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Kettunen S, Slita A, Suoranta T, Räty I, Laidinen S, Ylä‐Herttuala E, Ruotsalainen A, Ylä‐Herttuala S. Myocardial infarction activates the 9p21.3 orthologous locus expression, but its absence does not alter cardiac pathophysiology in ischemia. Physiol Rep 2025; 13:e70344. [PMID: 40405527 PMCID: PMC12098971 DOI: 10.14814/phy2.70344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 04/08/2025] [Accepted: 04/08/2025] [Indexed: 05/24/2025] Open
Abstract
Genetic variation in the 9p21.3 chromosomal region has one of the strongest associations known for coronary artery disease (CAD) that often leads to myocardial infarction (MI). This risk locus encodes a long noncoding RNA, ANRIL, which has been suggested to regulate the neighboring cyclin-dependent kinase inhibitors 2A and B (Cdkn2A/B), the key regulators of cell proliferation. In this study, we aimed to clarify the role of the 9p21.3 risk locus in acute and chronic myocardial ischemia in mice. Mice carrying a deletion equivalent to the human CAD risk interval (Chr4Δ70kb/Δ70kb) and wild type mice were exposed to MI and followed until 5 days or 4 weeks. In the wild type mice, expression of a lncRNA, Ak148321, was increased after MI, and Cdkn2a was upregulated in chronic ischemia. Chr4Δ70kb/Δ70kb downregulated both Cdkn2a/b, but this did not affect the survival or cardiac pathology after MI. These results suggest that the 9p21.3 locus is activated in response to cardiac ischemia. However, deficiency in the risk locus does not play a role in the cardiac pathophysiology in mice, supporting the studies suggesting the risk locus being more involved in the development of CAD, rather than the subsequent MI.
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Affiliation(s)
- Sanna Kettunen
- A.I. Virtanen InstituteUniversity of Eastern FinlandKuopioFinland
| | - Anna Slita
- A.I. Virtanen InstituteUniversity of Eastern FinlandKuopioFinland
| | - Tuisku Suoranta
- A.I. Virtanen InstituteUniversity of Eastern FinlandKuopioFinland
| | - Iida Räty
- A.I. Virtanen InstituteUniversity of Eastern FinlandKuopioFinland
| | | | | | | | - Seppo Ylä‐Herttuala
- A.I. Virtanen InstituteUniversity of Eastern FinlandKuopioFinland
- Heart Center and Gene Therapy UnitKuopio University HospitalKuopioFinland
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2
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Pi H, Wang G, Wang Y, Zhang M, He Q, Zheng X, Yin K, Zhao G, Jiang T. Immunological perspectives on atherosclerotic plaque formation and progression. Front Immunol 2024; 15:1437821. [PMID: 39399488 PMCID: PMC11466832 DOI: 10.3389/fimmu.2024.1437821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 09/09/2024] [Indexed: 10/15/2024] Open
Abstract
Atherosclerosis serves as the primary catalyst for numerous cardiovascular diseases. Growing evidence suggests that the immune response is involved in every stage of atherosclerotic plaque evolution. Rapid, but not specific, innate immune arms, including neutrophils, monocytes/macrophages, dendritic cells (DCs) and other innate immune cells, as well as pattern-recognition receptors and various inflammatory mediators, contribute to atherogenesis. The specific adaptive immune response, governed by T cells and B cells, antibodies, and immunomodulatory cytokines potently regulates disease activity and progression. In the inflammatory microenvironment, the heterogeneity of leukocyte subpopulations plays a very important regulatory role in plaque evolution. With advances in experimental techniques, the fine mechanisms of immune system involvement in atherosclerotic plaque evolution are becoming known. In this review, we examine the critical immune responses involved in atherosclerotic plaque evolution, in particular, looking at atherosclerosis from the perspective of evolutionary immunobiology. A comprehensive understanding of the interplay between plaque evolution and plaque immunity provides clues for strategically combating atherosclerosis.
