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Queiroz M, Sena CM. Perivascular adipose tissue: a central player in the triad of diabetes, obesity, and cardiovascular health. Cardiovasc Diabetol 2024; 23:455. [PMID: 39732729 PMCID: PMC11682657 DOI: 10.1186/s12933-024-02549-9] [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: 09/14/2024] [Accepted: 12/17/2024] [Indexed: 12/30/2024] Open
Abstract
Perivascular adipose tissue (PVAT) is a dynamic tissue that affects vascular function and cardiovascular health. The connection between PVAT, the immune system, obesity, and vascular disease is complex and plays a pivotal role in the pathogenesis of vascular diseases such as atherosclerosis, hypertension, and vascular inflammation. In cardiometabolic diseases, PVAT becomes a significant source of proflammatory adipokines, leading to increased infiltration of immune cells, in cardiometabolic diseases, PVAT becomes a significant source of proinflammatory adipokines, leading to increased infiltration of immune cells, promoting vascular smooth muscle cell proliferation and migrationpromoting vascular smooth muscle cell proliferation and migration. This exacerbates vascular dysfunction by impairing endothelial cell function and promoting endothelial activation. Dysregulated PVAT also contributes to hemodynamic alterations and hypertension through enhanced sympathetic nervous system activity and impaired vasodilatory capacity of PVAT-derived factors. Therapeutic interventions targeting key components of this interaction, such as modulating PVAT inflammation, restoring adipokine balance, and attenuating immune cell activation, hold promise for mitigating obesity-related vascular complications. Lifestyle interventions, pharmacological agents targeting inflammatory pathways, and surgical approaches aimed at reducing PVAT mass or improving adipose tissue function are potential therapeutic avenues for managing vascular diseases associated with obesity and PVAT dysfunction.
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Affiliation(s)
- Marcelo Queiroz
- Institute of Physiology, iCBR, Faculty of Medicine, University of Coimbra, Subunit 1, polo 3, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal
| | - Cristina M Sena
- Institute of Physiology, iCBR, Faculty of Medicine, University of Coimbra, Subunit 1, polo 3, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.
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Li J, Tian Z, Zhang T, Jin J, Zhang X, Xie P, Lin H, Gu J, Wu Y, Wang X, Zhang S, Yan X, Guo D, Wang Z, Zhang Q. Single-cell view and a novel protective macrophage subset in perivascular adipose tissue in T2DM. Cell Mol Biol Lett 2024; 29:148. [PMID: 39627688 PMCID: PMC11616190 DOI: 10.1186/s11658-024-00668-5] [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: 04/11/2024] [Accepted: 11/14/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND Vasculopathy underlies diabetic complications, with perivascular adipose tissue (PVAT) playing crucial roles in its development. However, the changes in the cellular composition and function of PVAT, including the specific cell subsets and mechanisms implicated in type 2 diabetes mellitus (T2DM) vasculopathy, remain unclear. METHODS To address the above issues, we performed single-cell RNA sequencing on the stromal vascular fraction (SVF) of PVAT from normal and T2DM rats. Then, various bioinformatics tools and functional experiments were used to investigate the characteristic changes in the cellular profile of diabetic PVAT SVF, their implications, and the underlying mechanisms. RESULTS Our study reveals the single-cell landscape of the SVF of PVAT, demonstrating its considerable heterogeneity and significant alterations in T2DM, including an enhanced inflammatory response and elevated proportions of macrophages and natural killer (NK) cells. Moreover, macrophages are critical hubs for cross-talk among various cell populations. Notably, we identified a decreased Pdpn+ macrophage subpopulation in the PVAT of T2DM rats and confirmed this in mice and humans. In vitro and in vivo studies demonstrated that Pdpn+ macrophages alleviated insulin resistance and modulated adipokine/cytokine expression in adipocytes via the Pla2g2d-DHA/EPA-GPR120 pathway. This subset also enhances the function of vascular endothelial and smooth muscle cells, inhibits vascular inflammation and oxidative stress, and improves vasodilatory function, thereby protecting blood vessels. CONCLUSION Pdpn+ macrophages exhibit significant vascular protective effects by alleviating insulin resistance and modulating adipokine/cytokine expression in PVAT adipocytes. This macrophage subtype may therefore play pivotal roles in mitigating vascular complications in T2DM. Our findings also underscore the critical role of immune-metabolic cross-talk in maintaining tissue homeostasis.
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Affiliation(s)
- Jiaxuan Li
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China
- Shandong Provincial Hospital, Shandong Laboratory Animal Center, Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, 250021, China
- Key Laboratory of Endocrine Glucose and Lipids Metabolism and Brain Aging, Chinese Ministry of Education, Shandong First Medical University, Jinan, 250021, China
| | - Zhenyu Tian
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Tongxue Zhang
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Jiajia Jin
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Xinjie Zhang
- Department of Biology, University College London, London, NW1 2HE, UK
| | - Panpan Xie
- Department of Breast and Thyroid Surgery, Liaocheng People's Hospital, Liaocheng, 252000, China
| | - Haiyan Lin
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Junfei Gu
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China
- Department of Geriatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Yingjie Wu
- Shandong Provincial Hospital, Shandong Laboratory Animal Center, Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, 250021, China
- Key Laboratory of Endocrine Glucose and Lipids Metabolism and Brain Aging, Chinese Ministry of Education, Shandong First Medical University, Jinan, 250021, China
| | - Xiaowei Wang
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Shucui Zhang
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Xuefang Yan
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Dong Guo
- Department of Neurology, Liaocheng People's Hospital, Liaocheng, 252000, China.
| | - Zhe Wang
- Department of Geriatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
| | - Qunye Zhang
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China.
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Simantiris S, Pappa A, Papastamos C, Korkonikitas P, Antoniades C, Tsioufis C, Tousoulis D. Perivascular Fat: A Novel Risk Factor for Coronary Artery Disease. Diagnostics (Basel) 2024; 14:1830. [PMID: 39202318 PMCID: PMC11353828 DOI: 10.3390/diagnostics14161830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/17/2024] [Accepted: 08/20/2024] [Indexed: 09/03/2024] Open
Abstract
Perivascular adipose tissue (PVAT) interacts with the vascular wall and secretes bioactive factors which regulate vascular wall physiology. Vice versa, vascular wall inflammation affects the adjacent PVAT via paracrine signals, which induce cachexia-type morphological changes in perivascular fat. These changes can be quantified in pericoronary adipose tissue (PCAT), as an increase in PCAT attenuation in coronary computed tomography angiography images. Fat attenuation index (FAI), a novel imaging biomarker, measures PCAT attenuation around coronary artery segments and is associated with coronary artery disease presence, progression, and plaque instability. Beyond its diagnostic capacity, PCAT attenuation can also ameliorate cardiac risk stratification, thus representing an innovative prognostic biomarker of cardiovascular disease (CVD). However, technical, biological, and anatomical factors are weakly related to PCAT attenuation and cause variation in its measurement. Thus, to integrate FAI, a research tool, into clinical practice, a medical device has been designed to provide FAI values standardized for these factors. In this review, we discuss the interplay of PVAT with the vascular wall, the diagnostic and prognostic value of PCAT attenuation, and its integration as a CVD risk marker in clinical practice.
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Affiliation(s)
- Spyridon Simantiris
- 1st Cardiology Department, Hippokration Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.S.)
| | - Aikaterini Pappa
- Cardiology Department, Konstantopouleio General Hospital, 14233 Nea Ionia, Greece
| | - Charalampos Papastamos
- 1st Cardiology Department, Hippokration Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.S.)
| | | | - Charalambos Antoniades
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX1 3QT, UK
| | - Constantinos Tsioufis
- 1st Cardiology Department, Hippokration Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.S.)
| | - Dimitris Tousoulis
- 1st Cardiology Department, Hippokration Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.S.)
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Yang G, Liu Z, Dong S, Zhao X, Ge Z, Cheng Z, Zhang X, Wang K. Duodenal-jejunal bypass surgery activates eNOS and enhances antioxidant system by activating AMPK pathway to improve heart oxidative stress in diabetic cardiomyopathy rats. J Diabetes 2024; 16:e13516. [PMID: 38087869 PMCID: PMC11212293 DOI: 10.1111/1753-0407.13516] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 10/19/2023] [Accepted: 11/18/2023] [Indexed: 06/29/2024] Open
Abstract
BACKGROUND Diabetic cardiomyopathy is a serious complication of obesity with type 2 diabetes and is a major cause of mortality. Metabolic surgery, such as duodenal-jejunal bypass (DJB), can effectively improve diabetic cardiomyopathy; however, the underlying mechanisms remain elusive. Oxidative stress is one of the pivotal mechanisms of diabetic cardiomyopathy. Our objective was to investigate the effect and potential mechanisms of DJB on oxidative stress in the heart of diabetic cardiomyopathy rats. METHODS High-fat diet combined with intraperitoneal injection of streptozotocin was used to establish diabetic cardiomyopathy rats. DJB was performed on diabetic cardiomyopathy rats, and high glucose and palmitate were used to simulate diabetic cardiomyopathy in H9C2 cells in vitro. Sera from different groups of rats were used for experiments in vivo and in vitro. RESULTS DJB effectively improved oxidative stress and activated the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway to increase endothelial nitric oxide synthase (eNOS) phosphorylation level and the expression of antioxidative system-related proteins and genes in the heart of diabetic cardiomyopathy rats. AMPK agonists and serum from DJB rats activated the AMPK pathway to increase eNOS phosphorylation level and the expression of antioxidative system-related proteins and genes and decreased the content of reactive oxygen species in H9C2 cells, but this improvement was almost eliminated by the addition of AMPK inhibitors. CONCLUSIONS DJB activates eNOS and enhances the antioxidant system by activating the AMPK pathway-and not solely by improving blood glucose-to improve oxidative stress in the heart of diabetic cardiomyopathy rats.
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Affiliation(s)
- Guangwei Yang
- Department of General SurgeryQilu Hospital of Shandong UniversityJinanChina
| | - Zitian Liu
- Department of General SurgeryQilu Hospital of Shandong UniversityJinanChina
| | - Shuohui Dong
- Department of General SurgeryQilu Hospital of Shandong UniversityJinanChina
| | - Xiang Zhao
- Department of General SurgeryQilu Hospital of Shandong UniversityJinanChina
| | - Zheng Ge
- Department of General SurgeryQilu Hospital of Shandong UniversityJinanChina
| | - Zhiqiang Cheng
- Department of General SurgeryQilu Hospital of Shandong UniversityJinanChina
| | - Xiang Zhang
- Department of General SurgeryQilu Hospital of Shandong UniversityJinanChina
| | - Kexin Wang
- Department of General SurgeryQilu Hospital of Shandong UniversityJinanChina
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Cha MH, Choi HJ, Ma JY. Lysophosphatidylcholines Promote Influenza Virus Reproduction through the MAPK/JNK Pathway in PMA-Differentiated THP-1 Macrophages. Int J Mol Sci 2024; 25:6538. [PMID: 38928244 PMCID: PMC11204278 DOI: 10.3390/ijms25126538] [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: 05/13/2024] [Revised: 05/30/2024] [Accepted: 06/04/2024] [Indexed: 06/28/2024] Open
Abstract
Obesity and metabolic syndrome alter serum lipid profiles. They also increase vulnerability to viral infections and worsen the survival rate and symptoms after infection. How serum lipids affect influenza virus proliferation is unclear. Here, we investigated the effects of lysophosphatidylcholines on influenza A virus (IAV) proliferation. IAV particles in the culture medium were titrated using extraction-free quantitative PCR, and viral RNA and protein levels were assessed using real-time PCR and Western blot, respectively. RNA sequencing data were analyzed using PCA and heatmap analysis, and pathway analysis was performed using the KEGG mapper and PathIN tools. Statistical analysis was conducted using SPSS21.0. LPC treatment of THP-1 cells significantly increased IAV proliferation and IAV RNA and protein levels, and saturated LPC was more active in IAV RNA expression than unsaturated LPC was. The functional analysis of genes affected by LPCs showed that the expression of genes involved in IAV signaling, such as suppressor of cytokine signaling 3 (SOCS3), phosphoinositide-3-kinase regulatory subunit 3 (PI3K) and AKT serine/threonine kinase 3 (AKT3), Toll-like receptor 7 (TKR7), and interferon gamma receptor 1 (IFNGR1), was changed by LPC. Altered influenza A pathways were linked with MAPK and PI3K/AKT signaling. Treatment with inhibitors of MAPK or PI3K attenuated viral gene expression changes induced by LPCs. The present study shows that LPCs stimulated virus reproduction by modifying the cellular environment to one in which viruses proliferated better. This was mediated by the MAPK, JNK, and PI3K/AKT pathways. Further animal studies are needed to confirm the link between LPCs from serum or the respiratory system and IAV proliferation.
