanders with EE exhibit dysfunctional circulating extracellular microvesicles that induce a proinflammatory, proatherogenic endothelial phenotype.
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Affiliation(s)
- L Madden Brewster
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado
| | - Anthony R Bain
- Department of Kinesiology, University of Windsor, Windsor, Ontario, Canada
| | - Vinicius P Garcia
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado
| | - Hannah K Fandl
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado
| | - Rachel Stone
- Department of Kinesiology, University of Windsor, Windsor, Ontario, Canada
| | - Noah M DeSouza
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado.,Faculty of Health and Social Development, Centre for Heart, Lung and Vascular Health, University of British Columbia Okanagan, Kelowna, British Columbia, Canada
| | - Jared J Greiner
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado
| | | | | | | | | | - Philip N Ainslie
- Faculty of Health and Social Development, Centre for Heart, Lung and Vascular Health, University of British Columbia Okanagan, Kelowna, British Columbia, Canada
| | - Christopher A DeSouza
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado
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28
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Duraisamy P, Ravi S, Krishnan M, Livya CM, Manikandan B, Arunagirinathan K, Ramar M. Dynamic Role of Macrophage Sub Types for Development of Atherosclerosis and Potential Use of Herbal Immunomodulators as Imminent Therapeutic Strategy. Cardiovasc Hematol Agents Med Chem 2020; 20:2-12. [PMID: 33334298 DOI: 10.2174/1871525718666201217163207] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 10/20/2020] [Accepted: 10/27/2020] [Indexed: 11/22/2022]
Abstract
Atherosclerosis, a major contributor to cardiovascular disease is a global alarm causing mortality worldwide. Being a progressive disease in the arteries, it mainly causes recruitment of monocytes to the inflammatory sites and subside pathological conditions. Monocyte-derived macrophage mainly acts in foam cell formation by engorging the LDL molecules, oxidizes it into Ox-LDL and leads to plaque deposit development. Macrophages in general differentiate, proliferate and undergo apoptosis at the inflammatory site. Frequently two subtypes of macrophages M1 and M2 has to act crucially in balancing the micro-environmental conditions of endothelial cells in arteries. The productions of proinflammatory mediators like IL-1, IL-6, TNF-α by M1 macrophage has atherogenic properties majorly produced during the early progression of atherosclerotic plaques. To counteract cytokine productions and M1-M2 balance, secondary metabolites (phytochemicals) from plants act as a therapeutic agent in alleviating atherosclerosis progression. This review summarizes the fundamental role of the macrophage in atherosclerotic lesion formation along with its plasticity characteristic as well as recent therapeutic strategies using herbal components and anti-inflammatory cytokines as potential immunomodulators.
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Affiliation(s)
| | - Sangeetha Ravi
- Department of Zoology, University of Madras, Guindy Campus, Chennai - 600 025. India
| | - Mahalakshmi Krishnan
- Department of Zoology, University of Madras, Guindy Campus, Chennai - 600 025. India
| | - Catherene M Livya
- Department of Zoology, University of Madras, Guindy Campus, Chennai - 600 025. India
| | - Beulaja Manikandan
- Department of Biochemistry, Annai Veilankanni's College for Women, Chennai - 600 015. India
| | | | - Manikandan Ramar
- Department of Zoology, University of Madras, Guindy Campus, Chennai - 600 025. India
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29
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Prasher P, Sharma M. "Azole" as privileged heterocycle for targeting the inducible cyclooxygenase enzyme. Drug Dev Res 2020; 82:167-197. [PMID: 33137216 DOI: 10.1002/ddr.21753] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 10/12/2020] [Accepted: 10/16/2020] [Indexed: 12/22/2022]
Abstract
An over-expression of COX-2 isoenzyme belonging to the Cyclooxygenase Enzyme Family triggers the overproduction of pro-inflammatory prostaglandins that instigate the development of chronic inflammation and related disorders. Hence, the rationally designed drugs for mitigating over-activity of COX-2 isoenzyme play a regulatory role toward the alleviation of the progression of these disorders. However, a selective COX-2 inhibition chemotherapy prompts several side effects that necessitate the identification of novel molecular scaffolds for deliberating state-of-the-art drug designing strategies. The heterocyclic "azole" scaffold, being polar and hydrophilic, possesses remarkable physicochemical advantages for designing physiologically active molecules capable of interacting with a wide range of biological components, including enzymes, peptides, and metabolites. The substituted derivatives of azole nuclei enable a comprehensive SAR analysis for the appraisal of bioactive profile of the deliberated molecules for obtaining the rationally designed compounds with prominent activities. The comprehensive SAR analysis readily prompted the identification of Y-shaped molecules and the eminence of bulkier group for COX-2 selective inhibition. This review presents an epigrammatic collation of the pharmacophore-profile of the chemotherapeutics based on azole motif for a selective targeting of the COX-2 isoenzyme.
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Affiliation(s)
- Parteek Prasher
- UGC Sponsored Centre for Advanced Studies, Department of Chemistry, Guru Nanak Dev University, Amritsar, India.,Department of Chemistry, University of Petroleum & Energy Studies, Energy Acres, Dehradun, India
| | - Mousmee Sharma
- UGC Sponsored Centre for Advanced Studies, Department of Chemistry, Guru Nanak Dev University, Amritsar, India.,Department of Chemistry, Uttaranchal University, Arcadia Grant, Dehradun, India
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30
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Systemic Insulin Resistance and Metabolic Perturbations in Chow Fed Inducible Nitric Oxide Synthase Knockout Male Mice: Partial Reversal by Nitrite Supplementation. Antioxidants (Basel) 2020; 9:antiox9080736. [PMID: 32806494 PMCID: PMC7465804 DOI: 10.3390/antiox9080736] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 07/06/2020] [Accepted: 07/09/2020] [Indexed: 02/07/2023] Open
Abstract
iNOS, an important mediator of inflammation, has emerged as an important metabolic regulator. There are conflicting observations on the incidence of insulin resistance (IR) due to hyperglycemia/dyslipidemia in iNOS−/− mice. There are reports that high fat diet (HFD) fed mice exhibited no change, protection, or enhanced susceptibility to IR. Similar observations were also reported for low fat diet (LFD) fed KO mice. In the present study chow fed iNOS−/− mice were examined for the incidence of IR, and metabolic perturbations, and also for the effect of sodium nitrite supplementation (50 mg/L). In IR-iNOS−/− mice, we observed significantly higher body weight, BMI, adiposity, blood glucose, HOMA-IR, serum/tissue lipids, glucose intolerance, enhanced gluconeogenesis, and disrupted insulin signaling. Expression of genes involved in hepatic and adipose tissue lipid uptake, synthesis, oxidation, and gluconeogenesis was upregulated with concomitant downregulation of genes for hepatic lipid excretion. Nitrite supplementation restored NO levels, significantly improved systemic IR, glucose tolerance, and also reduced lipid accumulation by rescuing hepatic insulin sensitivity, glucose, and lipid homeostasis. Obesity, gluconeogenesis, and adipose tissue insulin signaling were only partially reversed in nitrite supplemented iNOS−/− mice. Our results thus demonstrate that nitrite supplementation to iNOS−/− mice improves insulin sensitivity and metabolic homeostasis, thus further highlighting the metabolic role of iNOS.