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Affiliation(s)
- Hui Pi
- Affiliated Qingyuan Hospital, Guangzhou Medical University (Qingyuan People’s Hospital), Qingyuan, Guangdong, China
- Department of Microbiology and Immunology, Dali University, Dali, Yunnan, China
| | - Guangliang Wang
- Affiliated Qingyuan Hospital, Guangzhou Medical University (Qingyuan People’s Hospital), Qingyuan, Guangdong, China
| | - Yu Wang
- Affiliated Qingyuan Hospital, Guangzhou Medical University (Qingyuan People’s Hospital), Qingyuan, Guangdong, China
| | - Ming Zhang
- Affiliated Qingyuan Hospital, Guangzhou Medical University (Qingyuan People’s Hospital), Qingyuan, Guangdong, China
| | - Qin He
- Department of Microbiology and Immunology, Dali University, Dali, Yunnan, China
| | - Xilong Zheng
- Departments of Biochemistry and Molecular Biology and Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Kai Yin
- Department of General Practice, The Fifth Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China
| | - Guojun Zhao
- Affiliated Qingyuan Hospital, Guangzhou Medical University (Qingyuan People’s Hospital), Qingyuan, Guangdong, China
| | - Ting Jiang
- Affiliated Qingyuan Hospital, Guangzhou Medical University (Qingyuan People’s Hospital), Qingyuan, Guangdong, China
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Tappia PS, Shah AK, Dhalla NS. The Efficacy of Vitamins in the Prevention and Treatment of Cardiovascular Disease. Int J Mol Sci 2024; 25:9761. [PMID: 39337248 PMCID: PMC11432297 DOI: 10.3390/ijms25189761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/04/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
Vitamins are known to affect the regulation of several biochemical and metabolic pathways that influence cellular function. Adequate amounts of both hydrophilic and lipophilic vitamins are required for maintaining normal cardiac and vascular function, but their deficiencies can contribute to cardiovascular abnormalities. In this regard, a deficiency in the lipophilic vitamins, such as vitamins A, D, and E, as well as in the hydrophilic vitamins, such as vitamin C and B, has been associated with suboptimal cardiovascular function, whereas additional intakes have been suggested to reduce the risk of atherosclerosis, hypertension, ischemic heart disease, arrhythmias, and heart failure. Here, we have attempted to describe the association between low vitamin status and cardiovascular disease, and to offer a discussion on the efficacy of vitamins. While there are inconsistencies in the impact of a deficiency in vitamins on the development of cardiovascular disease and the benefits associated with supplementation, this review proposes that specific vitamins may contribute to the prevention of cardiovascular disease in individuals at risk rather than serve as an adjunct therapy.
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Affiliation(s)
- Paramjit S Tappia
- Asper Clinical Research Institute, St. Boniface Hospital, Winnipeg, MB R2H 2A6, Canada
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
| | - Anureet K Shah
- Department of Nutrition and Food Science, California State University Los Angeles, Los Angeles, CA 90032, USA
| | - Naranjan S Dhalla
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
- Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R2E 0J9, Canada
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Zhang Z, Rodriguez M, Zheng Z. Clot or Not? Reviewing the Reciprocal Regulation Between Lipids and Blood Clotting. Arterioscler Thromb Vasc Biol 2024; 44:533-544. [PMID: 38235555 PMCID: PMC10922732 DOI: 10.1161/atvbaha.123.318286] [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] [Indexed: 01/19/2024]
Abstract
Both hyperlipidemia and thrombosis contribute to the risks of atherosclerotic cardiovascular diseases, which are the leading cause of death and reduced quality of life in survivors worldwide. The accumulation of lipid-rich plaques on arterial walls eventually leads to the rupture or erosion of vulnerable lesions, triggering excessive blood clotting and leading to adverse thrombotic events. Lipoproteins are highly dynamic particles that circulate in blood, carry insoluble lipids, and are associated with proteins, many of which are involved in blood clotting. A growing body of evidence suggests a reciprocal regulatory relationship between blood clotting and lipid metabolism. In this review article, we summarize the observations that lipoproteins and lipids impact the hemostatic system, and the clotting-related proteins influence lipid metabolism. We also highlight the gaps that need to be filled in this area of research.