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Affiliation(s)
- Min-Ho Cha
- Korean Medicine (KM) Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu 41062, Republic of Korea;
| | | | - Jin-Yeul Ma
- Korean Medicine (KM) Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu 41062, Republic of Korea;
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Engin A. Endothelial Dysfunction in Obesity and Therapeutic Targets. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:489-538. [PMID: 39287863 DOI: 10.1007/978-3-031-63657-8_17] [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: 09/19/2024]
Abstract
Parallel to the increasing prevalence of obesity in the world, the mortality from cardiovascular disease has also increased. Low-grade chronic inflammation in obesity disrupts vascular homeostasis, and the dysregulation of adipocyte-derived endocrine and paracrine effects contributes to endothelial dysfunction. Besides the adipose tissue inflammation, decreased nitric oxide (NO)-bioavailability, insulin resistance (IR), and oxidized low-density lipoproteins (oxLDLs) are the main factors contributing to endothelial dysfunction in obesity and the development of cardiorenal metabolic syndrome. While normal healthy perivascular adipose tissue (PVAT) ensures the dilation of blood vessels, obesity-associated PVAT leads to a change in the profile of the released adipo-cytokines, resulting in a decreased vasorelaxing effect. Higher stiffness parameter β, increased oxidative stress, upregulation of pro-inflammatory cytokines, and nicotinamide adenine dinucleotide phosphate (NADP) oxidase in PVAT turn the macrophages into pro-atherogenic phenotypes by oxLDL-induced adipocyte-derived exosome-macrophage crosstalk and contribute to the endothelial dysfunction. In clinical practice, carotid ultrasound, higher leptin levels correlate with irisin over-secretion by human visceral and subcutaneous adipose tissues, and remnant cholesterol (RC) levels predict atherosclerotic disease in obesity. As a novel therapeutic strategy for cardiovascular protection, liraglutide improves vascular dysfunction by modulating a cyclic adenosine monophosphate (cAMP)-independent protein kinase A (PKA)-AMP-activated protein kinase (AMPK) pathway in PVAT in obese individuals. Because the renin-angiotensin-aldosterone system (RAAS) activity, hyperinsulinemia, and the resultant IR play key roles in the progression of cardiovascular disease in obesity, RAAS-targeted therapies contribute to improving endothelial dysfunction. By contrast, arginase reciprocally inhibits NO formation and promotes oxidative stress. Thus, targeting arginase activity as a key mediator in endothelial dysfunction has therapeutic potential in obesity-related vascular comorbidities. Obesity-related endothelial dysfunction plays a pivotal role in the progression of type 2 diabetes (T2D). The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone (thiazolidinedione), is a popular drug for treating diabetes; however, it leads to increased cardiovascular risk. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin (EMPA) significantly improves endothelial dysfunction and mortality occurring through redox-dependent mechanisms. Although endothelial dysfunction and oxidative stress are alleviated by either metformin or EMPA, currently used drugs to treat obesity-related diabetes neither possess the same anti-inflammatory potential nor simultaneously target endothelial cell dysfunction and obesity equally. While therapeutic interventions with glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide or bariatric surgery reverse regenerative cell exhaustion, support vascular repair mechanisms, and improve cardiometabolic risk in individuals with T2D and obesity, the GLP-1 analog exendin-4 attenuates endothelial endoplasmic reticulum stress.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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Valentini A, Cardillo C, Della Morte D, Tesauro M. The Role of Perivascular Adipose Tissue in the Pathogenesis of Endothelial Dysfunction in Cardiovascular Diseases and Type 2 Diabetes Mellitus. Biomedicines 2023; 11:3006. [PMID: 38002006 PMCID: PMC10669084 DOI: 10.3390/biomedicines11113006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 10/27/2023] [Accepted: 11/05/2023] [Indexed: 11/26/2023] Open
Abstract
Cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM) are two of the four major chronic non-communicable diseases (NCDs) representing the leading cause of death worldwide. Several studies demonstrate that endothelial dysfunction (ED) plays a central role in the pathogenesis of these chronic diseases. Although it is well known that systemic chronic inflammation and oxidative stress are primarily involved in the development of ED, recent studies have shown that perivascular adipose tissue (PVAT) is implicated in its pathogenesis, also contributing to the progression of atherosclerosis and to insulin resistance (IR). In this review, we describe the relationship between PVAT and ED, and we also analyse the role of PVAT in the pathogenesis of CVDs and T2DM, further assessing its potential therapeutic target with the aim of restoring normal ED and reducing global cardiovascular risk.
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Affiliation(s)
- Alessia Valentini
- Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy; (A.V.); (D.D.M.)
| | - Carmine Cardillo
- Department of Aging, Policlinico A. Gemelli IRCCS, 00168 Roma, Italy;
- Department of Translational Medicine and Surgery, Catholic University, 00168 Rome, Italy
| | - David Della Morte
- Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy; (A.V.); (D.D.M.)
| | - Manfredi Tesauro
- Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy; (A.V.); (D.D.M.)
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Elliott J, Bailey SR. Consequences of adiponectin deficiency: Can they be related to the pathophysiology of laminitis? Equine Vet J 2023; 55:346-349. [PMID: 36878858 DOI: 10.1111/evj.13932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 02/22/2023] [Indexed: 03/08/2023]
Affiliation(s)
- Jonathan Elliott
- Department of Comparative Biomedical Sciences, The Royal Veterinary College University of London, London, UK
| | - Simon R Bailey
- Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Melbourne, Victoria, Australia
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Sahinturk S. Metformin relaxes rat thoracic aorta via nitric oxide, AMPK, potassium channels, and PKC. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2023; 26:1030-1040. [PMID: 37605728 PMCID: PMC10440136 DOI: 10.22038/ijbms.2023.69728.15179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 04/10/2023] [Indexed: 08/23/2023]
Abstract
Objectives The present research aimed to identify the functional effects and underlying mechanisms of metformin on the rat thoracic aorta. Materials and Methods Thoracic aorta segments of Wistar Albino rats were put in the chambers of an isolated tissue bath system. The resting tone was adjusted to 1 g. Following the equilibration time, potassium chloride or phenylephrine was used to contract the vascular segments. The vessel segments were cumulatively treated with metformin (10-7-10-3 M) when a steady contraction was achieved. The described experimental approach was repeated after incubations with signaling pathway inhibitors and selective blockers of potassium channels to identify the effect mechanisms of metformin. Results Metformin had a potent vasorelaxant effect in a concentration-dependent way (P<0.001). After the endothelium was removed, the vasorelaxant effect level of metformin was significantly reduced. The level of vasorelaxant effect of metformin was increased by the maintenance of perivascular adipose tissue. Following administrations of L-NAME, methylene blue, compound C, BIM-I, and potassium channel blockers, the level of vasodilatory action of metformin was significantly reduced (P<0.001). Conclusion According to the results of this investigation, metformin significantly relaxes the thoracic aorta segments of rats. Metformin-mediated vasorelaxation involves the activation of numerous subtypes of potassium channels, including BKCa, IKCa, Kv, Kir, and K2p channels, as well as endothelium-dependent processes, including AMPK and eNOS/NO/sGS signaling pathways. Moreover, metformin-induced vasorelaxation is mediated through PVAT activation and the PKC signaling pathway.
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Affiliation(s)
- Serdar Sahinturk
- Bursa Uludag University Medicine School, Physiology Department, Bursa, Turkey
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Vosseler A, Machann J, Fritsche L, Prystupa K, Kübler C, Häring HU, Birkenfeld AL, Stefan N, Peter A, Fritsche A, Wagner R, Heni M. Interscapular fat is associated with impaired glucose tolerance and insulin resistance independent of visceral fat mass. Obesity (Silver Spring) 2022; 30:2233-2241. [PMID: 36192827 DOI: 10.1002/oby.23554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 06/24/2022] [Accepted: 07/11/2022] [Indexed: 11/10/2022]
Abstract
OBJECTIVE Dysregulated body fat distribution is a major determinant of various diseases. In particular, increased visceral fat mass and ectopic lipids in the liver are linked to metabolic disorders such as insulin resistance and type 2 diabetes. Furthermore, interscapular fat is considered to be a metabolically active fat compartment. METHODS This study measured interscapular fat mass and investigated its relationship with glucose metabolism in 822 individuals with a wide range of BMI values and different glucose tolerance statuses. Magnetic resonance imaging was used to quantify body fat depots, and an oral glucose tolerance test was performed to determine glucose metabolism. RESULTS Elevated interscapular fat mass was positively associated with age, BMI, and total body, visceral, and subcutaneous adipose tissue mass. High interscapular fat mass associated with elevated fasting glucose levels, glucose levels at 2 hours during the oral glucose tolerance test, glycated hemoglobin, and insulin resistance, independent of sex, age, and total body and visceral fat mass. CONCLUSIONS In conclusion, interscapular fat might be a highly specific fat compartment with a potential impact on glucose metabolism and the pathogenesis of diabetes mellitus.
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Affiliation(s)
- Andreas Vosseler
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Jürgen Machann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Section of Experimental Radiology, Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Louise Fritsche
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Katsiaryna Prystupa
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
| | - Christian Kübler
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Hans-Ulrich Häring
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Andreas L Birkenfeld
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Norbert Stefan
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Andreas Peter
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Andreas Fritsche
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Robert Wagner
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine-University and University Hospital Düsseldorf, Düsseldorf, Germany
| | - Martin Heni
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
- Division of Endocrinology and Diabetology, Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
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11
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Li H, Konja D, Wang L, Wang Y. Sex Differences in Adiposity and Cardiovascular Diseases. Int J Mol Sci 2022; 23:ijms23169338. [PMID: 36012601 PMCID: PMC9409326 DOI: 10.3390/ijms23169338] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/11/2022] [Accepted: 08/17/2022] [Indexed: 11/16/2022] Open
Abstract
Body fat distribution is a well-established predictor of adverse medical outcomes, independent of overall adiposity. Studying body fat distribution sheds insights into the causes of obesity and provides valuable information about the development of various comorbidities. Compared to total adiposity, body fat distribution is more closely associated with risks of cardiovascular diseases. The present review specifically focuses on the sexual dimorphism in body fat distribution, the biological clues, as well as the genetic traits that are distinct from overall obesity. Understanding the sex determinations on body fat distribution and adiposity will aid in the improvement of the prevention and treatment of cardiovascular diseases (CVD).
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12
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Mitidieri E, Turnaturi C, Vanacore D, Sorrentino R, d'Emmanuele di Villa Bianca R. The Role of Perivascular Adipose Tissue-Derived Hydrogen Sulfide in the Control of Vascular Homeostasis. Antioxid Redox Signal 2022; 37:84-97. [PMID: 35442088 DOI: 10.1089/ars.2021.0147] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Significance: Emerging evidence suggests that perivascular adipose tissue (PVAT) has a relevant role in the control of vascular tone in physiology and pathology. Healthy PVAT has anticontractile, anti-inflammatory, and antioxidative actions. Accumulating data from both human and experimental animal models indicate that PVAT dysfunction is conceivably coupled to cardiovascular diseases, and it is associated with vascular inflammation, oxidative stress, and arterial remodeling. Therefore, "healthy" PVAT may constitute a novel therapeutic target for the prevention and treatment of cardiovascular diseases. Recent Advances: Hydrogen sulfide (H2S) has been recognized as a vascular anti-contractile factor released from PVAT. The enzymes deputed to H2S biosynthesis are variously expressed in PVAT and strictly dependent on the vascular bed and species. Metabolic and cardiovascular diseases can alter the morphological and secretory characteristics of PVAT, influencing also the H2S signaling. Here, we discuss the role of PVAT-derived H2S in healthy conditions and its relevance in alterations occurring in vascular disorders. Critical Issues: We discuss how a better understanding may help in the prevention of vascular dysfunction related to alteration in PVAT-released H2S as well as the importance of the interplay between PVAT and H2S. Future Directions: We propose future directions to evaluate the contribution of each enzyme involved in H2S biosynthesis and their alteration/switch occurring in vascular disorders and the remaining challenges in investigating the role of H2S. Antioxid. Redox Signal. 37, 84-97.
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Affiliation(s)
- Emma Mitidieri
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Carlotta Turnaturi
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Domenico Vanacore
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Raffaella Sorrentino
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, Naples, Italy
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13
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Liu B, Deng B, Jiang X, Xu Y, Chen S, Cai M, Deng S, Ding W, Xu H, Zhang S, Tan ZB, Chen R, Zhang J. 10-gingerol, a natural AMPK agonist, suppresses neointimal hyperplasia and inhibits vascular smooth muscle cells proliferation. Food Funct 2022; 13:3234-3246. [DOI: 10.1039/d1fo03610f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Background: Abnormal proliferation of vascular smooth muscle cells (VSMCs) in the intimal region is a key event in the development of neointimal hyperplasia. 10-G, a bioactive compound found in ginger,...