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31
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Malekmohammad K, Sewell RD, Rafieian-Kopaei M. Mechanisms of Medicinal Plant Activity on Nitric Oxide (NO) Bioavailability as Prospective Treatments for Atherosclerosis. Curr Pharm Des 2020; 26:2591-2601. [DOI: 10.2174/1381612826666200318152049] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 02/28/2020] [Indexed: 02/07/2023]
Abstract
Background and objective:
Atherosclerosis is one of the leading causes of human morbidity globally
and reduced bioavailability of vascular nitric oxide (NO) has a critical role in the progression and development of
the atherosclerotic disease. Loss of NO bioavailability, for example via a deficiency of the substrate (L-arginine)
or cofactors for endothelial nitric oxide synthase (eNOS), invariably leads to detrimental vascular effects such as
impaired endothelial function and increased smooth muscle cell proliferation, deficiency of the substrate (Larginine)
or cofactors for eNOS. Various medicinal plants and their bioactive compounds or secondary metabolites
with fewer side effects are potentially implicated in preventing cardiovascular disease by increasing NO
bioavailability, thereby ameliorating endothelial dysfunction. In this review, we describe the most notable medicinal
plants and their bioactive compounds that may be appropriate for enhancing NO bioavailability, and
treatment of atherosclerosis.
Methods:
The material in this article was obtained from noteworthy scientific databases, including Web of Science,
PubMed, Science Direct, Scopus and Google Scholar.
Results:
Medicinal plants and their bioactive compounds influence NO production through diverse mechanisms
including the activation of the nuclear factor kappa B (NF-κB) signaling pathway, activating protein kinase C
(PKC)-α, stimulating protein tyrosine kinase (PTK), reducing the conversion of nitrite to NO via nitrate-nitrite
reduction pathways, induction of eNOS, activating the phosphatidylinositol 3-kinase (PI3K)/serine threonine
protein kinase B (AKT) (PI3K/AKT/eNOS/NO) pathway and decreasing oxidative stress.
Conclusion:
Medicinal plants and/or their constituent bioactive compounds may be considered as safe therapeutic
options for enhancing NO bioavailability and prospective preventative therapy for atherosclerosis.
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Affiliation(s)
| | - Robert D.E. Sewell
- Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NB. Wales, United Kingdom
| | - Mahmoud Rafieian-Kopaei
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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32
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Gutowska K, Formanowicz D, Formanowicz P. Selected Aspects of Tobacco-Induced Prothrombotic State, Inflammation and Oxidative Stress: Modeled and Analyzed Using Petri Nets. Interdiscip Sci 2019; 11:373-386. [PMID: 30584644 PMCID: PMC6660494 DOI: 10.1007/s12539-018-0310-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 11/23/2018] [Accepted: 11/26/2018] [Indexed: 11/27/2022]
Abstract
Many factors, such as endothelial dysfunction, inflammation and hemostatic disturbances, affect formation and progression of atherosclerotic plaque. In our study, we have focused on hemostatic disturbances with particular emphasis on the extrinsic pathways of coagulation. Thrombin is a main enzyme of coagulation and it is engaged in many different subprocesses. It leads to activation of factors of the coagulation cascade, transition of fibrinogen to fibrin monomer, endothelial damage, inflammation, activation of platelets and proliferation. In our study, selected aspects of disorders in prothrombotic states influenced by cigarette smoke have been modeled and analyzed. Tobacco-induced increased tissue factor, which is associated with less plasminogen activator and increased plasminogen activator-1 inhibitor, has been included in the presented model. These disorders together with accompanying inflammatory state are closely related to thrombus formation and cardiovascular disease promotion. The proposed model has been built using Petri nets and the analysis has been based mainly on t-invariants. Using the Petri net theory to model and analyze the investigated phenomena allows to better understand them by revealing some interesting dependencies in the studied biological system. It explains how tobacco smoke affects the analyzed processes and how harmful these effects are.
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Affiliation(s)
- Kaja Gutowska
- Institute of Computing Science, Poznan University of Technology, Piotrowo 2, 60-965 Poznan, Poland
| | - Dorota Formanowicz
- Department of Clinical Biochemistry and Laboratory Medicine, Poznan University of Medical Sciences, Rokietnicka 8, 60-806 Poznan, Poland
| | - Piotr Formanowicz
- Institute of Computing Science, Poznan University of Technology, Piotrowo 2, 60-965 Poznan, Poland
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland
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Sucic M, Luetic K, Jandric I, Drmic D, Sever AZ, Vuletic LB, Halle ZB, Strinic D, Kokot A, Seiwerth RS, Zoricic I, Blagaic AB, Seiwerth S, Sikiric P. Therapy of the rat hemorrhagic cystitis induced by cyclophosphamide. Stable gastric pentadecapeptide BPC 157, L-arginine, L-NAME. Eur J Pharmacol 2019; 861:172593. [PMID: 31401154 DOI: 10.1016/j.ejphar.2019.172593] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 08/01/2019] [Accepted: 08/07/2019] [Indexed: 02/07/2023]
Abstract
We focused on the cyclophosphamide-induced hemorrhagic cystitis (100 mg/kg/day intraperitoneally throughout three days) as a particular NO-system disturbance, and therapy possibilities. We demonstrated that it may be attenuated by subsequent administration of the NOS substrate L-arginine (100 mg/kg/day intraperitoneally), aggravated by NOS-blocker L-NAME (5 mg/kg/day intraperitoneally), all influenced by the stable gastric pentadecapeptide BPC 157 (10 μg/kg/day, 10 ng/kg/day, intraperitoneally or perorally, in drinking water). Regularly, cyclophosphamide dose- and time-dependently induced severe hemorrhagic cystitis lesions, gross lesions, and corresponding urothelial necrosis, vesical edema, erosion, hemorrhage, inflammation, and ulceration, microscopically. The bladder wet weight dramatically increased. Functionally, already after first cyclophosphamide administration, there is an increased leak point pressure. Until the second cyclophosphamide administration, L-arginine consistently attenuated regular cyclophosphamide-induced severe hemorrhagic cystitis lesions, grossly and microscopically, but not functionally. L-NAME aggravated these lesions and eradicated beneficial effect of L-arginine when combined. BPC 157 administration after cyclophosphamide, given in either dose or in either regimen markedly attenuated all cyclophosphamide lesions, grossly, microscopically. The increase of the bladder wet weight was consistently attenuated. Functionally, increased leak point pressure was reversed to the values noted in normal rats. The similar findings were noted in rats that received BPC 157 together with L-NAME or L-arginine, given alone or combined. Thus, the lesions are NO-related based on the administration of L-NAME as well as administration of L-arginine, and their mutual interaction, and counteraction by BPC 157 application. Likewise, we reveal new therapeutic possibilities, emphasizing stable gastric pentadecapeptide BPC 157 and L-arginine, versus L-NAME in rats underwent cyclophosphamide-induced cystitis.