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Affiliation(s)
- Ziyu Zhang
- Blood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, Wisconsin 53226, USA
| | - Maya Rodriguez
- Blood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, Wisconsin 53226, USA
- College of Arts and Sciences, Marquette University, Milwaukee, Wisconsin 53233, USA
| | - Ze Zheng
- Blood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, Wisconsin 53226, USA
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
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Cetinkaya Z, Kelesoglu S, Tuncay A, Yilmaz Y, Karaca Y, Karasu M, Secen O, Cinar A, Harman M, Sahin S, Akin Y, Yavcin O. The Role of Pan-Immune-Inflammation Value in Determining the Severity of Coronary Artery Disease in NSTEMI Patients. J Clin Med 2024; 13:1295. [PMID: 38592192 PMCID: PMC10931938 DOI: 10.3390/jcm13051295] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 02/21/2024] [Accepted: 02/22/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Even though medication and interventional therapy have improved the death rate for non-ST elevation myocardial infarction (NSTEMI) patients, these patients still have a substantial residual risk of cardiovascular events. Early identification of high-risk individuals is critical for improving prognosis, especially in this patient group. The focus of recent research has switched to finding new related indicators that can help distinguish high-risk patients. For this purpose, we examined the relationship between the pan-immune-inflammation value (PIV) and the severity of coronary artery disease (CAD) defined by the SYNTAX score (SxS) in NSTEMI patients. METHODS Based on the SxS, CAD patients were split into three groups. To evaluate the risk variables of CAD, multivariate logistic analysis was employed. RESULTS The PIV (odds ratio: 1.003; 95% CI: 1.001-1.005; p = 0.005) was found to be an independent predictor of a high SxS in the multivariate logistic regression analysis. Additionally, there was a positive association between the PIV and SxS (r: 0.68; p < 0.001). The PIV predicted the severe coronary lesion in the receiver-operating characteristic curve analysis with a sensitivity of 91% and specificity of 81.1%, using an appropriate cutoff value of 568.2. CONCLUSIONS In patients with non-STEMI, the PIV, a cheap and easily measured laboratory variable, was substantially correlated with a high SxS and the severity of CAD.
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Affiliation(s)
- Zeki Cetinkaya
- Department of Cardiology, Ministry of Health, Elazıg Fethi Sekin City Hospital, Elazıg 23280, Turkey; (Z.C.); (Y.K.); (M.K.); (O.S.); (S.S.); (Y.A.); (O.Y.)
| | - Saban Kelesoglu
- Department of Cardiology, Erciyes University Faculty of Medicine, Kayseri 38039, Turkey
| | - Aydin Tuncay
- Department of Cardiovascular Surgery, Erciyes University Faculty of Medicine, Kayseri 38039, Turkey
| | - Yucel Yilmaz
- Department of Cardiology, University of Health Sciences, Kayseri Education and Research Hospital, Kayseri 38100, Turkey; (Y.Y.); (A.C.)
| | - Yucel Karaca
- Department of Cardiology, Ministry of Health, Elazıg Fethi Sekin City Hospital, Elazıg 23280, Turkey; (Z.C.); (Y.K.); (M.K.); (O.S.); (S.S.); (Y.A.); (O.Y.)
| | - Mehdi Karasu
- Department of Cardiology, Ministry of Health, Elazıg Fethi Sekin City Hospital, Elazıg 23280, Turkey; (Z.C.); (Y.K.); (M.K.); (O.S.); (S.S.); (Y.A.); (O.Y.)
| | - Ozlem Secen
- Department of Cardiology, Ministry of Health, Elazıg Fethi Sekin City Hospital, Elazıg 23280, Turkey; (Z.C.); (Y.K.); (M.K.); (O.S.); (S.S.); (Y.A.); (O.Y.)
| | - Ahmet Cinar
- Department of Cardiology, University of Health Sciences, Kayseri Education and Research Hospital, Kayseri 38100, Turkey; (Y.Y.); (A.C.)
| | - Murat Harman
- Department of Cardiology, Fırat University Faculty of Medicine, Elazıg 23119, Turkey;
| | - Seyda Sahin
- Department of Cardiology, Ministry of Health, Elazıg Fethi Sekin City Hospital, Elazıg 23280, Turkey; (Z.C.); (Y.K.); (M.K.); (O.S.); (S.S.); (Y.A.); (O.Y.)
| | - Yusuf Akin
- Department of Cardiology, Ministry of Health, Elazıg Fethi Sekin City Hospital, Elazıg 23280, Turkey; (Z.C.); (Y.K.); (M.K.); (O.S.); (S.S.); (Y.A.); (O.Y.)
| | - Ozkan Yavcin
- Department of Cardiology, Ministry of Health, Elazıg Fethi Sekin City Hospital, Elazıg 23280, Turkey; (Z.C.); (Y.K.); (M.K.); (O.S.); (S.S.); (Y.A.); (O.Y.)