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14
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Zhang X, Zhang H, Yang X, Qin Q, Sun X, Hou Y, Chen D, Jia M, Su X, Chen Y. Angiotensin II upregulates endothelin receptors through the adenosine monophosphate-activated protein kinase/sirtuin 1 pathway in vascular smooth muscle cells. J Pharm Pharmacol 2021; 73:1652-1662. [PMID: 34570873 DOI: 10.1093/jpp/rgab137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Accepted: 08/26/2021] [Indexed: 11/13/2022]
Abstract
OBJECTIVES This study was designed to test our hypothesis that angiotensin II (Ang II) upregulates endothelin (ET) receptors in vascular smooth muscle cells (VSMCs). METHODS Rat superior mesenteric artery (SMA) without endothelium was cultured in serum-free medium for 24 h in the presence of Ang II with or without metformin or nicotinamide. In vivo, rats were implanted subcutaneously with a mini-osmotic pump infusing AngII (500 ng/kg/min) for 4 weeks. The level of protein expression was determined using Western blotting. The contractile response to ET receptor agonists was studied using sensitive myography. Caudal artery blood pressure (BP) was measured using non-invasive tail-cuff plethysmography. KEY FINDINGS The results showed that Ang II significantly increased ET receptors and decreased phosphorylated-adenosine monophosphate-activated protein kinase α (p-AMPKα) in SMA. Furthermore, metformin significantly inhibited Ang II-upregulated ET receptors and upregulated Ang II-decreased sirtuin 1 (Sirt1). However, this effect was reversed by nicotinamide. Moreover, the in-vivo results showed that metformin not only inhibited Ang II-induced upregulation of ET receptors but also recovered Ang II-decreased p-AMPKα and Sirt1. In addition, metformin significantly inhibited Ang II-elevated BP. However, the effect was reversed by nicotinamide, except for p-AMPKα. CONCLUSIONS Ang II upregulated ET receptors in VSMCs to elevate BP by inhibiting AMPK, thereby inhibiting Sirt1.
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Affiliation(s)
- Xin Zhang
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Hongmei Zhang
- The First Affiliated Hospital of Xi'an Medical University, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Xinpu Yang
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Qiaohong Qin
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Xia Sun
- School of Basic and Medical Sciences, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Ying Hou
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Di Chen
- School of Basic and Medical Sciences, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Min Jia
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Xingli Su
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, China
- School of Basic and Medical Sciences, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Yulong Chen
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, China
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15
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Ruiyang B, Panayi A, Ruifang W, Peng Z, Siqi F. Adiponectin in psoriasis and its comorbidities: a review. Lipids Health Dis 2021; 20:87. [PMID: 34372872 PMCID: PMC8353790 DOI: 10.1186/s12944-021-01510-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 07/20/2021] [Indexed: 02/08/2023] Open
Abstract
Psoriasis is a chronic, immune-mediated inflammatory skin disease characterized by abnormal T cell activation and excessive proliferation of keratinocytes. In addition to skin manifestations, psoriasis has been associated with multiple metabolic comorbidities, such as obesity, insulin resistance, and diabetes. An increasing amount of evidence has highlighted the core role of adipokines in adipose tissue and the immune system. This review focus on the role of adiponectin in the pathophysiology of psoriasis and its comorbidities, highlighting the future research avenues.
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Affiliation(s)
- Bai Ruiyang
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Adriana Panayi
- Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, 75 Francis St., Boston, MA, 02115, USA
| | - Wu Ruifang
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Zhang Peng
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
| | - Fu Siqi
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
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16
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Li X, Ma Z, Zhu YZ. Regional Heterogeneity of Perivascular Adipose Tissue: Morphology, Origin, and Secretome. Front Pharmacol 2021; 12:697720. [PMID: 34239444 PMCID: PMC8259882 DOI: 10.3389/fphar.2021.697720] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 06/10/2021] [Indexed: 12/11/2022] Open
Abstract
Perivascular adipose tissue (PVAT) is a unique fat depot with local and systemic impacts. PVATs are anatomically, developmentally, and functionally different from classical adipose tissues and they are also different from each other. PVAT adipocytes originate from different progenitors and precursors. They can produce and secrete a wide range of autocrine and paracrine factors, many of which are vasoactive modulators. In the context of obesity-associated low-grade inflammation, these phenotypic and functional differences become more evident. In this review, we focus on the recent findings of PVAT’s heterogeneity by comparing commonly studied adipose tissues around the thoracic aorta (tPVAT), abdominal aorta (aPVAT), and mesenteric artery (mPVAT). Distinct origins and developmental trajectory of PVAT adipocyte potentially contribute to regional heterogeneity. Regional differences also exist in ways how PVAT communicates with its neighboring vasculature by producing specific adipokines, vascular tone regulators, and extracellular vesicles in a given microenvironment. These insights may inspire new therapeutic strategies targeting the PVAT.
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Affiliation(s)
- Xinzhi Li
- School of Pharmacy and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Zhongyuan Ma
- Department of Cardiothoracic Surgery, Zhuhai People's Hospital, Jinan University Medical School, Guangzhou, China
| | - Yi Zhun Zhu
- School of Pharmacy and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
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17
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Rodríguez C, Muñoz M, Contreras C, Prieto D. AMPK, metabolism, and vascular function. FEBS J 2021; 288:3746-3771. [PMID: 33825330 DOI: 10.1111/febs.15863] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 03/04/2021] [Accepted: 04/04/2021] [Indexed: 12/12/2022]
Abstract
Adenosine monophosphate-activated protein kinase (AMPK) is a cellular energy sensor activated during energy stress that plays a key role in maintaining energy homeostasis. This ubiquitous signaling pathway has been implicated in multiple functions including mitochondrial biogenesis, redox regulation, cell growth and proliferation, cell autophagy and inflammation. The protective role of AMPK in cardiovascular function and the involvement of dysfunctional AMPK in the pathogenesis of cardiovascular disease have been highlighted in recent years. In this review, we summarize and discuss the role of AMPK in the regulation of blood flow in response to metabolic demand and the basis of the AMPK physiological anticontractile, antioxidant, anti-inflammatory, and antiatherogenic actions in the vascular system. Investigations by others and us have demonstrated the key role of vascular AMPK in the regulation of endothelial function, redox homeostasis, and inflammation, in addition to its protective role in the hypoxia and ischemia/reperfusion injury. The pathophysiological implications of AMPK involvement in vascular function with regard to the vascular complications of metabolic disease and the therapeutic potential of AMPK activators are also discussed.
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Affiliation(s)
- Claudia Rodríguez
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain
| | - Mercedes Muñoz
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain
| | - Cristina Contreras
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain
| | - Dolores Prieto
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain
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18
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Liu Y, Sun Y, Hu C, Liu J, Gao A, Han H, Chai M, Zhang J, Zhou Y, Zhao Y. Perivascular Adipose Tissue as an Indication, Contributor to, and Therapeutic Target for Atherosclerosis. Front Physiol 2020; 11:615503. [PMID: 33391033 PMCID: PMC7775482 DOI: 10.3389/fphys.2020.615503] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 11/30/2020] [Indexed: 12/15/2022] Open
Abstract
Perivascular adipose tissue (PVAT) has been identified to have significant endocrine and paracrine functions, such as releasing bioactive adipokines, cytokines, and chemokines, rather than a non-physiological structural tissue. Considering the contiguity with the vascular wall, PVAT could play a crucial role in the pathogenic microenvironment of atherosclerosis. Growing clinical evidence has shown an association between PVAT and atherosclerosis. Moreover, based on computed tomography, the fat attenuation index of PVAT was verified as an indication of vulnerable atherosclerotic plaques. Under pathological conditions, such as obesity and diabetes, PVAT shows a proatherogenic phenotype by increasing the release of factors that induce endothelial dysfunction and inflammatory cell infiltration, thus contributing to atherosclerosis. Growing animal and human studies have investigated the mechanism of the above process, which has yet to be fully elucidated. Furthermore, traditional treatments for atherosclerosis have been proven to act on PVAT, and we found several studies focused on novel drugs that target PVAT for the prevention of atherosclerosis. Emerging as an indication, contributor to, and therapeutic target for atherosclerosis, PVAT warrants further investigation.
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Affiliation(s)
- Yan Liu
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
| | - Yan Sun
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
| | - Chengping Hu
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
| | - Jinxing Liu
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
| | - Ang Gao
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
| | - Hongya Han
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
| | - Meng Chai
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
| | - Jianwei Zhang
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
| | - Yujie Zhou
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
| | - Yingxin Zhao
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
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19
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Zhang F, Feng J, Zhang J, Kang X, Qian D. Quercetin modulates AMPK/SIRT1/NF-κB signaling to inhibit inflammatory/oxidative stress responses in diabetic high fat diet-induced atherosclerosis in the rat carotid artery. Exp Ther Med 2020; 20:280. [PMID: 33200005 DOI: 10.3892/etm.2020.9410] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 07/14/2020] [Indexed: 12/21/2022] Open
Abstract
Inflammation and oxidative stress serve interrelated roles in the development of atherosclerosis and other vascular diseases. Quercetin has been previously reported to exhibit numerous beneficial properties towards several metabolic conditions and cardiovascular disease. The present study aimed to evaluate the effects of quercetin on the 5'adenosine monophosphate-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/NF-κB signaling pathway and inflammatory/oxidative stress response in diabetic-induced atherosclerosis in the carotid artery of rats. Male Wistar rats were used to create a diabetes-induced atherosclerosis model by the administration of high fat diet (HFD) with streptozotocin, which lasted for 8 weeks. Control and diabetic rats received quercetin (30 mg/kg/day; orally) for the last 2 weeks of the diabetic period. Plasma lipid profile and vascular levels of oxidative stress markers, inflammatory cytokines, NF-κB signaling proteins and SIRT1 expression were evaluated using ELISA and western blotting. Quercetin treatment in HFD diabetic rats was reported to improve the lipid profile and reduce the number of atherosclerotic lesions, atherogenic index and malondialdehyde levels, whilst increasing the activity of enzymatic antioxidants in the carotid artery. Additionally, the inflammatory response was suppressed by quercetin administration, as indicated by the reduced NF-κB and IL-1β levels, and increased IL-10 levels. Furthermore, SIRT1 expression was revealed to be significantly increased in response to quercetin treatment compared with non-treated HFD rats. However, these effects of quercetin were abolished or reversed by the administration of compound-C (0.2 mg/kg), a specific AMPK blocker, in HFD rats. Therefore, quercetin may have promising potential in ameliorating atherosclerotic pathophysiology in the rat carotid artery by inhibiting oxidative stress and inflammatory responses mechanistically by modulating the AMPK/SIRT1/NF-κB signaling pathway.
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Affiliation(s)
- Fengwei Zhang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Jia Feng
- Department of Endocrinology, Ninth Hospital of Xi'an, Xi'an, Shaanxi 710054, P.R. China
| | - Jingyu Zhang
- Department of Gastroenterology, Tangdu Hospital, Air Force Military Medical University, Xi'an, Shaanxi 710082, P.R. China
| | - Xin Kang
- Department of Endocrinology, Xi'an International Medical Center Hospital, Xi'an, Shaanxi 710100, P.R. China
| | - Dun Qian
- Department of Cardiology, Xi'an Lintong Development Zone Boren Hospital, Xi'an, Shaanxi 710600, P.R. China
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20
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Palla G, Ramírez-Morán C, Montt-Guevara MM, Salazar-Pousada D, Shortrede J, Simoncini T, Grijalva-Grijalva I, Pérez-López FR, Chedraui P. Perimenopause, body fat, metabolism and menopausal symptoms in relation to serum markers of adiposity, inflammation and digestive metabolism. J Endocrinol Invest 2020; 43:809-820. [PMID: 31925754 DOI: 10.1007/s40618-019-01168-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 12/19/2019] [Indexed: 01/22/2023]
Abstract
BACKGROUND Perimenopausal women gain weight that may alter inflammatory status, endocrine equilibrium, and the intensity of vasomotor symptoms. OBJECTIVE To measure serum levels of markers related to adiposity, inflammation/angiogenesis and digestive metabolism and correlate them with body mass index (BMI), waist-to-hip ratio (WHR), metabolic parameters and menopausal symptoms (assessed with the 10-item Cervantes Scale [CS-10]). METHODS Serum of perimenopausal women (n = 24), STRAW stages-2 and -1, was analyzed using the Bio-Plex 200 System technology to assess 30 proposed analytes. The MetS was defined by the American Heart Association criteria and women were divided as: normal BMI (NBMI), excessive BMI (EBMI), and EBMI with MetS (EBMI-MetS). RESULTS Weight, BMI, abdominal circumference, WHR, systolic blood pressure, glucose and triglyceride levels were significantly higher and high-density lipoprotein cholesterol (HDL-C) was lower in EBMI-MetS women compared to NBMI ones. Insulin, C-peptide, resistin, adipsin, GIP, leptin, IL-6, FGF21 and PAI-1 levels were significantly higher and ghrelin and IGFBP-1 lower in EBMI-MetS women as compared to NBMI ones. Spearman's correlation of pooled data showed a significant positive correlation between abdominal perimeter and WHR and C-peptide, insulin, adipsin, resistin, leptin, PAI-1 and FGF21 and a negative correlation with IGFBP-1 levels. Total CS-10 scores and hot flush intensity did not differ between studied groups, yet positively correlated with anthropometric values but not with studied analytes. CONCLUSION Perimenopausal women with EBMI and the MetS showed an altered metabolic profile, but no differences in menopausal symptoms which also did not correlate with changes in studied biomarkers.