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Affiliation(s)
- Mario Sucic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Kresimir Luetic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Ivan Jandric
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Anita Zenko Sever
- Department of Pathology, School of Medicine, University of Zagreb, Salata 10, 10000, Zagreb, Croatia
| | - Lovorka Batelja Vuletic
- Department of Pathology, School of Medicine, University of Zagreb, Salata 10, 10000, Zagreb, Croatia
| | - Zeljka Belosic Halle
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Dean Strinic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, Faculty of Medicine, J.J. Strossmayer University of Osijek, J.Huttlera 4, 31000, Osijek, Croatia
| | - Ranka Serventi Seiwerth
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Ivan Zoricic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Salata 10, 10000, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia.
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Brożek GM, Jankowski M, Zejda JE. Acute respiratory responses to the use of e-cigarette: an intervention study. Sci Rep 2019; 9:6844. [PMID: 31048778 PMCID: PMC6497705 DOI: 10.1038/s41598-019-43324-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 04/18/2019] [Indexed: 11/09/2022] Open
Abstract
The goal of our study was to assess acute respiratory responses to using e-cigarettes in exclusive e-cigarette users (E-Group) and dual users (T/E-Group) and to compare these effects with responses to smoking tobacco-cigarettes in tobacco smokers (T-Group). The study included 120 adults (age: 21.7 ± 2.1 years) divided into 4 groups (n = 30 each): Controls, T-, E-, T/E-Group. Spirometric status, O2 saturation, exhaled FeNO levels, exhaled CO levels, and airway temperature were assessed before the use of an e-cigarette (E-, T/E-Group) or tobacco cigarette as well as 'minute 1' and 'minute 30' after smoking. Controls used an e-cigarette without e-liquid. Lower (p < 0.05) baseline values of FeNO were found in T-Group (15.4 ppb) and in T/E-Group (15.0 ppb) than in Controls (19.6 ppb). Following exposure, and compared with Controls, T-, and T/E-Group had a significant decrease (p < 0.05) in PEF and MEF75. Mean FeNO values decreased on 'minute 1' in T-Group (by 2.1 ppb), E-Group (by 1.5 ppb) and in T/E-Group (by 2.2 ppb). Other effects included increase in temperature of exhaled air (p < 0.05). The use of e-cigarettes is associated with decreased FeNO and airflow indices (PEF, MEF75), but an increase in airway temperature. These changes are similar to those after exposure to tobacco cigarette smoke.
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Affiliation(s)
- Grzegorz M Brożek
- Department of Epidemiology, School of Medicine, Medical University of Silesia in Katowice, Medykow 18 Str, 40-752, Katowice, Poland.
| | - Mateusz Jankowski
- Department of Epidemiology, School of Medicine, Medical University of Silesia in Katowice, Medykow 18 Str, 40-752, Katowice, Poland
| | - Jan E Zejda
- Department of Epidemiology, School of Medicine, Medical University of Silesia in Katowice, Medykow 18 Str, 40-752, Katowice, Poland
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Amic F, Drmic D, Bilic Z, Krezic I, Zizek H, Peklic M, Klicek R, Pajtak A, Amic E, Vidovic T, Rakic M, Milkovic Perisa M, Horvat Pavlov K, Kokot A, Tvrdeic A, Boban Blagaic A, Zovak M, Seiwerth S, Sikiric P. Bypassing major venous occlusion and duodenal lesions in rats, and therapy with the stable gastric pentadecapeptide BPC 157, L-NAME and L-arginine. World J Gastroenterol 2018; 24:5366-5378. [PMID: 30598581 PMCID: PMC6305534 DOI: 10.3748/wjg.v24.i47.5366] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 11/26/2018] [Accepted: 11/30/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate whether duodenal lesions induced by major venous occlusions can be attenuated by BPC 157 regardless nitric oxide (NO) system involvement. METHODS Male Wistar rats underwent superior anterior pancreaticoduodenal vein (SAPDV)-ligation and were treated with a bath at the ligated SAPDV site (BPC 157 10 μg, 10 ng/kg per 1 mL bath/rat; L-NAME 5 mg/kg per 1 mL bath/rat; L-arginine 100 mg/kg per 1 mL bath/rat, alone and/or together; or BPC 157 10 μg/kg instilled into the rat stomach, at 1 min ligation-time). We recorded the vessel presentation (filled/appearance or emptied/disappearance) between the 5 arcade vessels arising from the SAPDV on the ventral duodenum side, the inferior anterior pancreaticoduodenal vein (IAPDV) and superior mesenteric vein (SMV) as bypassing vascular pathway to document the duodenal lesions presentation; increased NO- and oxidative stress [malondialdehyde (MDA)]-levels in duodenum. RESULTS Unlike the severe course in the SAPDV-ligated controls, after BPC 157 application, the rats exhibited strong attenuation of the mucosal lesions and serosal congestion, improved vessel presentation, increased interconnections, increased branching by more than 60% from the initial value, the IAPDV and SMV were not congested. Interestingly, after 5 min and 30 min of L-NAME and L-arginine treatment alone, decreased mucosal and serosal duodenal lesions were observed; their effect was worsened at 24 h, and no effect on the collateral vessels and branching was seen. Together, L-NAME+L-arginine antagonized each other's response, and thus, there was an NO-related effect. With BPC 157, all SAPDV-ligated rats receiving L-NAME and/or L-arginine appeared similar to the rats treated with BPC 157 alone. Also, BPC 157 in SAPDV-ligated rats normalized levels of NO and MDA, two oxidative stress markers, in duodenal tissues. CONCLUSION BPC 157, rapidly bypassing occlusion, rescued the original duodenal flow through IAPDV to SMV flow, an effect related to the NO system and reduction of free radical formation.