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Panasenko OM, Vladimirov YA, Sergienko VI. Free Radical Lipid Peroxidation Induced by Reactive Halogen Species. BIOCHEMISTRY. BIOKHIMIIA 2024; 89:S148-S179. [PMID: 38621749 DOI: 10.1134/s0006297924140098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/08/2023] [Accepted: 07/15/2023] [Indexed: 04/17/2024]
Abstract
The review is devoted to the mechanisms of free radical lipid peroxidation (LPO) initiated by reactive halogen species (RHS) produced in mammals, including humans, by heme peroxidase enzymes, primarily myeloperoxidase (MPO). It has been shown that RHS can participate in LPO both in the initiation and branching steps of the LPO chain reactions. The initiation step of RHS-induced LPO mainly involves formation of free radicals in the reactions of RHS with nitrite and/or with amino groups of phosphatidylethanolamine or Lys. The branching step of the oxidative chain is the reaction of RHS with lipid hydroperoxides, in which peroxyl and alkoxyl radicals are formed. The role of RHS-induced LPO in the development of human inflammatory diseases (cardiovascular and neurodegenerative diseases, cancer, diabetes, rheumatoid arthritis) is discussed in detail.
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Affiliation(s)
- Oleg M Panasenko
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, Moscow, Russia.
| | - Yury A Vladimirov
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, Moscow, Russia
| | - Valery I Sergienko
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, Moscow, Russia
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Otunla AA, Shanmugarajah K, Davies AH, Lucia Madariaga M, Shalhoub J. The Biological Parallels Between Atherosclerosis and Cardiac Allograft Vasculopathy: Implications for Solid Organ Chronic Rejection. Cardiol Rev 2024; 32:2-11. [PMID: 38051983 DOI: 10.1097/crd.0000000000000437] [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] [Indexed: 11/25/2022]
Abstract
Atherosclerosis and solid organ chronic rejection are pervasive chronic disease states that account for significant morbidity and mortality in developed countries. Recently, a series of shared molecular pathways have emerged, revealing biological parallels from early stages of development up to the advanced forms of pathology. These shared mechanistic processes are inflammatory in nature, reflecting the importance of inflammation in both disorders. Vascular inflammation triggers endothelial dysfunction and disease initiation through aberrant vasomotor control and shared patterns of endothelial activation. Endothelial dysfunction leads to the recruitment of immune cells and the perpetuation of the inflammatory response. This drives lesion formation through the release of key cytokines such as IFN-y, TNF-alpha, and IL-2. Continued interplay between the adaptive and innate immune response (represented by T lymphocytes and macrophages, respectively) promotes lesion instability and thrombotic complications; hallmarks of advanced disease in both atherosclerosis and solid organ chronic rejection. The aim of this study is to identify areas of overlap between atherosclerosis and chronic rejection. We then discuss new approaches to improve current understanding of the pathophysiology of both disorders, and eventually design novel therapeutics.