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Affiliation(s)
- G Palla
- Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - C Ramírez-Morán
- Instituto de Investigación e Innovación en Salud Integral, Facultad de Ciencias Médicas, Universidad Católica de Santiago de Guayaquil, Guayaquil, Ecuador
| | - M M Montt-Guevara
- Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - D Salazar-Pousada
- Instituto de Investigación e Innovación en Salud Integral, Facultad de Ciencias Médicas, Universidad Católica de Santiago de Guayaquil, Guayaquil, Ecuador
| | - J Shortrede
- Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - T Simoncini
- Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - I Grijalva-Grijalva
- Instituto de Investigación e Innovación en Salud Integral, Facultad de Ciencias Médicas, Universidad Católica de Santiago de Guayaquil, Guayaquil, Ecuador
| | - F R Pérez-López
- Red de Investigación de Obstetricia, Ginecología y Reproducción, Instituto de Investigaciones Sanitarias de Aragón, University of Zaragoza, Faculty of Medicine, Zaragoza, Spain
| | - P Chedraui
- Instituto de Investigación e Innovación en Salud Integral, Facultad de Ciencias Médicas, Universidad Católica de Santiago de Guayaquil, Guayaquil, Ecuador.
- Facultad de Ciencias de la Salud, Universidad Católica "Nuestra Señora de la Asunción", Asunción, Paraguay.
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21
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Moustafa Ahmed Y, Shehata Messiha BA, El-Sayed El-Daly M, Abo-Saif AA. Effects of ticagrelor, empagliflozin and tamoxifen against experimentally-induced vascular reactivity defects in rats in vivo and in vitro. Pharmacol Rep 2019; 71:1034-1043. [PMID: 31600634 DOI: 10.1016/j.pharep.2019.06.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 05/19/2019] [Accepted: 06/05/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND In the current investigation, the effects of the P2Y12 blocker ticagrelor, the sodium/glucose transporter-2-inhibitor empagliflozin, and the selective estrogen receptor modulator tamoxifen were examined against rheumatoid arthritis (RA)/diabetes mellitus (DM)-co-morbidity-induced defects in vascular reactivity. METHODS After model setting, rats were allocated into a normal control, an RA/DM-co-morbidity, and three treatment groups receiving ticagrelor, empagliflozin and tamoxifen. Aorta tissue was isolated for enzyme-linked immunosorbent assay (ELISA) and western blot estimation of the pro-inflammatory molecules angiotensin-II (Ang-II) and endothelin-1 (ET-1), the adhesion molecules P-selectin and vascular cell adhesion molecule-1 (VCAM-1), the energy preserving molecule adenosine-5'-monophosphate-activated protein kinase (AMPK), and the anti-inflammatory molecule vasoactive intestinal peptide (VIP). Estimations of endothelial nitric oxide synthase (eNOS) and matrix metalloproteinase (MMP)-2 were performed immunohistochemically, together with histopathological examination using hematoxylin and eosin and Masson trichrome staining. An in vitro study on rat aortic strips was conducted to assess aorta vasorelaxation. RESULTS Ticagrelor, empagliflozin and tamoxifen significantly increased aorta tissue AMPK and eNOS and decreased Ang-II, ET-1, P-selectin, VCAM-1 and VIP levels compared with RA/DM-co-morbidity, coupled with improved acetylcholine vasorelaxation in vitro. CONCLUSION Ticagrelor, empagliflozin and tamoxifen may correct vascular reactivity defects, where modulation of vascular AMPK, eNOS, Ang-II, ET-1, P-selectin, VCAM-1 and MMP-2 underline their protective effects.
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Affiliation(s)
- Yasmin Moustafa Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt
| | | | | | - Ali Ahmed Abo-Saif
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt
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22
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Han F, Hou N, Liu Y, Huang N, Pan R, Zhang X, Mao E, Sun X. Liraglutide improves vascular dysfunction by regulating a cAMP-independent PKA-AMPK pathway in perivascular adipose tissue in obese mice. Biomed Pharmacother 2019; 120:109537. [PMID: 31605951 DOI: 10.1016/j.biopha.2019.109537] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 10/01/2019] [Accepted: 10/02/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Perivascular adipose tissue (PVAT) attenuates its anti-contractile effect through an endothelial-dependent mechanism that aggravates endothelial dysfunction in obesity. The present study was conducted to explore whether liraglutide could improve vascular dysfunction, including the anti-contractile effect of PVAT and endothelial function, by modulating PVAT-related signaling pathways in obesity. METHODS C57BL/6 mice were fed a normal-chow diet or a high-fat diet (HFD) with or without liraglutide treatment. Vascular function of the thoracic aorta with or without PVAT were measured. Protein levels of components of the PKA-AMPK-PGC1α and antioxidant signaling pathway in PVAT were determined by western blotting. Brown adipose tissue-related gene in PVAT was measured by qRT-PCR. RESULTS Metabolic profiles of HFD-fed mice were improved after treatment with liraglutide. Liraglutide improved PVAT-induced anti-contractile capability and PVAT-induced endothelial dysfunction in HFD-fed mice both in vivo and ex vivo. However, blocking PKA, or AMPK, but not cAMP, attenuated these beneficial effects of liraglutide. Treating HFD-fed mice with liraglutide activated the AMPK/eNOS pathway and induced browning-related gene expression. Moreover, liraglutide increased antioxidant capability. The protective effects were related to activation of a cAMP-independent PKA-AMPK pathway, as demonstrated by western blot and PCR. CONCLUSIONS Liraglutide improved vascular dysfunction by modulating a cAMP-independent PKA-AMPK pathway in PVAT in HFD-induced obese mice. The findings provide a novel mechanism for the cardiovascular protection of liraglutide by modulating PVAT function in obesity.
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Affiliation(s)
- Fang Han
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Ningning Hou
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Yongping Liu
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Na Huang
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Ruiyan Pan
- Department of Pharmacology, Weifang Medical University, Weifang, China
| | - Xing Zhang
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, China
| | - Enwen Mao
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Xiaodong Sun
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China.
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23
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Chen H, Vanhoutte PM, Leung SWS. Vascular adenosine monophosphate-activated protein kinase: Enhancer, brake or both? Basic Clin Pharmacol Toxicol 2019; 127:81-91. [PMID: 31671245 DOI: 10.1111/bcpt.13357] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 10/24/2019] [Indexed: 12/25/2022]
Abstract
Adenosine monophosphate-activated protein kinase (AMPK), expressed/present ubiquitously in the body, contributes to metabolic regulation. In the vasculature, activation of AMPK is associated with several beneficial biological effects including enhancement of vasodilatation, reduction of oxidative stress and inhibition of inflammatory reactions. The vascular protective effects of certain anti-diabetic (metformin and sitagliptin) or lipid-lowering (simvastatin and fenofibrate) therapeutic agents, of active components of Chinese medicinal herbs (resveratrol and berberine) and of pharmacological agents (AICAR, A769662 and PT1) have been attributed to the activation of AMPK (in endothelial cells, vascular smooth muscle cells and/or perivascular adipocytes), independently of changes in the metabolic profile (eg glucose tolerance and/or plasma lipoprotein levels), leading to improved endothelium-derived nitric oxide-mediated vasodilatation and attenuated endothelium-derived cyclooxygenase-dependent vasoconstriction. By contrast, endothelial AMPK activation with pharmacological agents or by genetic modification is associated with reduced endothelium-dependent relaxations in small blood vessels and elevated systolic blood pressure. Indeed, AMPK activators inhibit endothelium-dependent hyperpolarization (EDH)-type relaxations in superior mesenteric arteries, partly by inhibiting endothelial calcium-activated potassium channel signalling. Therefore, AMPK activation is not necessarily beneficial in terms of endothelial function. The contribution of endothelial AMPK in the regulation of vascular tone, in particular in the microvasculature where EDH plays a more important role, remains to be characterized.
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Affiliation(s)
- Hui Chen
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
| | - Paul Michel Vanhoutte
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.,State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Cardiovascular and Renal Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Susan Wai Sum Leung
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
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24
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Son M, Oh S, Lee HS, Chung DM, Jang JT, Jeon YJ, Choi CH, Park KY, Son KH, Byun K. Ecklonia Cava Extract Attenuates Endothelial Cell Dysfunction by Modulation of Inflammation and Brown Adipocyte Function in Perivascular Fat Tissue. Nutrients 2019; 11:E2795. [PMID: 31731817 PMCID: PMC6893767 DOI: 10.3390/nu11112795] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 11/12/2019] [Accepted: 11/13/2019] [Indexed: 12/19/2022] Open
Abstract
It is well known that perivascular fat tissue (PVAT) dysfunction can induce endothelial cell (EC) dysfunction, an event which is related with various cardiovascular diseases. In this study, we evaluated whether Ecklonia cava extract (ECE) and pyrogallol-phloroglucinol-6,6-bieckol (PPB), one component of ECE, could attenuate EC dysfunction by modulating diet-induced PVAT dysfunction mediated by inflammation and ER stress. A high fat diet (HFD) led to an increase in the number and size of white adipocytes in PVAT; PPB and ECE attenuated those increases. Additionally, ECE and PPB attenuated: (i) an increase in the number of M1 macrophages and the expression level of monocyte chemoattractant protein-1 (MCP-1), both of which are related to increases in macrophage infiltration and induction of inflammation in PVAT, and (ii) the expression of pro-inflammatory cytokines (e.g., tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, chemerin) in PVAT which led to vasoconstriction. Furthermore, ECE and PPB: (i) enhanced the expression of adiponectin and IL-10 which had anti-inflammatory and vasodilator effects, (ii) decreased HFD-induced endoplasmic reticulum (ER) stress and (iii) attenuated the ER stress mediated reduction in sirtuin type 1 (Sirt1) and peroxisome proliferator-activated receptor γ (PPARγ) expression. Protective effects against decreased Sirt1 and PPARγ expression led to the restoration of uncoupling protein -1 (UCP-1) expression and the browning process in PVAT. PPB or ECE attenuated endothelial dysfunction by enhancing the pAMPK-PI3K-peNOS pathway and reducing the expression of endothelin-1 (ET-1). In conclusion, PPB and ECE attenuated PVAT dysfunction and subsequent endothelial dysfunction by: (i) decreasing inflammation and ER stress, and (ii) modulating brown adipocyte function.
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Affiliation(s)
- Myeongjoo Son
- Department of Anatomy & Cell Biology, Gachon University College of Medicine, Incheon 21936, Korea;
- Functional Cellular Networks Laboratory, College of Medicine, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea; (S.O.); (H.S.L.)
| | - Seyeon Oh
- Functional Cellular Networks Laboratory, College of Medicine, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea; (S.O.); (H.S.L.)
| | - Hye Sun Lee
- Functional Cellular Networks Laboratory, College of Medicine, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea; (S.O.); (H.S.L.)
| | - Dong-Min Chung
- Shinwoo cooperation. Ltd. 991, Worasan-ro, Munsan-eup, Jinju, Gyeongsangnam-do 52839, Korea;
| | - Ji Tae Jang
- Aqua Green Technology Co., Ltd., Smart Bldg., Jeju Science Park, Cheomdan-ro, Jeju 63309, Korea;
| | - You-Jin Jeon
- Department of Marine Life Science, Jeju National University, Jeju 63243, Korea;
| | - Chang Hu Choi
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Korea; (C.H.C.); (K.Y.P.)
| | - Kook Yang Park
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Korea; (C.H.C.); (K.Y.P.)
| | - Kuk Hui Son
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Korea; (C.H.C.); (K.Y.P.)
| | - Kyunghee Byun
- Department of Anatomy & Cell Biology, Gachon University College of Medicine, Incheon 21936, Korea;
- Functional Cellular Networks Laboratory, College of Medicine, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea; (S.O.); (H.S.L.)
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25
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Fantin F, Giani A, Zoico E, Rossi AP, Mazzali G, Zamboni M. Weight Loss and Hypertension in Obese Subjects. Nutrients 2019; 11:E1667. [PMID: 31330870 PMCID: PMC6682923 DOI: 10.3390/nu11071667] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 07/15/2019] [Accepted: 07/16/2019] [Indexed: 02/07/2023] Open
Abstract
Arterial hypertension is strongly related to overweight and obesity. In obese subjects, several mechanisms may lead to hypertension such as insulin and leptin resistance, perivascular adipose tissue dysfunction, renal impairment, renin-angiotensin-aldosterone-system activation and sympathetic nervous system activity. Weight loss (WL) seems to have positive effects on blood pressure (BP). The aim of this review was to explain the mechanisms linking obesity and hypertension and to evaluate the main studies assessing the effect of WL on BP. We analysed studies published in the last 10 years (13 studies either interventional or observational) showing the effect of WL on BP. Different WL strategies were taken into account-diet and lifestyle modification, pharmacological intervention and bariatric surgery. Although a positive effect of WL could be identified in each study, the main difference seems to be the magnitude and the durability of BP reduction over time. Nevertheless, further follow-up data are needed: there is still a lack of evidence about long term effects of WL on hypertension. Hence, given the significant results obtained in several recent studies, weight management should always be pursued in obese patients with hypertension.