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Affiliation(s)
- Fedor Amic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Zdenko Bilic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Ivan Krezic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Helena Zizek
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Marina Peklic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Robert Klicek
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Alen Pajtak
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Enio Amic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Tinka Vidovic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Mislav Rakic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Marija Milkovic Perisa
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Katarina Horvat Pavlov
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Antonio Kokot
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Ante Tvrdeic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Mario Zovak
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Sven Seiwerth
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
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Chu H, Li H, Guan X, Yan H, Zhang X, Cui X, Li X, Cheng M. Resveratrol protects late endothelial progenitor cells from TNF-α-induced inflammatory damage by upregulating Krüppel-like factor-2. Mol Med Rep 2018; 17:5708-5715. [PMID: 29484436 PMCID: PMC5866013 DOI: 10.3892/mmr.2018.8621] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 01/03/2018] [Indexed: 12/30/2022] Open
Abstract
Cardiovascular risk factors can negatively influence late endothelial progenitor cell (EPCs) number and functions, thus EPCs biology is a clinical implications for cardiovascular diseases. The present study aimed to investigate the potential protective effects of resveratrol (RES) on tumor necrosis factor (TNF)-α-induced inflammatory damage in late endothelial progenitor cells (EPCs) and to elucidate the underlying mechanisms. Late EPCs at passages 3–5 were pretreated with RES at a concentration of 20 µmol/l for 12 h and subsequently incubated with TNF-α (10 ng/ml) for 24 h. The adhesion, migration, proliferation and vasculogenesis of EPCs were subsequently detected. Furthermore, the mRNA expression levels of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Nitric oxide (NO) levels in the supernatant were determined using a colorimetric assay kit. Additionally, the mRNA and protein expression of Krüppel-like factor-2 (KLF2) was determined by RT-qPCR and western blot analysis, respectively. The results indicated that TNF-α markedly inhibited the proliferation, adhesion, migration and vasculogenesis of late EPCs. However, RES ameliorated the effects induced by TNF-α. Furthermore, exposure of EPCs to TNF-α decreased the levels of NO secretion and KLF2 expression at the mRNA and protein levels, but upregulated the levels of inflammatory factors, including ICAM-1 and MCP-1, compared with the control group. RES significantly inhibited TNF-α-induced inflammatory damage through upregulation of KLF2 expression and downregulation of the expression of ICAM-1 and MCP-1. In conclusion, RES may exert protective effects on the cardiovascular system, as demonstrated by the amelioration of TNF-α-induced inflammation in EPCs following RES treatment, and may therefore be used in the future for the prevention of cardiovascular disease.
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Affiliation(s)
- Hairong Chu
- Clinical Medical College, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Hong Li
- Clinical Medical College, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Xiumei Guan
- Clinical Medical College, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Hong Yan
- Clinical Medical College, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Xiaoyun Zhang
- Clinical Medical College, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Xiaodong Cui
- Clinical Medical College, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Xin Li
- Clinical Medical College, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Min Cheng
- Clinical Medical College, Weifang Medical University, Weifang, Shandong 261053, P.R. China
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Garczorz W, Gallego-Colon E, Kosowska A, Kłych-Ratuszny A, Woźniak M, Marcol W, Niesner KJ, Francuz T. Exenatide exhibits anti-inflammatory properties and modulates endothelial response to tumor necrosis factor α-mediated activation. Cardiovasc Ther 2018; 36. [PMID: 29283509 DOI: 10.1111/1755-5922.12317] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 11/30/2017] [Accepted: 12/20/2017] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION Cardiovascular disease is the main cause of mortality and morbidity in the industrialized world. Incretin-mimetic compounds such as exenatide are currently used in the treatment of type 2 diabetes. AIMS We investigated the effects of incretin drugs on apoptosis, adhesion molecule expression, and concentration of extracellular matrix (ECM) metalloproteinases under inflammatory conditions within the context of atherosclerotic plaque formation of both human coronary artery endothelial cells (hCAECs) and human aortic endothelial cells (hAoECs). TNF-α-stimulated hCAEC and hAoEC were treated with exenatide (1 and 10 nmol/L) and GLP-1 (10 and 100 nmol/L) then evaluated for caspase 3/7 activity and assayed for protein levels of adhesion molecules sICAM-1, sVCAM-1, and P-selectin. Concentrations of matrix metalloproteinases (MMPs) MMP-1, MMP-2, MMP-9, and their inhibitors-tissue inhibitor of metalloproteinases (TIMPs), TIMP-1, TIMP-2 were also measured to evaluate the effects on extracellular matrix turnover within an inflammatory environment. Intracellular signaling pathways were evaluated via transfection of endothelial cells with a GFP vector under the NF-κB promoter. RESULTS Our experimental data suggest that GLP-1 receptor (GLP-1R) agonists downregulate activation of NF-κB and adhesion molecules ICAM and VCAM, but not P-selectin, in both endothelial cell lines. Exendin-4 and GLP-1 modulate the expression of MMPs and TIMPs, with statistically significant effects observed at high concentrations of both incretins. Expressive modulation may be mediated by NF-κB as observed by activation of the vector when stimulated under inflammatory conditions. CONCLUSION These findings indicate that GLP-1 analogs have anti-inflammatory properties in endothelial cells that may play an important role in preventing atherosclerosis.