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Affiliation(s)
- Afolarin A Otunla
- From the Medical Sciences Division, University of Oxford, Oxford, United Kingdom
| | | | - Alun H Davies
- Section of Vascular Surgery, Department of Surgery & Cancer, Imperial College London, London, United Kingdom
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London, United Kingdom
| | | | - Joseph Shalhoub
- Section of Vascular Surgery, Department of Surgery & Cancer, Imperial College London, London, United Kingdom
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London, United Kingdom
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8
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Maaninka K, Neuvonen M, Kerkelä E, Hyvärinen K, Palviainen M, Kamali-Moghaddam M, Federico A, Greco D, Laitinen S, Öörni K, Siljander PR. OxLDL sensitizes platelets for increased formation of extracellular vesicles capable of finetuning macrophage gene expression. Eur J Cell Biol 2023; 102:151311. [PMID: 36963245 DOI: 10.1016/j.ejcb.2023.151311] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 03/10/2023] [Accepted: 03/14/2023] [Indexed: 03/17/2023] Open
Abstract
Platelet extracellular vesicles (PEVs) generated upon platelet activation may play a role in inflammatory pathologies such as atherosclerosis. Oxidized low-density lipoprotein (oxLDL), a well-known contributor to atherogenesis, activates platelets and presensitizes them for activation by other agonists. We studied the effect of oxLDL on the secretion, composition, and inflammatory functions of PEVs using contemporary EV analytics. Platelets were activated by co-stimulation with thrombin (T) and collagen (C) ± oxLDL and characterized by high-resolution flow cytometry, nanoparticle tracking analysis, proximity extension assay, western blot, and electron microscopy. The effect of PEVs on macrophage differentiation and functionality was examined by analyzing macrophage surface markers, cytokine secretion, and transcriptome. OxLDL upregulated TC-induced formation of CD61+, P-selectin+ and phosphatidylserine+ PEVs. Blocking the scavenger receptor CD36 significantly suppressed the oxLDL+TC-induced PEV formation, and HDL caused a slight but detectable suppression. The inflammatory protein cargo differed between the PEVs from stimulated and unstimulated platelets. Both oxLDL+TC- and TC-induced PEVs enhanced macrophage HLA-DR and CD86 expression and decreased CD11c expression as well as secretion of several cytokines. Pathways related to cell cycle and regulation of gene expression, and immune system signaling were overrepresented in the differentially expressed genes between TC PEV -treated vs. control macrophages and oxLDL+TC PEV -treated vs. control macrophages, respectively. In conclusion, we speculate that oxLDL and activated platelets contribute to proatherogenic processes by increasing the number of PEVs that provide an adhesive and procoagulant surface, contain inflammatory mediators, and subtly finetune the macrophage gene expression.
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Affiliation(s)
- Katariina Maaninka
- EV group, Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, and CURED, Drug Research Program, Faculty of Pharmacy, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland; EV Core, Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
| | - Maarit Neuvonen
- EV group, Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, and CURED, Drug Research Program, Faculty of Pharmacy, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland.
| | - Erja Kerkelä
- Finnish Red Cross Blood Service (FRCBS), Helsinki, Finland.
| | - Kati Hyvärinen
- Finnish Red Cross Blood Service (FRCBS), Helsinki, Finland.
| | - Mari Palviainen
- EV group, Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, and CURED, Drug Research Program, Faculty of Pharmacy, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland; EV Core, Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
| | - Masood Kamali-Moghaddam
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
| | - Antonio Federico
- Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
| | - Dario Greco
- Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
| | - Saara Laitinen
- Finnish Red Cross Blood Service (FRCBS), Helsinki, Finland.
| | - Katariina Öörni
- Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland.
| | - Pia Rm Siljander
- EV group, Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, and CURED, Drug Research Program, Faculty of Pharmacy, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland; EV Core, Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