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Affiliation(s)
- Francesco Fantin
- Department of Medicine, Section of Geriatrics, University of Verona Healthy Aging Center, Verona, Piazzale Stefani 1, 37126 Verona, Italy.
| | - Anna Giani
- Department of Medicine, Section of Geriatrics, University of Verona Healthy Aging Center, Verona, Piazzale Stefani 1, 37126 Verona, Italy
| | - Elena Zoico
- Department of Medicine, Section of Geriatrics, University of Verona Healthy Aging Center, Verona, Piazzale Stefani 1, 37126 Verona, Italy
| | - Andrea P Rossi
- Department of Medicine, Section of Geriatrics, University of Verona Healthy Aging Center, Verona, Piazzale Stefani 1, 37126 Verona, Italy
| | - Gloria Mazzali
- Department of Medicine, Section of Geriatrics, University of Verona Healthy Aging Center, Verona, Piazzale Stefani 1, 37126 Verona, Italy
| | - Mauro Zamboni
- Department of Medicine, Section of Geriatrics, University of Verona Healthy Aging Center, Verona, Piazzale Stefani 1, 37126 Verona, Italy
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26
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Zhang J, Deng B, Jiang X, Cai M, Liu N, Zhang S, Tan Y, Huang G, Jin W, Liu B, Liu S. All- Trans-Retinoic Acid Suppresses Neointimal Hyperplasia and Inhibits Vascular Smooth Muscle Cell Proliferation and Migration via Activation of AMPK Signaling Pathway. Front Pharmacol 2019; 10:485. [PMID: 31143119 PMCID: PMC6521230 DOI: 10.3389/fphar.2019.00485] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 04/17/2019] [Indexed: 12/17/2022] Open
Abstract
The proliferation and migration of vascular smooth muscle cells (VSMC) is extensively involved in pathogenesis of neointimal hyperplasia. All-trans-retinoic acid (ATRA) is a natural metabolite of vitamin A. Here, we investigated the involvement of AMP-activated protein kinase (AMPK) in the anti-neointimal hyperplasia effects of ATRA. We found that treatment with ATRA significantly reduced neointimal hyperplasia in the left common carotid artery ligation mouse model. ATRA reduced the proliferation and migration of VSMC, A7r5 and HASMC cell lines. Our results also demonstrated that ATRA altered the expression of proliferation-related proteins, including CyclinD1, CyclinD3, CyclinA2, CDK2, CDK4, and CDK6 in VSMC. ATRA dose-dependently enhanced the phosphorylation level of AMPKα (Thr172) in the left common carotid artery of experimental mice. Also, the phosphorylation level of AMPKα in A7r5 and HASMC was significantly increased. In addition, ATRA dose-dependently reduced the phosphorylation levels of mTOR and mTOR target proteins p70 S6 kinase (p70S6K) and 4E-binding protein 1 (4EBP1) in A7r5 and HASMC. Notably, the inhibition of AMPKα by AMPK inhibitor (compound C) negated the protective effect of ATRA on VSMC proliferation in A7r5. Also, knockdown of AMPKα by siRNA partly abolished the anti-proliferative and anti-migratory effects of ATRA in HASMC. Molecular docking analysis showed that ATRA could dock to the agonist binding site of AMPK, and the binding energy between AMPK and ATRA was -7.91 kcal/mol. Molecular dynamics simulations showed that the binding of AMPK-ATRA was stable. These data demonstrated that ATRA might inhibit neointimal hyperplasia and suppress VSMC proliferation and migration by direct activation of AMPK and inhibition of mTOR signaling.
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Affiliation(s)
- Jingzhi Zhang
- Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Bo Deng
- Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaoli Jiang
- Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Min Cai
- Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ningning Liu
- Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shuangwei Zhang
- Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yongzhen Tan
- Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Guiqiong Huang
- Department of Internal Medicine, Huizhou Hospital of Traditional Chinese Medicine, Huizhou, China
| | - Wen Jin
- Department of Cardiology, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Bin Liu
- Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shiming Liu
- Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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27
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Abstract
Perivascular adipose tissue (PVAT) refers to the local aggregate of adipose tissue surrounding the vascular tree, exhibiting phenotypes from white to brown and beige adipocytes. Although PVAT has long been regarded as simply a structural unit providing mechanical support to vasculature, it is now gaining reputation as an integral endocrine/paracrine component, in addition to the well-established modulator endothelium, in regulating vascular tone. Since the discovery of anti-contractile effect of PVAT in 1991, the use of multiple rodent models of reduced amounts of PVAT has revealed its regulatory role in vascular remodeling and cardiovascular implications, including atherosclerosis. PVAT does not only release PVAT-derived relaxing factors (PVRFs) to activate multiple subsets of endothelial and vascular smooth muscle potassium channels and anti-inflammatory signals in the vasculature, but it does also provide an interface for neuron-adipocyte interactions in the vascular wall to regulate arterial vascular tone. In this review, we outline our current understanding towards PVAT and attempt to provide hints about future studies that can sharpen the therapeutic potential of PVAT against cardiovascular diseases and their complications.
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Affiliation(s)
- Chak Kwong Cheng
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, SAR, China
- Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Hamidah Abu Bakar
- Health Sciences Department, Universiti Selangor, 40000, Shah Alam, Selangor, Malaysia
| | - Maik Gollasch
- Experimental and Clinical Research Center (ECRC)-a joint cooperation between the Charité-University Medicine Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125, Berlin, Germany.
- Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany.
| | - Yu Huang
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, SAR, China.
- Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, SAR, China.
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28
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Schneider MK, Xue B, Shi H. Activation of the sympathetic nervous system suppresses mouse white adipose tissue hyperplasia through the β1 adrenergic receptor. Physiol Rep 2019; 6:e13645. [PMID: 29611347 PMCID: PMC5880815 DOI: 10.14814/phy2.13645] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 02/11/2018] [Accepted: 02/12/2018] [Indexed: 12/13/2022] Open
Abstract
Adipose tissue (AT) expands via both hypertrophy and hyperplasia during the development of obesity. While AT hypertrophy involves the increase in size of existing adipocytes, hyperplasia is the process of creating new adipocytes from the pool of adipocyte precursor cells (APCs), which includes adipocyte progenitor cells and preadipocytes. Prior studies have implicated a role of the sympathetic nervous system (SNS) in regulation of hyperplasia in white adipose tissue (WAT). Here, we aimed to determine the mechanisms underlying SNS regulation of APC proliferation in mouse WAT. Using flow cytometry with antibodies against various cell surface markers, along with an intracellular marker of proliferation (Ki67), we quantitated the percentages and proliferative status of adipocyte progenitor cells and preadipocytes in the stromal vascular fraction (SVF) of WAT. In vivo SNS activation through cold exposure, as well as in vitro adrenergic stimulation via exposure to the canonical SNS neurotransmitter norepinephrine (NE), inhibited preadipocyte proliferation. Pretreatment with propranolol, a β1‐ and β2‐adrenergic receptor (AR) antagonist, trended toward rescuing the inhibitory effects of NE in primary cell culture. The selective β1‐AR agonist dobutamine diminished preadipocyte proliferation both in vivo and in vitro, whereas the selective β2‐AR agonist, salbutamol, promoted proliferation in vitro, suggesting that the β1‐AR may mediate the inhibitory effect of NE on preadipocyte proliferation. Taken together, we conclude that SNS activation suppresses preadipocyte proliferation via activation of the β1 AR in WAT.
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Affiliation(s)
- Mary K Schneider
- Department of Biology and Center for Obesity Reversal, Georgia State University, Atlanta, Georgia
| | - Bingzhong Xue
- Department of Biology and Center for Obesity Reversal, Georgia State University, Atlanta, Georgia
| | - Hang Shi
- Department of Biology and Center for Obesity Reversal, Georgia State University, Atlanta, Georgia
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29
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Ye M, Ruan CC, Fu M, Xu L, Chen D, Zhu M, Zhu D, Gao P. Developmental and functional characteristics of the thoracic aorta perivascular adipocyte. Cell Mol Life Sci 2019; 76:777-789. [PMID: 30448891 PMCID: PMC11105183 DOI: 10.1007/s00018-018-2970-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 11/01/2018] [Accepted: 11/13/2018] [Indexed: 12/21/2022]
Abstract
Thoracic aorta perivascular adipose tissue (T-PVAT) has critical roles in regulating vascular homeostasis. However, the developmental characteristics and cellular lineage of adipocyte in the T-PVAT remain unclear. We show that T-PVAT contains three long strip-shaped fat depots, anterior T-PVAT (A-T-PVAT), left lateral T-PVAT (LL-T-PVAT), and right lateral T-PVAT (RL-T-PVAT). A-T-PVAT displays a distinct transcriptional profile and developmental origin compared to the two lateral T-PVATs (L-T-PVAT). Lineage tracing studies indicate that A-T-PVAT adipocytes are primarily derived from SM22α+ progenitors, whereas L-T-PVAT contains both SM22α+ and Myf5+ cells. We also show that L-T-PVAT contains more UCP1+ brown adipocytes than A-T-PVAT, and L-T-PVAT exerts a greater relaxing effect on aorta than A-T-PVAT. Angiotensin II-infused hypertensive mice display greater macrophage infiltration into A-T-PVAT than L-T-PVAT. These combined results indicate that L-T-PVAT has a distinct development from A-T-PVAT with different cellular lineage, and suggest that L-T-PVAT and A-T-PVAT have different physiological and pathological functions.
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Affiliation(s)
- Maoqing Ye
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Cheng-Chao Ruan
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
| | - Mengxia Fu
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lian Xu
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dongrui Chen
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Minsheng Zhu
- State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing, China
| | - Dingliang Zhu
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Pingjin Gao
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
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30
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Yuan T, Yang T, Chen H, Fu D, Hu Y, Wang J, Yuan Q, Yu H, Xu W, Xie X. New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis. Redox Biol 2019; 20:247-260. [PMID: 30384259 PMCID: PMC6205410 DOI: 10.1016/j.redox.2018.09.025] [Citation(s) in RCA: 431] [Impact Index Per Article: 71.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 09/12/2018] [Accepted: 09/29/2018] [Indexed: 02/06/2023] Open
Abstract
Oxidative stress and inflammation interact in the development of diabetic atherosclerosis. Intracellular hyperglycemia promotes production of mitochondrial reactive oxygen species (ROS), increased formation of intracellular advanced glycation end-products, activation of protein kinase C, and increased polyol pathway flux. ROS directly increase the expression of inflammatory and adhesion factors, formation of oxidized-low density lipoprotein, and insulin resistance. They activate the ubiquitin pathway, inhibit the activation of AMP-protein kinase and adiponectin, decrease endothelial nitric oxide synthase activity, all of which accelerate atherosclerosis. Changes in the composition of the gut microbiota and changes in microRNA expression that influence the regulation of target genes that occur in diabetes interact with increased ROS and inflammation to promote atherosclerosis. This review highlights the consequences of the sustained increase of ROS production and inflammation that influence the acceleration of atherosclerosis by diabetes. The potential contributions of changes in the gut microbiota and microRNA expression are discussed.
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Affiliation(s)
- Ting Yuan
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan Province 646000, China
| | - Ting Yang
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan Province 646000, China
| | - Huan Chen
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan Province 646000, China.
| | - Danli Fu
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan Province 646000, China
| | - Yangyang Hu
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan Province 646000, China
| | - Jing Wang
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan Province 646000, China
| | - Qing Yuan
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan Province 646000, China
| | - Hong Yu
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan Province 646000, China
| | - Wenfeng Xu
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan Province 646000, China
| | - Xiang Xie
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan Province 646000, China.
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31
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Sena CM, Leandro A, Azul L, Seiça R, Perry G. Vascular Oxidative Stress: Impact and Therapeutic Approaches. Front Physiol 2018; 9:1668. [PMID: 30564132 PMCID: PMC6288353 DOI: 10.3389/fphys.2018.01668] [Citation(s) in RCA: 147] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 11/06/2018] [Indexed: 12/13/2022] Open
Abstract
Oxidative stress has been defined as an imbalance between oxidants and antioxidants and more recently as a disruption of redox signaling and control. It is generally accepted that oxidative stress can lead to cell and tissue injury having a fundamental role in vascular dysfunction. Physiologically, reactive oxygen species (ROS) control vascular function by modulating various redox-sensitive signaling pathways. In vascular disorders, oxidative stress instigates endothelial dysfunction and inflammation, affecting several cells in the vascular wall. Vascular ROS are derived from multiple sources herein discussed, which are prime targets for therapeutic development. This review focuses on oxidative stress in vascular physiopathology and highlights different strategies to inhibit ROS production.
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Affiliation(s)
- Cristina M. Sena
- Institute of Physiology, Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Adriana Leandro
- Institute of Physiology, Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Lara Azul
- Institute of Physiology, Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Raquel Seiça
- Institute of Physiology, Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - George Perry
- College of Sciences, One UTSA Circle, University of Texas at San Antonio, San Antonio, TX, United States
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Qi XY, Qu SL, Xiong WH, Rom O, Chang L, Jiang ZS. Perivascular adipose tissue (PVAT) in atherosclerosis: a double-edged sword. Cardiovasc Diabetol 2018; 17:134. [PMID: 30305178 PMCID: PMC6180425 DOI: 10.1186/s12933-018-0777-x] [Citation(s) in RCA: 126] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 10/06/2018] [Indexed: 02/06/2023] Open
Abstract
Perivascular adipose tissue (PVAT), the adipose tissue that surrounds most of the vasculature, has emerged as an active component of the blood vessel wall regulating vascular homeostasis and affecting the pathogenesis of atherosclerosis. Although PVAT characteristics resemble both brown and white adipose tissues, recent evidence suggests that PVAT develops from its own distinct precursors implying a closer link between PVAT and vascular system. Under physiological conditions, PVAT has potent anti-atherogenic properties mediated by its ability to secrete various biologically active factors that induce non-shivering thermogenesis and metabolize fatty acids. In contrast, under pathological conditions (mainly obesity), PVAT becomes dysfunctional, loses its thermogenic capacity and secretes pro-inflammatory adipokines that induce endothelial dysfunction and infiltration of inflammatory cells, promoting atherosclerosis development. Since PVAT plays crucial roles in regulating key steps of atherosclerosis development, it may constitute a novel therapeutic target for the prevention and treatment of atherosclerosis. Here, we review the current literature regarding the roles of PVAT in the pathogenesis of atherosclerosis.