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Affiliation(s)
- Wojciech Garczorz
- Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Enrique Gallego-Colon
- Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Agnieszka Kosowska
- Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Agnieszka Kłych-Ratuszny
- Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Michał Woźniak
- Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Wiesław Marcol
- Department of Physiology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - K J Niesner
- College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Tomasz Francuz
- Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
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Li XH, Xue WL, Wang MJ, Zhou Y, Zhang CC, Sun C, Zhu L, Liang K, Chen Y, Tao BB, Tan B, Yu B, Zhu YC. H 2S regulates endothelial nitric oxide synthase protein stability by promoting microRNA-455-3p expression. Sci Rep 2017; 7:44807. [PMID: 28322298 PMCID: PMC5359669 DOI: 10.1038/srep44807] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 02/15/2017] [Indexed: 12/11/2022] Open
Abstract
The aims of the present study are to determine whether hydrogen sulfide (H2S) is involved in the expression of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production, and to identify the role of microRNA-455-3p (miR-455-3p) during those processes. In cultured human umbilical vein endothelial cells (HUVECs), the expression of miR-455-3p, eNOS protein and the NO production was detected after administration with 50 μM NaHS. The results indicated that H2S could augment the expression of miR-455-3p and eNOS protein, leading to the increase of NO level. We also found that overexpression of miR-455-3p in HUVECs increased the protein levels of eNOS whereas inhibition of miR-455-3p decreased it. Moreover, H2S and miR-455-3p could no longer increase the protein level of eNOS in the presence of proteasome inhibitor, MG-132. In vivo, miR-455-3p and eNOS expression were considerably increased in C57BL/6 mouse aorta, muscle and heart after administration with 50 μmol/kg/day NaHS for 7 days. We also identified that H2S levels and miR-455-3p expression increased in human atherosclerosis plaque while H2S levels decreased in plasma of atherosclerosis patients. Our data suggest that the stability of eNOS protein and the NO production could be regulated by H2S through miR-455-3p.
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Affiliation(s)
- Xing-Hui Li
- Research Center on Aging and Medicine, Fudan University, Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wen-Long Xue
- Research Center on Aging and Medicine, Fudan University, Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ming-Jie Wang
- Research Center on Aging and Medicine, Fudan University, Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yu Zhou
- Research Center on Aging and Medicine, Fudan University, Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Cai-Cai Zhang
- Research Center on Aging and Medicine, Fudan University, Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China.,Department of physiology, Hainan Medical College, Haikou, Hainan 571101, China
| | - Chen Sun
- Research Center on Aging and Medicine, Fudan University, Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lei Zhu
- Department of Vascular Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Kun Liang
- Department of Vascular Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Ying Chen
- Research Center on Aging and Medicine, Fudan University, Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Bei-Bei Tao
- Research Center on Aging and Medicine, Fudan University, Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Bo Tan
- Department of Clinical Pharmacology, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Bo Yu
- Department of Vascular Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Yi-Chun Zhu
- Research Center on Aging and Medicine, Fudan University, Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
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Cyclophosphamide induced stomach and duodenal lesions as a NO-system disturbance in rats: L-NAME, L-arginine, stable gastric pentadecapeptide BPC 157. Inflammopharmacology 2017; 25:255-264. [PMID: 28255738 DOI: 10.1007/s10787-017-0330-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 02/15/2017] [Indexed: 12/13/2022]
Abstract
We revealed a new point with cyclophosphamide (150 mg/kg/day intraperitoneally for 7 days): we counteracted both rat stomach and duodenal ulcers and increased NO- and MDA-levels in these tissues. As a NO-system effect, BPC 157 therapy (10 µg/kg, 10 ng/kg, intraperitoneally once a day or in drinking water, till the sacrifice) attenuated the increased NO- and MDA-levels and nullified, in rats, severe cyclophosphamide-ulcers and even stronger stomach and duodenal lesions after cyclophosphamide + L-NAME (5 mg/kg intraperitoneally once a day). L-arginine (100 mg/kg intraperitoneally once a day not effective alone) led L-NAME-values only to the control values (cyclophosphamide + L-NAME + L-arginine-rats). Briefly, rats were sacrificed at 24 h after last administration on days 1, 2, 3, or 7, and assessment included sum of longest lesions diameters (mm) in the stomach and duodenum, oxidative stress by quantifying thiobarbituric acid reactivity as malondialdehyde equivalents (MDA), NO in stomach and duodenal tissue samples using the Griess reaction. All these parameters were highly exaggerated in rats who underwent cyclophosphamide treatment. We identified high MDA-tissue values, high NO-tissue values, ulcerogenic and beneficial potential in cyclophosphamide-L-NAME-L-arginine-BPC 157 relationships. This suggests that in cyclophosphamide damaged rats, NO excessive release generated by the inducible isozyme, damages the vascular wall and other tissue cells, especially in combination with reactive oxygen intermediates, while failing endothelial production and resulting in further aggravation by L-NAME which was inhibited by L-arginine. Finally, BPC 157, due to its special relations with NO-system, may both lessen increased MDA- and NO-tissues values and counteract effects of both cyclophosphamide and L-NAME on stomach and duodenal lesions.
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40
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Park J, Pramanick S, Kim J, Lee J, Kim WJ. Nitric oxide-activatable gold nanoparticles for specific targeting and photo-thermal ablation of macrophages. Chem Commun (Camb) 2017; 53:11229-11232. [DOI: 10.1039/c7cc06420a] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Nitric oxide-activatable gold nanoparticles can be utilized as a useful NO sensing tool and a photo-thermal agent for specific inflammation-associated macrophages.