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Huang J, Tao H, Yancey PG, Leuthner Z, May-Zhang LS, Jung JY, Zhang Y, Ding L, Amarnath V, Liu D, Collins S, Davies SS, Linton MF. Scavenging dicarbonyls with 5'-O-pentyl-pyridoxamine increases HDL net cholesterol efflux capacity and attenuates atherosclerosis and insulin resistance. Mol Metab 2022; 67:101651. [PMID: 36481344 PMCID: PMC9792904 DOI: 10.1016/j.molmet.2022.101651] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 11/29/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Oxidative stress contributes to the development of insulin resistance (IR) and atherosclerosis. Peroxidation of lipids produces reactive dicarbonyls such as Isolevuglandins (IsoLG) and malondialdehyde (MDA) that covalently bind plasma/cellular proteins, phospholipids, and DNA leading to altered function and toxicity. We examined whether scavenging reactive dicarbonyls with 5'-O-pentyl-pyridoxamine (PPM) protects against the development of IR and atherosclerosis in Ldlr-/- mice. METHODS Male or female Ldlr-/- mice were fed a western diet (WD) for 16 weeks and treated with PPM versus vehicle alone. Plaque extent, dicarbonyl-lysyl adducts, efferocytosis, apoptosis, macrophage inflammation, and necrotic area were measured. Plasma MDA-LDL adducts and the in vivo and in vitro effects of PPM on the ability of HDL to reduce macrophage cholesterol were measured. Blood Ly6Chi monocytes and ex vivo 5-ethynyl-2'-deoxyuridine (EdU) incorporation into bone marrow CD11b+ monocytes and CD34+ hematopoietic stem and progenitor cells (HSPC) were also examined. IR was examined by measuring fasting glucose/insulin levels and tolerance to insulin/glucose challenge. RESULTS PPM reduced the proximal aortic atherosclerosis by 48% and by 46% in female and male Ldlr-/- mice, respectively. PPM also decreased IR and hepatic fat and inflammation in male Ldlr-/- mice. Importantly, PPM decreased plasma MDA-LDL adducts and prevented the accumulation of plaque MDA- and IsoLG-lysyl adducts in Ldlr-/- mice. In addition, PPM increased the net cholesterol efflux capacity of HDL from Ldlr-/- mice and prevented both the in vitro impairment of HDL net cholesterol efflux capacity and apoAI crosslinking by MPO generated hypochlorous acid. Moreover, PPM decreased features of plaque instability including decreased proinflammatory M1-like macrophages, IL-1β expression, myeloperoxidase, apoptosis, and necrotic core. In contrast, PPM increased M2-like macrophages, Tregs, fibrous cap thickness, and efferocytosis. Furthermore, PPM reduced inflammatory monocytosis as evidenced by decreased blood Ly6Chi monocytes and proliferation of bone marrow monocytes and HSPC from Ldlr-/- mice. CONCLUSIONS PPM has pleotropic atheroprotective effects in a murine model of familial hypercholesterolemia, supporting the therapeutic potential of reactive dicarbonyl scavenging in the treatment of IR and atherosclerotic cardiovascular disease.
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Affiliation(s)
- Jiansheng Huang
- Department of Medicine, Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Huan Tao
- Department of Medicine, Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Patricia G. Yancey
- Department of Medicine, Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Zoe Leuthner
- Department of Medicine, Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Linda S. May-Zhang
- Department of Pharmacology, Vanderbilt University, Nashville, TN, United States
| | - Ju-Yang Jung
- Department of Medicine, Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Youmin Zhang
- Department of Medicine, Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Lei Ding
- Department of Medicine, Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Venkataraman Amarnath
- Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Dianxin Liu
- Department of Medicine, Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Sheila Collins
- Department of Medicine, Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, United States,Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, United States
| | - Sean S. Davies
- Department of Pharmacology, Vanderbilt University, Nashville, TN, United States
| | - MacRae F. Linton
- Department of Medicine, Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, United States,Department of Pharmacology, Vanderbilt University, Nashville, TN, United States,Corresponding author. Department of Cardiovascular Medicine, Atherosclerosis Research Unit, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN, United States.
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10
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Martos-Folgado I, del Monte-Monge A, Lorenzo C, Busse CE, Delgado P, Mur SM, Cobos-Figueroa L, Escolà-Gil JC, Martín-Ventura JL, Wardemann H, Ramiro AR. MDA-LDL vaccination induces athero-protective germinal-center-derived antibody responses. Cell Rep 2022; 41:111468. [DOI: 10.1016/j.celrep.2022.111468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 08/13/2022] [Accepted: 09/19/2022] [Indexed: 11/16/2022] Open
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11
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Zhang K, Xu Y, Yang Y, Guo M, Zhang T, Zong B, Huang S, Suo L, Ma B, Wang X, Wu Y, Brugger D, Chen Y. Gut microbiota-derived metabolites contribute negatively to hindgut barrier function development at the early weaning goat model. ANIMAL NUTRITION 2022; 10:111-123. [PMID: 35663372 PMCID: PMC9136126 DOI: 10.1016/j.aninu.2022.04.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 12/27/2021] [Accepted: 04/11/2022] [Indexed: 11/24/2022]
Abstract