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Affiliation(s)
- Xiao-Yan Qi
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang, 421001 China
| | - Shun-Lin Qu
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang, 421001 China
| | - Wen-Hao Xiong
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang, 421001 China
| | - Oren Rom
- Cardiovascular Research Center, University of Michigan, Ann Arbor, MI USA
| | - Lin Chang
- Cardiovascular Research Center, University of Michigan, Ann Arbor, MI USA
| | - Zhi-Sheng Jiang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang, 421001 China
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Hsieh CT, Chang FR, Tsai YH, Wu YC, Hsieh TJ. 2-Bromo-4'-methoxychalcone and 2-Iodo-4'-methoxychalcone Prevent Progression of Hyperglycemia and Obesity via 5'-Adenosine-Monophosphate-Activated Protein Kinase in Diet-Induced Obese Mice. Int J Mol Sci 2018; 19:ijms19092763. [PMID: 30223438 PMCID: PMC6163633 DOI: 10.3390/ijms19092763] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 09/12/2018] [Accepted: 09/13/2018] [Indexed: 12/26/2022] Open
Abstract
Obesity and diabetes are global health-threatening issues. Interestingly, the mechanism of these pathologies is quite different among individuals. The discovery and development of new categories of medicines from diverse sources are urgently needed for preventing and treating diabetes and other metabolic disorders. Previously, we reported that chalcones are important for preventing biological disorders, such as diabetes. In this study, we demonstrate that the synthetic halogen-containing chalcone derivatives 2-bromo-4′-methoxychalcone (compound 5) and 2-iodo-4′-methoxychalcone (compound 6) can promote glucose consumption and inhibit cellular lipid accumulation via 5′-adenosine-monophosphate-activated protein kinase (AMPK) activation and acetyl-CoA carboxylase 1 (ACC) phosphorylation in 3T3-L1 adipocytes and C2C12 skeletal myotubes. In addition, the two compounds significantly prevented body weight gain and impaired glucose tolerance, hyperinsulinemia, and insulin resistance, which collectively help to delay the progression of hyperglycemia in high-fat-diet-induced obese C57BL/6 mice. These findings indicate that 2-bromo-4′-methoxychalcone and 2-iodo-4′-methoxychalcone could act as AMPK activators, and may serve as lead compounds for a new class of medicines that target obesity and diabetes.
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Affiliation(s)
- Chi-Ting Hsieh
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Fang-Rong Chang
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan.
| | - Yi-Hong Tsai
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Yang-Chang Wu
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Tusty-Jiuan Hsieh
- Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
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Intrauterine exposure to metformin: Evaluation of endothelial and perivascular adipose tissue function in abdominal aorta of adult offspring. Life Sci 2018; 207:72-79. [PMID: 29852188 DOI: 10.1016/j.lfs.2018.05.050] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 05/19/2018] [Accepted: 05/28/2018] [Indexed: 01/08/2023]
Abstract
The biguanide metformin (MET) has been used during pregnancy for treatment of polycystic ovary syndrome and gestational diabetes. MET crosses the placenta and maternal treatment can expose the progeny to this drug during important phases of body development. Direct vascular protective effects have been described with the treatment of metformin. Nevertheless, it is unclear whether intrauterine exposure to metformin is safe for the vascular system of offspring. Thus, the present study aimed to investigate the intrinsic effects of metformin exposure in utero in the offspring abdominal aorta reactivity, in the presence and absence of perivascular adipose tissue (PVAT) and endothelium. For this, Wistar rats were treated with metformin 293 mg/kg/day (MET) or water (CTR) by gavage during the gestational period. The abdominal aorta reactivity to phenylephrine, acetylcholine, and sodium nitroprusside was evaluated in male adult offspring. It was observed that abdominal aorta relaxation was similar between MET and CTR groups in the presence or absence of PVAT. In addition, the contraction to phenylephrine was similar between MET and CTR groups in the presence and absence of PVAT and endothelium. Therefore, metformin exposure during pregnancy had no intrinsic effect on the offspring abdominal aorta PVAT and endothelial function, demonstrating it to be safe to the vascular system of the offspring.
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35
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Ou H, Liu C, Feng W, Xiao X, Tang S, Mo Z. Role of AMPK in atherosclerosis via autophagy regulation. SCIENCE CHINA-LIFE SCIENCES 2018; 61:1212-1221. [PMID: 29656339 DOI: 10.1007/s11427-017-9240-2] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 12/05/2017] [Indexed: 01/12/2023]
Abstract
Atherosclerosis is characterized by the accumulation of lipids and deposition of fibrous elements in the vascular wall, which is the primary cause of cardiovascular diseases. Adenosine monophosphate-activated protein kinase (AMPK) is a metabolic sensor of energy metabolism that regulates multiple physiological processes, including lipid and glucose metabolism and the normalization of energy imbalances. Overwhelming evidence indicates that AMPK activation markedly attenuates atherosclerosis development. Autophagy inhibits cell apoptosis and inflammation and promotes cholesterol efflux and efferocytosis. Physiological autophagy is essential for maintaining normal cardiovascular function. Increasing evidence demonstrates that autophagy occurs in developing atherosclerotic plaques. Emerging evidence indicates that AMPK regulates autophagy via a downstream signaling pathway. The complex relationship between AMPK and autophagy has attracted the attention of many researchers because of this close relationship to atherosclerosis development. This review demonstrates the role of AMPK and autophagy in atherosclerosis. An improved understanding of this interrelationship will create novel preventive and therapeutic strategies for atherosclerosis.
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Affiliation(s)
- Hanxiao Ou
- Clinical Anatomy & Reproductive Medicine Application Institute, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, 421001, China
| | - Chuhao Liu
- Clinical Anatomy & Reproductive Medicine Application Institute, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, 421001, China.,2016 Grade Excellent Doctor Class of Medical School, University of South China, Hengyang, 421001, China
| | - Wenjie Feng
- Clinical Anatomy & Reproductive Medicine Application Institute, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, 421001, China.,2015 Grade Medical Imaging Class of Medical School, University of South China, Hengyang, 421001, China
| | - Xinwen Xiao
- Clinical Anatomy & Reproductive Medicine Application Institute, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, 421001, China.,2015 Grade Medical Imaging Class of Medical School, University of South China, Hengyang, 421001, China
| | - Shengsong Tang
- Clinical Anatomy & Reproductive Medicine Application Institute, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, 421001, China. .,Center for Life Science, Hunan University of Medicine, Huaihua, 418000, China.
| | - Zhongcheng Mo
- Clinical Anatomy & Reproductive Medicine Application Institute, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, 421001, China.
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Almabrouk TAM, White AD, Ugusman AB, Skiba DS, Katwan OJ, Alganga H, Guzik TJ, Touyz RM, Salt IP, Kennedy S. High Fat Diet Attenuates the Anticontractile Activity of Aortic PVAT via a Mechanism Involving AMPK and Reduced Adiponectin Secretion. Front Physiol 2018; 9:51. [PMID: 29479319 PMCID: PMC5812172 DOI: 10.3389/fphys.2018.00051] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 01/16/2018] [Indexed: 01/31/2023] Open
Abstract
Background and aim: Perivascular adipose tissue (PVAT) positively regulates vascular function through production of factors such as adiponectin but this effect is attenuated in obesity. The enzyme AMP-activated protein kinase (AMPK) is present in PVAT and is implicated in mediating the vascular effects of adiponectin. In this study, we investigated the effect of an obesogenic high fat diet (HFD) on aortic PVAT and whether any changes involved AMPK. Methods: Wild type Sv129 (WT) and AMPKα1 knockout (KO) mice aged 8 weeks were fed normal diet (ND) or HFD (42% kcal fat) for 12 weeks. Adiponectin production by PVAT was assessed by ELISA and AMPK expression studied using immunoblotting. Macrophages in PVAT were identified using immunohistochemistry and markers of M1 and M2 macrophage subtypes evaluated using real time-qPCR. Vascular responses were measured in endothelium-denuded aortic rings with or without attached PVAT. Carotid wire injury was performed and PVAT inflammation studied 7 days later. Key results: Aortic PVAT from KO and WT mice was morphologically indistinct but KO PVAT had more infiltrating macrophages. HFD caused an increased infiltration of macrophages in WT mice with increased expression of the M1 macrophage markers Nos2 and Il1b and the M2 marker Chil3. In WT mice, HFD reduced the anticontractile effect of PVAT as well as reducing adiponectin secretion and AMPK phosphorylation. PVAT from KO mice on ND had significantly reduced adiponectin secretion and no anticontractile effect and feeding HFD did not alter this. Wire injury induced macrophage infiltration of PVAT but did not cause further infiltration in KO mice. Conclusions: High-fat diet causes an inflammatory infiltrate, reduced AMPK phosphorylation and attenuates the anticontractile effect of murine aortic PVAT. Mice lacking AMPKα1 phenocopy many of the changes in wild-type aortic PVAT after HFD, suggesting that AMPK may protect the vessel against deleterious changes in response to HFD.
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Affiliation(s)
- Tarek A M Almabrouk
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.,Medical School, University of Zawia, Zawia, Libya
| | - Anna D White
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Azizah B Ugusman
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.,Department of Physiology, National University of Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Dominik S Skiba
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.,Jagiellonian University College of Medicine, Krakow, Poland
| | - Omar J Katwan
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.,Department of Biochemistry, College of Medicine, University of Diyala, Baqubah, Iraq
| | - Husam Alganga
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.,Medical School, University of Zawia, Zawia, Libya
| | - Tomasz J Guzik
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.,Jagiellonian University College of Medicine, Krakow, Poland
| | - Rhian M Touyz
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Ian P Salt
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Simon Kennedy
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
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Guo R, Han M, Song J, Liu J, Sun Y. Adiponectin and its receptors are involved in hypertensive vascular injury. Mol Med Rep 2017; 17:209-215. [PMID: 29115432 PMCID: PMC5780128 DOI: 10.3892/mmr.2017.7878] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 09/07/2017] [Indexed: 01/08/2023] Open
Abstract
Adipocyte-derived adiponectin (APN) is involved in the protection against cardiovascular disease, but the endogenous APN and its receptor expression in the perivascular adipocytes and their role in hypertensive vascular injury remain unclear. The present study aimed to detect endogenous APN and its receptor expression and their protective effects against hypertensive vascular injury. APN was mainly expressed in the perivascular adipocytes, while its receptors AdipoR1 and AdipoR2 were ubiquitously expressed in the blood vessels. Angiotensin II (Ang II)-induced hypertension resulted in a significant decrease of APN and AdipoR1 and AdipoR2 in the perivascular adipocytes and vascular cells. The migration assay used demonstrated that APN attenuated Ang II-induced vascular smooth muscle cells migration and p38 phosphorylation Furthermore, the in vivo study demonstrated that APN receptor agonist AdipoRon attenuated Ang II-induced hypertensive vascular hypertrophy and fibrosis. Taken together, the present study indicated that perivascular adipocytes-derived APN attenuated hypertensive vascular injury possibly via its receptor-mediated inhibition of p38 signaling pathway.
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Affiliation(s)
- Ruimin Guo
- Emergency Medicine, Putuo Hospital Affiliated to Shanghai Traditional Chinese Medicine University, Shanghai 200333, P.R. China
| | - Min Han
- Emergency Medicine, Putuo Hospital Affiliated to Shanghai Traditional Chinese Medicine University, Shanghai 200333, P.R. China
| | - Juan Song
- Emergency Medicine, Putuo Hospital Affiliated to Shanghai Traditional Chinese Medicine University, Shanghai 200333, P.R. China
| | - Jun Liu
- Emergency Medicine, Putuo Hospital Affiliated to Shanghai Traditional Chinese Medicine University, Shanghai 200333, P.R. China
| | - Yanni Sun
- Emergency Medicine, Putuo Hospital Affiliated to Shanghai Traditional Chinese Medicine University, Shanghai 200333, P.R. China
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38
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Zaborska KE, Wareing M, Austin C. Comparisons between perivascular adipose tissue and the endothelium in their modulation of vascular tone. Br J Pharmacol 2017; 174:3388-3397. [PMID: 27747871 PMCID: PMC5610163 DOI: 10.1111/bph.13648] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 09/16/2016] [Accepted: 09/28/2016] [Indexed: 01/06/2023] Open
Abstract
The endothelium is an established modulator of vascular tone; however, the recent discovery of the anti-contractile nature of perivascular adipose tissue (PVAT) suggests that the fat, which surrounds many blood vessels, can also modulate vascular tone. Both the endothelium and PVAT secrete vasoactive substances, which regulate vascular function. Many of these factors are common to both the endothelium and PVAT; therefore, this review will highlight the potential shared mechanisms in the modulation of vascular tone. Endothelial dysfunction is a hallmark of many vascular diseases, including hypertension and obesity. Moreover, PVAT dysfunction is now being reported in several cardio-metabolic disorders. Thus, this review will also discuss the mechanistic insights into endothelial and PVAT dysfunction in order to evaluate whether PVAT modulation of vascular contractility is similar to that of the endothelium in health and disease. LINKED ARTICLES This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc.