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Affiliation(s)
- Junghong Park
- Center for Self-assembly and Complexity
- Institute for Basic Science
- Pohang 790-784
- Korea
- Department of Chemistry
| | - Swapan Pramanick
- Center for Self-assembly and Complexity
- Institute for Basic Science
- Pohang 790-784
- Korea
- Department of Chemistry
| | - Jinhwan Kim
- Center for Self-assembly and Complexity
- Institute for Basic Science
- Pohang 790-784
- Korea
- Department of Chemistry
| | - Jihyun Lee
- Center for Self-assembly and Complexity
- Institute for Basic Science
- Pohang 790-784
- Korea
- Department of Chemistry
| | - Won Jong Kim
- Center for Self-assembly and Complexity
- Institute for Basic Science
- Pohang 790-784
- Korea
- Department of Chemistry
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Chu W, Guan L, Huang D, Ren Y, Zhou Y. Lovastatin exerts protective effects on endothelial cells via upregulation of PTK2B. Exp Ther Med 2016; 12:1741-1749. [PMID: 27602089 PMCID: PMC4998215 DOI: 10.3892/etm.2016.3547] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 06/06/2016] [Indexed: 01/18/2023] Open
Abstract
Statins are HMG-CoA reductase inhibitors that are used to decrease the blood levels of low-density lipoprotein (LDL). In addition, they have been shown to exert pleiotropic protective effects in the absence of LDL-lowering activity. The present study investigated the effects of lovastatin on global gene expression in human umbilical vein endothelial cells (HUVECs), in order to further explore its ability to protect against oxidized (ox)-LDL-induced cytotoxicity. HUVECs were treated with lovastatin for 2–24 h, and gene expression patterns were analyzed using cDNA microarrays. The results suggested that numerous genes were regulated by lovastatin, including certain genes associated with cell survival, such as PTK2B, BCL2 and MAP3K3. In particular, PTK2B, which has been shown to exert anti-apoptotic effects against ox-LDL-induced cell injury, was upregulated by lovastatin. Knockdown of PTK2B was able to attenuate ox-LDL-induced cell injury, and this was associated with decreased levels of phosphorylated-AKT and eNOS, and inhibition of mitochondrial-dependent apoptosis. In conclusion, the results of the present study suggested that lovastatin protects against ox-LDL-induced cell injury, potentially via the upregulation of PTK2B, which regulates the anti-apoptosis signaling pathway.
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Affiliation(s)
- Weiwei Chu
- Department of Cadre Health Care, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang 312000, P.R. China
| | - Lili Guan
- Department of Endocrinology and Metabolism, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang 312000, P.R. China
| | - Dihua Huang
- Department of Endocrinology and Metabolism, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang 312000, P.R. China
| | - Yuezhong Ren
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Yan Zhou
- Department of Cardiovascular Medicine, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang 312000, P.R. China
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The balance between the pro-inflammatory effect of plasma noradrenaline and the anti-inflammatory effect of neuronal noradrenaline determines the peripheral effects of noradrenaline. Med Hypotheses 2015; 85:517-29. [DOI: 10.1016/j.mehy.2014.08.026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 08/18/2014] [Accepted: 08/24/2014] [Indexed: 12/22/2022]
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Velsko IM, Chukkapalli SS, Rivera-Kweh MF, Chen H, Zheng D, Bhattacharyya I, Gangula PR, Lucas AR, Kesavalu L. Fusobacterium nucleatum Alters Atherosclerosis Risk Factors and Enhances Inflammatory Markers with an Atheroprotective Immune Response in ApoE(null) Mice. PLoS One 2015; 10:e0129795. [PMID: 26079509 PMCID: PMC4469693 DOI: 10.1371/journal.pone.0129795] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Accepted: 05/13/2015] [Indexed: 12/20/2022] Open
Abstract
The American Heart Association supports an association between periodontal disease (PD) and atherosclerotic vascular disease (ASVD) but does not as of yet support a causal relationship. Recently, we have shown that major periodontal pathogens Porphyromonas gingivalis and Treponema denticola are causally associated with acceleration of aortic atherosclerosis in ApoEnull hyperlipidemic mice. The aim of this study was to determine if oral infection with another significant periodontal pathogen Fusobacterium nucleatum can accelerate aortic inflammation and atherosclerosis in the aortic artery of ApoEnull mice. ApoEnull mice (n = 23) were orally infected with F. nucleatum ATCC 49256 and euthanized at 12 and 24 weeks. Periodontal disease assessments including F. nucleatum oral colonization, gingival inflammation, immune response, intrabony defects, and alveolar bone resorption were evaluated. Systemic organs were evaluated for infection, aortic sections were examined for atherosclerosis, and inflammatory markers were measured. Chronic oral infection established F. nucleatum colonization in the oral cavity, induced significant humoral IgG (P=0.0001) and IgM (P=0.001) antibody response (12 and 24 weeks), and resulted in significant (P=0.0001) alveolar bone resorption and intrabony defects. F. nucleatum genomic DNA was detected in systemic organs (heart, aorta, liver, kidney, lung) indicating bacteremia. Aortic atherosclerotic plaque area was measured and showed a local inflammatory infiltrate revealed the presence of F4/80+ macrophages and CD3+ T cells. Vascular inflammation was detected by enhanced systemic cytokines (CD30L, IL-4, IL-12), oxidized LDL and serum amyloid A, as well as altered serum lipid profile (cholesterol, triglycerides, chylomicrons, VLDL, LDL, HDL), in infected mice and altered aortic gene expression in infected mice. Despite evidence for systemic infection in several organs and modulation of known atherosclerosis risk factors, aortic atherosclerotic lesions were significantly reduced after F. nucleatum infection suggesting a potential protective function for this member of the oral microbiota.
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Affiliation(s)
- Irina M. Velsko
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America
| | - Sasanka S. Chukkapalli
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America
| | - Mercedes. F. Rivera-Kweh
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America
| | - Hao Chen
- Cardiovascular Medicine and Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Donghang Zheng
- Cardiovascular Medicine and Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Indraneel Bhattacharyya
- Oral Diagnostic Sciences, College of Dentistry, University of Florida, Gainesville, Florida, United States of America
| | - Pandu R. Gangula
- Department of Oral Biology and Research, CWHR Meharry Medical College, Nashville, Tennessee, United States of America
- Department of Physiology, CWHR Meharry Medical College, Nashville, Tennessee, United States of America
| | - Alexandra R. Lucas
- Cardiovascular Medicine and Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Lakshmyya Kesavalu
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America
- * E-mail:
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Endothelial function, folate pharmacogenomics, and neurocognition in psychotic disorders. Schizophr Res 2015; 164:115-21. [PMID: 25728832 PMCID: PMC4409513 DOI: 10.1016/j.schres.2015.02.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 02/03/2015] [Accepted: 02/06/2015] [Indexed: 12/12/2022]
Abstract
Cardiovascular disease (CVD) is a well-described complication of schizophrenia, however, mechanisms connecting CVD with other facets of psychotic disorders, such as neurocognition, are not understood. The current study examined folate metabolism as a potential mechanism of CVD and neurocognitive deficits by: 1) using endothelial dysfunction as a biomarker of CVD, and 2) comparing enzymes associated with neurocognition, CVD, and critical to folate metabolism, methylenetetrahydrofolate reductase (MTHFR) and catechol-o-methyl transferase (COMT). Endothelial function was assessed in 147 participants with schizophrenia, schizoaffective disorder, and psychotic disorder not otherwise specified grouped by MTHFR and COMT allele status. Regression models were used to compare neurocognitive performance based on the Brief Assessment of Cognition in Schizophrenia (BACS). Overall, endothelial function predicted BACS composite z-scores after controlling for age, race, level of education, serum folate levels, and MTHFR/COMT risk allele status. Participants with at least one or more MTHFR and/or COMT risk alleles had lower BACS Composite and BACS Symbol Coding adjusted mean z-scores than those with both MTHFR CC and COMT Met/Met genotypes. Thus, endothelial dysfunction may contribute to the neurocognitive deficits seen in psychotic disorders. CVD interventions may not only reduce CVD-related morbidity, but also lessen progressive neurocognitive deficits reported in psychotic disorders.
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Chukkapalli SS, Rivera-Kweh MF, Velsko IM, Chen H, Zheng D, Bhattacharyya I, Gangula PR, Lucas AR, Kesavalu L. Chronic oral infection with major periodontal bacteria Tannerella forsythia modulates systemic atherosclerosis risk factors and inflammatory markers. Pathog Dis 2015; 73:ftv009. [PMID: 25663343 DOI: 10.1093/femspd/ftv009] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Tannerella forsythia is a Gram-negative anaerobic organism that inhabits the subgingival cavity and initiates connective tissue destruction and alveolar bone resorption in periodontal disease (PD). PD is a chronic immunoinflammatory disease and has been linked to several systemic diseases including atherosclerosis. This study evaluated the effects of a chronic oral infection with T. forsythia ATCC 43037 on the induction of PD, inflammatory markers and atherosclerosis risk factors in hyperlipidemic ApoE(null) mice. Mice were orally infected for 12 and 24 weeks prior to euthanasia. Bacterial colonization of the oral cavity and bacteremia was confirmed via isolation of genomic DNA from oral plaque and tissues. Oral infection elicited significantly elevated levels of serum IgG and IgM antibodies and alveolar bone resorption compared to control mice. Tannerella forsythia-infected mice had increased serum amyloid A, and significantly reduced serum nitric oxide when compared to controls. Tannerella forsythia chronic infection also significantly increased serum lipoproteins suggesting altered cholesterol metabolism and potential for aortic inflammation. Despite enhanced acute phase reactants and altered lipid profiles, T. forsythia infection was associated with decreased aortic plaque. This study investigates the potential of a known periodontal bacterial pathogen found in atherosclerotic plaque in humans to accelerate atherosclerosis in hyperlipdemic mice.
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Affiliation(s)
- Sasanka S Chukkapalli
- Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA
| | | | - Irina M Velsko
- Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA
| | - Hao Chen
- Medicine and Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Donghang Zheng
- Medicine and Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Indraneel Bhattacharyya
- Oral Diagnostic Sciences, College of Dentistry, University of Florida, Gainesville, FL 32610, USA
| | - Pandu R Gangula
- Department of Physiology, Department of Oral Biology and Research, School of Medicine and School of Dentistry, CWHR Nashville, TN 37208, USA
| | - Alexandra R Lucas
- Medicine and Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Lakshmyya Kesavalu
- Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA Dept. of Periodontology and Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA
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Ma S, Ma CCH. Recent developments in the effects of nitric oxide-donating statins on cardiovascular disease through regulation of tetrahydrobiopterin and nitric oxide. Vascul Pharmacol 2014; 63:63-70. [PMID: 25139660 DOI: 10.1016/j.vph.2014.08.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2014] [Revised: 08/01/2014] [Accepted: 08/04/2014] [Indexed: 10/24/2022]
Abstract
Since the discovery of the importance of nitric oxide (NO) to the human body three decades ago, numerous laboratory and clinical studies have been done to explore its potential therapeutic actions on many organs. In the cardiovascular system, NO works as a volatile signaling molecule regulating the vascular permeability and vascular tone, preventing thrombosis and inflammation, as well as inhibiting the smooth muscle hyperplasia. Thus, NO is important in the prevention and treatment of cardiovascular disease. NO is synthesized by NO synthase (NOS) with tetrahydrobiopterin (BH4) as the crucial cofactor. Many studies have been done to form nitric oxide donors so as to deliver NO directly to the vessel walls. In addition, NO moieties have been incorporated into existing therapeutic agents to enhance the NO bioavailability, including statins. Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA), the rate-limiting enzyme of the mevalonate pathway. By inhibiting this pathway, statins lower blood cholesterol and exert their pleiotropic effects through activity in reaction cascades, such as Rho/ROCK and Rac 1/NADPH oxidase pathways. Statins have also been observed to implement their non-lipid effects by promoting BH4 synthesis with increase of NO bioavailability. Furthermore, NO-donating statins in laboratory studies have demonstrated to produce better therapeutic effects than their parent's drugs. They offer better anti-inflammatory, anti-proliferative and antithrombotic actions on cardiovascular system. They also cause better revascularization in peripheral ischemia and produce greater enhancement in limb reperfusion and salvage. In addition, it has been shown that NO-donating statin caused less myotoxicity, the most common side effect related to treatment with statins. The initial studies have demonstrated the superior therapeutic effects of NO-donating statins while producing fewer side effects.
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Affiliation(s)
- Sze Ma
- Hong Kong Baptist Hospital, Hong Kong; National University Ireland, Ireland; Royal College of Physicians of Ireland, Ireland
| | - Christopher Cheng-Hwa Ma
- NHS Dumfries & Galloway, GMC 7411692, United Kingdom; King's College London School of Medicine, United Kingdom.
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Malek HA, Shata A. Effect of a high dose of vitamin D on a rabbit model of atherosclerosis. Int J Immunopathol Pharmacol 2014; 27:195-201. [PMID: 25004831 DOI: 10.1177/039463201402700206] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Multifactorial factors have been involved in atherosclerosis. An association has been shown between osteoporosis and carotid atherosclerosis. This work evaluates the effect of vitamin D on regression of atherosclerosis. Forty-eight male rabbits were divided into: Group Ia: [Standard diet + saline for 4 weeks]; Group I b: [Standard diet + a high dose of vitamin D3 daily for 4 weeks]; Group IIa: [Cholesterolenriched diet for 4 weeks]; Group IIb: [Cholesterolenriched diet + a single high dose of vit D3, daily for 4 weeks. At the end of 4 weeks, the rabbits were sacrificed for assay in serum lipid profile, C reactive protein (CRP), vitamin D3 metabolite, calcium, soluble adhesion molecules (sVCAM and sICAM) and nitrite (NO) and malondialdehyde (MDA) released from isolated aortic rings. Results showed that vitamin D produced a significant reduction in the sera of lipid profile, CRP, and adhesion molecules, associated with a non-significant change in serum calcium and a significant increase in the body level of vitamin D3. Addition of vitamin D to the incubated aortic rings of the atherosclerotic rabbits resulted in a significant increase in NO and decrease in MDA release. It could be concluded that vitamin D has anti-atherosclerotic effects, and may exert these effects by inhibiting lipid peroxidation and stimulation of nitric oxide, resulting in attenuation of the inflammatory atherosclerotic process.