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Affiliation(s)
- K E Zaborska
- Institute of Cardiovascular SciencesUniversity of ManchesterUK
| | - M Wareing
- Maternal and Fetal Health Research Centre, Institute of Human DevelopmentUniversity of ManchesterUK
| | - C Austin
- Faculty of Health and Social CareEdge Hill UniversityUK
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39
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Nosalski R, Guzik TJ. Perivascular adipose tissue inflammation in vascular disease. Br J Pharmacol 2017; 174:3496-3513. [PMID: 28063251 PMCID: PMC5610164 DOI: 10.1111/bph.13705] [Citation(s) in RCA: 271] [Impact Index Per Article: 33.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Revised: 12/29/2016] [Accepted: 01/04/2017] [Indexed: 12/11/2022] Open
Abstract
Perivascular adipose tissue (PVAT) plays a critical role in the pathogenesis of cardiovascular disease. In vascular pathologies, perivascular adipose tissue increases in volume and becomes dysfunctional, with altered cellular composition and molecular characteristics. PVAT dysfunction is characterized by its inflammatory character, oxidative stress, diminished production of vaso-protective adipocyte-derived relaxing factors and increased production of paracrine factors such as resistin, leptin, cytokines (IL-6 and TNF-α) and chemokines [RANTES (CCL5) and MCP-1 (CCL2)]. These adipocyte-derived factors initiate and orchestrate inflammatory cell infiltration including primarily T cells, macrophages, dendritic cells, B cells and NK cells. Protective factors such as adiponectin can reduce NADPH oxidase superoxide production and increase NO bioavailability in the vessel wall, while inflammation (e.g. IFN-γ or IL-17) induces vascular oxidases and eNOS dysfunction in the endothelium, vascular smooth muscle cells and adventitial fibroblasts. All of these events link the dysfunctional perivascular fat to vascular dysfunction. These mechanisms are important in the context of a number of cardiovascular disorders including atherosclerosis, hypertension, diabetes and obesity. Inflammatory changes in PVAT's molecular and cellular responses are uniquely different from classical visceral or subcutaneous adipose tissue or from adventitia, emphasizing the unique structural and functional features of this adipose tissue compartment. Therefore, it is essential to develop techniques for monitoring the characteristics of PVAT and assessing its inflammation. This will lead to a better understanding of the early stages of vascular pathologies and the development of new therapeutic strategies focusing on perivascular adipose tissue. LINKED ARTICLES This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc.
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Affiliation(s)
- Ryszard Nosalski
- Institute of Cardiovascular and Medical SciencesUniversity of GlasgowScotlandUK
- Department of Internal and Agricultural MedicineJagiellonian University, Collegium MedicumKrakowPoland
| | - Tomasz J Guzik
- Institute of Cardiovascular and Medical SciencesUniversity of GlasgowScotlandUK
- Department of Internal and Agricultural MedicineJagiellonian University, Collegium MedicumKrakowPoland
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40
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Livingstone R, Boyle JG, Petrie JR. A new perspective on metformin therapy in type 1 diabetes. Diabetologia 2017; 60:1594-1600. [PMID: 28770327 PMCID: PMC5552844 DOI: 10.1007/s00125-017-4364-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 06/27/2017] [Indexed: 12/14/2022]
Abstract
Metformin is quite frequently used off-label in type 1 diabetes to limit insulin dose requirement. Guidelines recommend that it can improve glucose control in those who are overweight and obese but evidence in support of this is limited. Recently-published findings from the REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL) trial suggest that metformin therapy in type 1 diabetes can reduce atherosclerosis progression, weight and LDL-cholesterol levels. This provides a new perspective on metformin therapy in type 1 diabetes and suggests a potential role for reducing the long-term risk of cardiovascular disease.
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Affiliation(s)
- Rachel Livingstone
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK
| | - James G Boyle
- Glasgow Royal Infirmary, Glasgow, UK
- School of Medicine, University of Glasgow, Glasgow, UK
| | - John R Petrie
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK.
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41
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Murugesan V, Degerman E, Holmen-Pålbrink AK, Duner P, Knutsson A, Hultgårdh-Nilsson A, Rauch U. β-Sarcoglycan Deficiency Reduces Atherosclerotic Plaque Development in ApoE-Null Mice. J Vasc Res 2017; 54:235-245. [PMID: 28768281 DOI: 10.1159/000478014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 06/02/2017] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Smooth muscle cells are important for atherosclerotic plaque stability. Their proper ability to communicate with the extracellular matrix is crucial for maintaining the correct tissue integrity. In this study, we have investigated the role of β-sarcoglycan within the matrix-binding dystrophin-glycoprotein complex in the development of atherosclerosis. RESULTS Atherosclerotic plaque development was significantly reduced in ApoE-deficient mice lacking β-sarcoglycan, and their plaques contained an increase in differentiated smooth muscle cells. ApoE-deficient mice lacking β-sarcoglycan showed a reduction in ovarian adipose tissue and adipocyte size, while the total weight of the animals was not significantly different. Western blot analysis of adipose tissues showed a decreased activation of protein kinase B, while that of AMP-activated kinase was increased in mice lacking β-sarcoglycan. Analysis of plasma in β-sarcoglycan-deficient mice revealed reduced levels of leptin, adiponectin, insulin, cholesterol, and triglycerides but increased levels of IL-6, IL-17, and TNF-α. CONCLUSIONS Our results indicate that the dystrophin-glycoprotein complex and β-sarcoglycan can affect the atherosclerotic process. Furthermore, the results show the effects of β-sarcoglycan deficiency on adipose tissue and lipid metabolism, which may also have contributed to the atherosclerotic plaque reduction.
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Affiliation(s)
- Vignesh Murugesan
- Department of Experimental Medical Science, Lund University, Lund, Sweden
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42
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Lee HJ, Cantú SM, Donoso AS, Choi MR, Peredo HA, Puyó AM. Metformin prevents vascular prostanoid release alterations induced by a high-fat diet in rats. AUTONOMIC & AUTACOID PHARMACOLOGY 2017; 37:37-43. [PMID: 28621447 DOI: 10.1111/aap.12057] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 04/12/2017] [Accepted: 05/03/2017] [Indexed: 12/13/2022]
Abstract
Perivascular adipose tissue dysfunction induced by high-fat feeding leads to alterations in the modulation of inflammation, contractile activity of the vascular smooth muscle and endothelial function, all risk factors in the development of hypertension. Metformin, an activator of AMP-activated protein kinase (AMPK), is currently the first-line drug treatment for type 2 diabetes (T2DM) and metabolic syndrome. Besides its glucose-lowering effect, there is an interest in actions of this drug with potential relevance in cardiovascular diseases. The high-fat (HF) diet is an experimental model that resembles human metabolic syndrome. We have previously reported an altered pattern of prostanoid release in mesenteric vessels in this model. The aim of this study was to analyse the effects of metformin on mesenteric vascular bed prostanoid release, adiposity index and its relation to blood pressure in Sprague-Dawley rats fed a HF diet for 8 and 12 weeks. Eight groups were used: control (C8, C1), HF diet (HF8, HF12, 50% w/w bovine fat), metformin-treated (CMf8, CMf12, 500 mg/kg/day) and metformin-treated HF diet (HFMf8, HFMf12, both treatments). HF diet increased mesenteric vascular bed adiposity index (%, HF8: 1.7±0.1 vs C8: 0.9±0.04 and HF12: 1.8±0.1 vs C12: 0.8±0.1, P<.001); systolic blood pressure (SBP, mm Hg, HF8: 145±6 vs C8: 118±4, P<.01 and HF12: 151±1 vs C12: 121±3, P<.001). We found a positive correlation between these two parameters. Moreover HF diet increased the release of vasoconstrictor prostanoids such as thromboxane (TX) B2 (ng PR/mg of tissue, HF8: 117±6 vs C8: 66±2 and HF12: 123±6 vs C12: 62±5, P<.001) and prostaglandin (PG) F2α (ng/mg, HF8: 153±9 vs C8: 88±3 and HF12: 160±11 vs C12: 83±5, P<.001). We also found that this increase in the release of vasoconstrictor prostanoids positively correlates with the elevation of SBP. In addition, HF diet increases the release of PGE2 and decreases the prostacyclin (PGI2 )/TXA2 release ratio at 8 and 12 weeks of treatment compared to control groups. In the HFMf group, metformin treatment prevented all these increases in mesenteric vascular bed adiposity index (%, HFMf8: 1.3±0.2 vs HF8 and HFMf12: 1.3±0.1 vs HF12, P<.05); SBP (mm Hg, HFMf8: 127±2 vs HF8 and HFMf12: 132±1 vs HF12, P<.001); TXB2 release (ng PR/mg of tissue, HFMf8: 65±12 vs HF8, P<.05 and HFMf12: 53±3 vs HF12, P<.001) and PGF2 α (ng PR/mg of tissue, HFMf8: 99±13 vs HF8, P<.01 and HFMf12: 77±8 vs HF12, P<.001). Meanwhile metformin prevented the increment in PGE2 release only at 12 weeks. On the other hand, metformin improved the PGI2 /TXA2 ratio in both periods studied. In conclusion, metformin could exert beneficial effects on adipose tissue and the vascular system by improving endothelial dysfunction induced by an imbalance of vasoactive substances in mesenteric perivascular adipose tissue in this model.
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Affiliation(s)
- H J Lee
- Cátedra de Anatomía e Histología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, ININCA-CONICET, Buenos Aires, Argentina
| | - S M Cantú
- Cátedra de Anatomía e Histología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, ININCA-CONICET, Buenos Aires, Argentina
| | - A S Donoso
- Cátedra de Anatomía e Histología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, ININCA-CONICET, Buenos Aires, Argentina
| | - M R Choi
- Cátedra de Anatomía e Histología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, ININCA-CONICET, Buenos Aires, Argentina
| | - H A Peredo
- Cátedra de Anatomía e Histología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, ININCA-CONICET, Buenos Aires, Argentina
| | - A M Puyó
- Cátedra de Anatomía e Histología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, ININCA-CONICET, Buenos Aires, Argentina
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Kagota S, Iwata S, Maruyama K, Wakuda H, Shinozuka K. Functional Relationship between Arterial Tissue and Perivascular Adipose Tissue in Metabolic Syndrome. YAKUGAKU ZASSHI 2017; 136:693-7. [PMID: 27150921 DOI: 10.1248/yakushi.15-00262-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Metabolic syndrome is a complex of disorders that includes visceral obesity, insulin resistance, hypertension, and dyslipidemia. It is characterized by an increased risk for serious cardiovascular events. Adipocytes are now recognized to contribute to the development of cardiovascular complications in metabolic syndrome via the release of several bioactive substances (adipocytokines). Obesity induces an increase in the volume of perivascular adipose tissue (PVAT), which is located outside the blood vessels. In recent years, PVAT has been reported to produce/release vasoactive adipocytokines. Thus, PVAT can modulate vasomotor function by releasing vasorelaxing/vasocontracting factors, resulting in the development of cardiovascular disease due to metabolic syndrome. By using animal models (SHR/NDmcr-cp rats, SHRSP.Z-Lepr(fa)/IzmDmcr rats, and B6.BKS (D)-Lepr(fa)/J mice), we have demonstrated that chronic oxidative-nitrative stress is closely linked to the development of vascular dysfunction in response to nitric oxide (NO) in resistant arteries with increasing age/exposure to metabolic abnormalities. Further, our recent findings have led us to believe that PVAT helps in the regulation of vasodilation to compensate for the impaired vasodilation observed in pathophysiological conditions in the mesenteric arteries of SHRSP.Z-Lepr(fa)/IzmDmcr rats. However, a breakdown of the compensatory system occurs with long-term exposure to metabolic abnormalities. We propose the concept of the functional regulation of vascular tissue by PVAT in metabolic syndrome.
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Affiliation(s)
- Satomi Kagota
- Department of Pharmacology II, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University
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Zaborska KE, Edwards G, Austin C, Wareing M. The Role of O-GlcNAcylation in Perivascular Adipose Tissue Dysfunction of Offspring of High-Fat Diet-Fed Rats. J Vasc Res 2017; 54:79-91. [PMID: 28376507 PMCID: PMC5569708 DOI: 10.1159/000458422] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 01/27/2017] [Indexed: 12/31/2022] Open
Abstract
Perivascular adipose tissue (PVAT), which reduces vascular contractility, is dysfunctional in the male offspring of rats fed a high-fat diet (HFD), partially due to a reduced NO bioavailability. O-GlcNAcylation of eNOS decreases its activity, thus we investigated the role of O-GlcNAcylation in the prenatal programming of PVAT dysfunction. Female Sprague-Dawley rats were fed either a control (10% fat) or an obesogenic HFD (45% fat) diet for 12 weeks prior to mating, and throughout pregnancy and lactation. Offspring were weaned onto the control diet and were killed at 12 and 24 weeks of age. Mesenteric arteries from the 12-week-old offspring of HFD dams (HFDO) contracted less to U46619; these effects were mimicked by glucosamine in control arteries. PVAT from 12- and 24-week-old controls, but not from HFDO, exerted an anticontractile effect. Glucosamine attenuated the anticontractile effect of PVAT in the vessels from controls but not from HFDO. AMP-activated protein kinase (AMPK) activation (with A769662) partially restored an anticontractile effect in glucosamine-treated controls and HFDO PVAT. Glucosamine decreased AMPK activity and expression in HFDO PVAT, although phosphorylated eNOS expression was only reduced in that from males. The loss of anticontractile effect of HFDO PVAT is likely to result from increased O-GlcNAcylation, which decreased AMPK activity and, in males, decreased NO bioavailability.
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Affiliation(s)
- Karolina E Zaborska
- Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK
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Ramirez JG, O'Malley EJ, Ho WSV. Pro-contractile effects of perivascular fat in health and disease. Br J Pharmacol 2017; 174:3482-3495. [PMID: 28257140 DOI: 10.1111/bph.13767] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 02/23/2017] [Accepted: 02/23/2017] [Indexed: 12/28/2022] Open
Abstract
Perivascular adipose tissue (PVAT) is now recognized as an active player in vascular homeostasis. The expansion of PVAT in obesity and its possible role in vascular dysfunction have attracted much interest. In terms of the regulation of vascular tone and blood pressure, PVAT has been shown to release vasoactive mediators, for instance, angiotensin peptides, reactive oxygen species, chemokines and cytokines. The secretory profile of PVAT is altered by obesity, hypertension and other cardiovascular diseases, leading to an imbalance between its pro-contractile and anti-contractile effects. PVAT adipocytes represent an important source of the mediators, but infiltrating immune cells may become more important under conditions of hypoxia and inflammation. This review describes recent advances in the effects of PVAT on the regulation of vascular tone, highlighting the evidence for a pro-contractile action in health and disease. The role of the endothelium, vascular smooth muscle, immune cells and probably perivascular nerves in PVAT function is also discussed. LINKED ARTICLES This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc.
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Affiliation(s)
- J G Ramirez
- Vascular Biology Research Centre, St George's University of London, London, SW17 0RE, UK
| | - E J O'Malley
- Vascular Biology Research Centre, St George's University of London, London, SW17 0RE, UK
| | - W S V Ho
- Vascular Biology Research Centre, St George's University of London, London, SW17 0RE, UK
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Petrie JR, Chaturvedi N, Ford I, Hramiak I, Hughes AD, Jenkins AJ, E. Klein B, Klein R, Ooi TC, Rossing P, Sattar N, Stehouwer CDA, Colhoun HM. Metformin in adults with type 1 diabetes: Design and methods of REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL): An international multicentre trial. Diabetes Obes Metab 2017; 19:509-516. [PMID: 27935183 PMCID: PMC5357575 DOI: 10.1111/dom.12840] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 11/18/2016] [Accepted: 11/29/2016] [Indexed: 01/06/2023]
Abstract
AIMS Cardiovascular (CV) disease is a major cause of reduced life expectancy in type 1 diabetes (T1D). Intensive insulin therapy prevents CV complications but is constrained by hypoglycaemia and weight gain. Adjunct metformin reduces insulin dose requirement and stabilizes weight but there are no data on its cardiovascular effects. We have therefore initiated an international double-blind, randomized, placebo-controlled trial (REMOVAL: REducing with MetfOrmin Vascular Adverse Lesions in type 1 diabetes) to examine whether metformin reduces progression of atherosclerosis in adults with T1D. Individuals ≥40 years of age with T1D for ≥5 years are eligible if they have ≥3 of 10 specified CV risk factors. The enrolment target is 500 participants in 17 international centres. MATERIALS AND METHODS After 12 weeks of single-blind placebo-controlled run-in, participants with ≥ 70% adherence are randomized to metformin or matching placebo for 3 years with insulin titrated towards HbA1c 7.0% (53 mmol/mol). The primary endpoint is progression of averaged mean far wall common carotid intima-media thickness (cIMT) measured by ultrasonography at baseline, 12, 24 and 36 months. This design provides 90% power to detect a mean difference of 0.0167 mm in cIMT progression between treatment arms (α = 0.05), assuming that up to 20% withdraw or discontinue treatment. Other endpoints include HbA1c, weight, LDL cholesterol, insulin requirement, progression of retinopathy, endothelial function and frequency of hypoglycaemia. CONCLUSION REMOVAL is the largest clinical trial of adjunct metformin therapy in T1D to date and will provide clinically meaningful information on its potential to impact CV disease and other complications.
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Affiliation(s)
- John R. Petrie
- Institute of Cardiovascular and Medical SciencesUniversity of GlasgowGlasgowUK
| | - Nish Chaturvedi
- Institute of Cardiovascular ScienceUniversity College LondonLondonUK
| | - Ian Ford
- Institute of Cardiovascular and Medical SciencesUniversity of GlasgowGlasgowUK
| | | | - Alun D. Hughes
- Institute of Cardiovascular and Medical SciencesUniversity of GlasgowGlasgowUK
| | | | - Barbara E. Klein
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public HealthMadisonWisconsin
| | - Ron Klein
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public HealthMadisonWisconsin
| | - Teik Chye Ooi
- Ottawa Hospital Research InstituteThe Ottawa HospitalOttawaCanada
| | - Peter Rossing
- Steno Diabetes Center and the University of CopenhagenCopenhagenDenmark
| | - Naveed Sattar
- Institute of Cardiovascular and Medical SciencesUniversity of GlasgowGlasgowUK
| | - Coen D. A. Stehouwer
- Department of Internal Medicine and Cardiovascular Research Institute Maastricht (CARIM)Maastricht University Medical CentreMaastrichtThe Netherlands
| | - Helen M. Colhoun
- Institute of Genetics and Molecular MedicineUniversity of EdinburghUK
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Kagota S, Iwata S, Maruyama K, McGuire JJ, Shinozuka K. Time-Dependent Differences in the Influence of Perivascular Adipose Tissue on Vasomotor Functions in Metabolic Syndrome. Metab Syndr Relat Disord 2017; 15:233-239. [PMID: 28358621 DOI: 10.1089/met.2016.0146] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Metabolic syndrome (MetS) facilitates the development of cardiovascular disease due to atherosclerosis, which is accelerated by defects of the vascular endothelium. Vascular dysfunction in response to nitric oxide (NO) occurs in the mesenteric arteries of an animal model of MetS, SHRSP.Z-Leprfa/IzmDmcr (SHRSP.ZF) rats. Vascular responses to vasodilators are affected by perivascular adipose tissue (PVAT) that surrounds the outsides of arteries. In this study, we assessed the role of PVAT in vascular dysfunction observed in SHRSP.ZF. METHODS To determine the effects of PVAT on vasodilators in SHRSP.ZF and control Wistar-Kyoto (WKY) rats, we used organ bath bioassay techniques to assay acetylcholine and nitroprusside-induced relaxations of isolated mesenteric arterial ring preparations with PVAT intact or removed. RESULTS A PVAT-mediated enhancement of relaxations induced by acetylcholine and nitroprusside occurred in SHRSP.ZF at 20 weeks of age, but not at 10 and 30 weeks, and did not occur in WKY. Furthermore, the enhancing effects of PVAT from SHRSP.ZF at 20 weeks could not be substituted by replacement with PVAT from either WKY or 30-week-old SHRSP.ZF, was inhibited by NO synthase inhibitor, and abolished by removal of the arteries' endothelium. Cyclic guanosine monophosphate (cGMP) accumulation elicited by nitroprusside was higher in SHRSP.ZF arteries with PVAT than arteries without PVAT at 20 weeks, but the enhancement of cGMP accumulation did not occur at 30 weeks. CONCLUSIONS PVAT may regulate arterial tone by releasing diffusible vasorelaxing factor(s), which, through endothelium-derived NO production, compensates for impaired vasodilations at early stages of MetS.
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Affiliation(s)
- Satomi Kagota
- 1 Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University , Nishinomiya, Japan
| | - Saki Iwata
- 1 Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University , Nishinomiya, Japan
| | - Kana Maruyama
- 1 Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University , Nishinomiya, Japan
| | - John J McGuire
- 2 Faculty of Medicine, Division of BioMedical Sciences, Memorial University , St. John's, Canada
| | - Kazumasa Shinozuka
- 1 Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University , Nishinomiya, Japan
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Xu X, Chen Y, Song J, Hou F, Ma X, Liu B, Huang F. Mangiferin suppresses endoplasmic reticulum stress in perivascular adipose tissue and prevents insulin resistance in the endothelium. Eur J Nutr 2017; 57:1563-1575. [PMID: 28349253 DOI: 10.1007/s00394-017-1441-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 03/13/2017] [Indexed: 12/21/2022]
Abstract
PURPOSE Mangiferin is a naturally occurring glucosylxanthone with beneficial effects on glucose and lipid homeostasis. This study investigates the potential therapeutic effect of Mangiferin in perivascular adipose tissue (PVAT) and whether it contributes to regulating insulin action in the endothelium. METHODS Palmitate challenge evoked ROS-associated endoplasmic reticulum stress (ER stress) and NLRP3 inflammasome activation in PVAT. The conditioned medium from PA-stimulated PVAT was prepared to induce endothelial insulin resistance, and improved endothelium-dependent vasodilation in response to insulin was detected in vitro and in vivo. RESULTS Mangiferin treatment enhanced LKB1-dependent AMPK activity and suppressed ER stress with downregulation of TXNIP induction, leading to the inhibition of NLRP3 inflammasome activation evidenced by attenuated NLRP3 and cleaved caspase-1 expression as well as reduced IL-1β secretion. Moreover, Mangiferin restored insulin-mediated Akt and eNOS phosphorylations with increased NO production, immunohistochemistry examination of adipocytes, and endothelial tissue in high-fat diet-fed mice also showed that oral administration of Mangiferin inhibited ER stress and NLRP3 induction in PVAT, and then effectively prevented insulin resistance in the vessel endothelium. CONCLUSIONS Taken together, these results revealed that Mangiferin suppressed ER stress-associated NLRP3 inflammasome activation in PVAT through regulation of AMPK activity, which prevented endothelial insulin resistance. These findings suggested that the amelioration of PVAT dysfunction may be a therapeutic strategy for the prevention of endothelial insulin resistance.
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Affiliation(s)
- Xiaoshan Xu
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 639 Longmian Road, 211198, Nanjing, China
| | - Yupeng Chen
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 639 Longmian Road, 211198, Nanjing, China
| | - Junna Song
- Hebei University of Chinese Medicine, Pharmaceutical Botany Office, Hebei, China
| | - Fangjie Hou
- Hebei University of Chinese Medicine, Pharmacognosy Office, Hebei, China
| | - Xuelian Ma
- Scientific Research Center of Hebei University of Chinese Medicine, Hebei, China
| | - Baolin Liu
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 639 Longmian Road, 211198, Nanjing, China
| | - Fang Huang
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 639 Longmian Road, 211198, Nanjing, China.
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Tuomikoski P, Savolainen-Peltonen H. Vasomotor symptoms and metabolic syndrome. Maturitas 2017; 97:61-65. [PMID: 28159064 DOI: 10.1016/j.maturitas.2016.12.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2016] [Accepted: 12/16/2016] [Indexed: 12/28/2022]
Abstract
A vast majority of menopausal women suffer from vasomotor symptoms, such as hot flushes and night sweats, the mean duration of which may be up to 7-10 years. In addition to a decreased quality of life, vasomotor symptoms may have an impact on overall health. Vasomotor symptoms are associated with overactivity of the sympathetic nervous system, and sympathetic overdrive in turn is associated with metabolic syndrome, which is a known risk factor for cardiovascular disease. Menopausal hot flushes have a complex relationship to different features of the metabolic syndrome and not all data point towards an association between vasomotor symptoms and metabolic syndrome. Thus, it is still unclear whether vasomotor symptoms are an independent risk factor for metabolic syndrome. Research in this area is constantly evolving and we present here the most recent data on the possible association between menopausal vasomotor symptoms and the metabolic syndrome.
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Affiliation(s)
| | - Hanna Savolainen-Peltonen
- University of Helsinki, Helsinki, Finland; Helsinki University Hospital, Department of Obstetrics and Gynecology, 00029 Helsinki, Finland
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Abstract
Chronic inflammatory state in obesity causes dysregulation of the endocrine and paracrine actions of adipocyte-derived factors, which disrupt vascular homeostasis and contribute to endothelial vasodilator dysfunction and subsequent hypertension. While normal healthy perivascular adipose tissue (PVAT) ensures the dilation of blood vessels, obesity-associated PVAT leads to a change in profile of the released adipo-cytokines, resulting in a decreased vasorelaxing effect. Adipose tissue inflammation, nitric oxide (NO)-bioavailability, insulin resistance and oxidized low-density lipoprotein (oxLDL) are main participating factors in endothelial dysfunction of obesity. In this chapter, disruption of inter-endothelial junctions between endothelial cells, significant increase in the production of reactive oxygen species (ROS), inflammation mediators, which are originated from inflamed endothelial cells, the balance between NO synthesis and ROS , insulin signaling and NO production, and decrease in L-arginine/endogenous asymmetric dimethyl-L-arginine (ADMA) ratio are discussed in connection with endothelial dysfunction in obesity.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- , Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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