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Affiliation(s)
- H A Malek
- Clinical Pharmacology Department, Mansoura University, Egypt
| | - A Shata
- Clinical Pharmacology Department, Mansoura University, Egypt
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Chen XN, Xu J, Feng Z, Fan M, Han JY, Yang Z. Simvastatin combined with nifedipine enhances endothelial cell protection by inhibiting ROS generation and activating Akt phosphorylation. Acta Pharmacol Sin 2010; 31:813-20. [PMID: 20562903 DOI: 10.1038/aps.2010.58] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
AIM To investigate the protective effects of simvastatin (Sim) combined with nifedipine (Nif) on endothelial cells and elucidate the action mechanism. METHODS Human umbilical vein endothelial cells (HUVEC) were used. mRNA and protein levels were measured by using reverse-transcription polymerase chain reaction (RT-PCR) and Western blotting, respectively. Intracellular calcium and reactive oxygen species (ROS) were detected using confocal microscopy. The Griess assay was used to evaluate nitric oxide (NO) release. RESULTS Treatment of HUVEC with H(2)O(2) 100 micromol/L for 30 min inhibited the mRNA and protein expression of endothelial nitric oxide synthase (eNOS). With increased concentrations of Nif, eNOS mRNA and protein levels increased (P<0.05). Combined treatment with Sim 1.0 micromol/L and Nif 1.0 micromol/L significantly increased the mRNA and protein expression of eNOS and NO release compared with Sim or Nif alone (P<0.05). The combination significantly lowered the intracellular ROS level (P<0.05), which was correlated with the increase in eNOS and NO, but there was no visible change in intracellular calcium (P>0.05). Compared with individual drug treatment, Akt phosphorylation and the ratio of p-eNOS/eNOS were up-regulated in the combination group, and this effect was inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002. CONCLUSION The Sim-Nif combination effectively protects HUVEC against H(2)O(2) injury by inhibiting intracellular ROS generation, increasing the ratio of p-eNOS/eNOS and up-regulating Akt phosphorylation.
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Rasmusen C, Moinard C, Martin C, Tricottet V, Cynober L, Couderc R. L-arginine plus atorvastatin for prevention of atheroma formation in genetically hypercholesterolaemic rabbits. Br J Nutr 2007; 97:1083-9. [PMID: 17391569 DOI: 10.1017/s0007114507659066] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
We investigated the combined effect of dietary supplementation with L-arginine, which is the precursor of NO, and pharmacological treatment with atorvastatin, which is a 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, on the development of atherosclerosis in homozygous Watanabe heritable hyperlipidaemic rabbits. Rabbits were fed either standard rabbit chow (group C; n 9) as control, a 1.5 % L-arginine diet (group A; n 9), standard rabbit chow plus atorvastatin (2.5 mg/kg per d) in drinking water (group S; n 8), or standard rabbit chow plus a 1.5 % L-arginine diet with atorvastatin (group SA; n 8). Blood was sampled at 2-week intervals. After 8 weeks (T8), the aorta was harvested for topographic and histological analysis. Only the SA group showed decreases in total area of lesions (21 %) and the area of abdominal lesions (44 %) compared with the control group (P = 0.019). Furthermore, plaques in the SA group were smaller and less thick than those observed in the S group. Unexpectedly, plasma nitrite + nitrate levels were not modified under either the L-arginine diet alone or under L-arginine plus atorvastatin. The present study is the first to demonstrate that diet supplementation with L-arginine associated with a statin (atorvastatin) is more efficient in reducing lesion size than treatment with L-arginine or a statin alone. This is a relatively novel therapeutic approach associating a macronutrient and a drug.
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Affiliation(s)
- Carole Rasmusen
- Laboratory of Biological Nutrition EA 2498, Faculty of Pharmacy, Paris Descartes University, 4 Avenue de l'Observatoire, 75270 Paris Cedex 06, France
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López D, Orta X, Casós K, Sáiz MP, Puig-Parellada P, Farriol M, Mitjavila MT. Upregulation of endothelial nitric oxide synthase in rat aorta after ingestion of fish oil-rich diet. Am J Physiol Heart Circ Physiol 2004; 287:H567-72. [PMID: 15059781 DOI: 10.1152/ajpheart.01145.2003] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
A previous study with aortic segments isolated from rats fed a fish oil-rich diet indicated an increase in acetylcholine-induced nitric oxide (.NO)-mediated relaxation. However, it remained to be elucidated whether a fish oil-rich diet affects the vascular activity per se and the point of the.NO-cGMP pathway at which fish oil acts. For this purpose, two groups of Sprague-Dawley rats were fed a semipurified diet containing 5% lipids, either corn oil (CO) or menhaden oil (MO), for 8 wk. We studied the mRNA and protein levels of endothelial NO synthase (eNOS) and NOS activity. The bioavailability of vascular.NO was assessed directly by electron spin resonance spectroscopy. The levels of cGMP, l-arginine, and l-citrulline were also evaluated in homogenates. Superoxide anion (O(2)(-).) production and related antioxidant activities were also studied in aortic segments. The aortic content of eNOS mRNA was increased in rats fed the MO-rich diet. This resulted in increases in both eNOS protein levels (70% relative to the rats fed the CO-rich diet) and NOS activity (102%);.NO production increased by 90%, cGMP levels increased by 100%, and l-arginine decreased by 30%. No change in aortic O(2)(-). production was caused by dietary MO. The upregulation of the eNOS-cGMP pathway induced by dietary MO may contribute to the maintenance of vascular homeostasis and explain its beneficial effect in the prevention of arterial diseases.
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Affiliation(s)
- Diego López
- Departament de Fisiologia, Facultat de Biologia, Universitat de Barcelona, E-08028 Barcelona, Spain
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