Early weaning induces intestinal injury, leading to a series of long-term symptoms such as inflammation, malabsorption and diarrhea. In this study, we hypothesized that microbes and their metabolites modulate the host's inflammatory response to early weaning stress in a goat model. A total of 18 female Tibetan goat kids (n = 9) were weaned from their mothers at 28 d (D28) and 60 d (D60) postpartum. D60 and D28 groups were fed the same solid diet ad libitum from weaning to 75 d of age. The colonic epithelium was subject to RNA-sequencing, the caecal digesta metabolomics were assessed by liquid chromatography–tandem mass spectrometry (LC-MS/MS), and the caecal microbiota composition was analysed by 16S ribosomal RNA gene sequencing. We found that early weaning substantially increased the colonic pro-apoptotic gene expression of B-cell lymphoma associated X (Bax), caspase-9, and caspase-3, and decreased the expression of zonula occludens-1 (ZO-1) and claudin-1 (P < 0.01). In addition, a significant Bacteroides acidifaciens enrichment was observed in the hindgut of early-weaned goats (P < 0.01), which negatively correlated with lysophosphatidylcholine products. Similarly, the chemokine signaling, IL-17 signaling, and peroxisome proliferators-activated receptor (PPAR) signaling pathways were upregulated in the colonic mucosa of the early-weaned goats. By applying caecal microbiota transplantation from goats to defaunated C57/6J mice, we confirmed that caecal microbiota of D28 goat kids increased the relative abundance of B. acidifaciens and significantly up-regulated the genes of Bax, G protein–coupled receptor (GPR) 109A, GPR 43, fatty acid binding protein 6, nuclear receptor subfamily 1 group H member 3, angiotensin converting enzyme 2, and IL-6 expression (P < 0.05), and decreased ZO-1, and claudin-1 protein expression in the mice jejunum and colon (P < 0.001). These results proposed that the hindgut microbiota and metabolites mediate the barrier function weakening during early weaning, and the relative abundance of B. acidifaciens was negatively correlated with the hindgut barrier gene expression. This study demonstrates how weaning stress can affect key host–microbe interaction regulators in the hindgut, in a lysophosphatidylcholine dependent and independent manner. Furthermore, based on our mice data, these results are transferable to other mammal species.
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12
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Pei Y, Lui Y, Cai S, Zhou C, Hong P, Qian ZJ. A Novel Peptide Isolated from Microalgae Isochrysis zhanjiangensis Exhibits Anti-apoptosis and Anti-inflammation in Ox-LDL Induced HUVEC to Improve Atherosclerosis. PLANT FOODS FOR HUMAN NUTRITION (DORDRECHT, NETHERLANDS) 2022; 77:181-189. [PMID: 35476173 DOI: 10.1007/s11130-022-00965-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 04/05/2022] [Indexed: 06/14/2023]
Abstract
In the early stage, oxidized low density lipoprotein (ox-LDL) caused atherosclerosis, followed by human umbilical vein endothelial cells (HUVEC) damage, leading to a variety of cardiovascular related diseases. This study investigated the mechanism of nonapeptide (EMFGTSSET, ETT) isolated from in vitro gastrointestinal digestion of Isochrysis zhanjiang on endothelial cell inflammation and apoptosis induced by ox-LDL in atherosclerosis. At the cellular level, the results shown that ETT inhibited the up-regulation of oxidized low-density lipoprotein receptor-1 (LOX-1) induced by ox-LDL. Furthermore, ETT inhibited the fluorescence intensity of ROS, inflammatory factors (interleukin-6, interleukin-1β, and tumor necrosis factor-α) and the expression of cell adhesion molecules (vascular cell adhesion protein 1 and intercellular cell adhesion molecule-1). In addition, it also upregulates nuclear red blood cell 2 related factor 2 (Nrf2), heme oxygenase-1 (HO -1), p-Akt, and bcl-2 levels. But down-regulated the expression of p-p65, p-IκB-α, p-p38, p-ERK, p-JNK, bax, and cleaved caspase-9/-3 (c-c-9/-3), thereby inhibited ox-LDL induction inflammation and apoptosis of atherosclerosis. Through molecular docking, it was judged that the stable interaction between ETT and LOX-1 and VCAM-1 was maintained through hydrogen bonding. These results can provide a theoretical basis for ETT as a potential substance for the prevention and treatment of atherosclerosis, and further improve the value of Isochrysis zhanjiangensis.
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Affiliation(s)
- Yu Pei
- College of Food Science and Technology, School of Chemistry and Environment, Shenzhen Institute of Guangdong Ocean University, Zhanjiang 524088 and Shenzhen 518114, China
| | - Yi Lui
- College of Food Science and Technology, School of Chemistry and Environment, Shenzhen Institute of Guangdong Ocean University, Zhanjiang 524088 and Shenzhen 518114, China
| | - Shengxuan Cai
- College of Food Science and Technology, School of Chemistry and Environment, Shenzhen Institute of Guangdong Ocean University, Zhanjiang 524088 and Shenzhen 518114, China
| | - Chunxia Zhou
- College of Food Science and Technology, School of Chemistry and Environment, Shenzhen Institute of Guangdong Ocean University, Zhanjiang 524088 and Shenzhen 518114, China
- Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, 524025, China
| | - Pengzhi Hong
- College of Food Science and Technology, School of Chemistry and Environment, Shenzhen Institute of Guangdong Ocean University, Zhanjiang 524088 and Shenzhen 518114, China.
- Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, 524025, China.
| | - Zhong-Ji Qian
- College of Food Science and Technology, School of Chemistry and Environment, Shenzhen Institute of Guangdong Ocean University, Zhanjiang 524088 and Shenzhen 518114, China.
- Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, 524025, China.
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13
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Liu Y, Wang L, Li X, Luo M. Detailed sphingolipid profile responded to salt stress in cotton root and the GhIPCS1 is involved in the regulation of plant salt tolerance. PLANT SCIENCE : AN INTERNATIONAL JOURNAL OF EXPERIMENTAL PLANT BIOLOGY 2022; 316:111174. [PMID: 35151457 DOI: 10.1016/j.plantsci.2021.111174] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/23/2021] [Accepted: 12/27/2021] [Indexed: 05/24/2023]
Abstract
Sphingolipids are major structural components of membrane and active signaling molecules and play an important role in plant developmental processes and stress responses. As land salinization has increased globally, salinity has compromised the growth and productivity of crops such as cotton. Understanding the mechanisms of plant adaptation to salt stress is essential for breeding salt-tolerant crops. In this study, we explored the comprehensive metabolic profile of sphingolipids in cotton root under salt stress using lipidomics. 118 sphingolipid molecular species were identified, of which PhytoSph, PhytoCer, PhytoCer-OHFA, IPC, and GIPC were relatively high in content, and PhytoSph, PhytoCer, PhytoCer-OHFA, Phyto-GluCer, and IPC showed significant changes after salt stress, especially inositol phosphatidyl ceramide (IPC), which was significantly upregulated after salt treatment. Subsequently, we identified the genes encoding IPC synthase (IPCS), and ectopic expression of GhIPCS1 enhanced salt sensitivity in Arabidopsis, which might result from the disruption on the balance between various sphingolipid classes and/or molecular species. Overall, this study reveals key lipids and genes response to salt stress in cotton and provides a theoretical basis for the use of genetic engineering to improve cotton stress resistance.
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Affiliation(s)
- Yujie Liu
- Zhengzhou Research Base, State Key Laboratory of Cotton Biology, Zhengzhou University, Zhengzhou, China.
| | - Li Wang
- Zhengzhou Research Base, State Key Laboratory of Cotton Biology, Zhengzhou University, Zhengzhou, China; State Key Laboratory of Cotton Biology, Institute of Cotton Research, Chinese Academy of Agricultural Sciences, Anyang, China.
| | - Xing Li
- Zhengzhou Research Base, State Key Laboratory of Cotton Biology, Zhengzhou University, Zhengzhou, China.
| | - Ming Luo
- Zhengzhou Research Base, State Key Laboratory of Cotton Biology, Zhengzhou University, Zhengzhou, China; Key Laboratory of Biotechnology and Crop Quality, Improvement of Ministry of Agriculture, Biotechnology Research Center, Southwest University, Chongqing, China.
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14
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Brandau A, Ibrahim N, Klopf J, Hayden H, Ozsvar-Kozma M, Afonyushkin T, Bleichert S, Fuchs L, Watzinger V, Nairz V, Manville E, Kessler V, Stangl H, Eilenberg W, Neumayer C, Brostjan C. Association of Lipoproteins with Neutrophil Extracellular Traps in Patients with Abdominal Aortic Aneurysm. Biomedicines 2022; 10:biomedicines10020217. [PMID: 35203427 PMCID: PMC8869298 DOI: 10.3390/biomedicines10020217] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/15/2022] [Accepted: 01/17/2022] [Indexed: 02/01/2023] Open
Abstract
Neutrophil extracellular traps (NETs) are DNA–protein structures released by neutrophils in response to various stimuli, including oxidized, low-density lipoprotein (oxLDL). Accumulating evidence suggests a role for NETs in the pathogenesis of abdominal aortic aneurysm (AAA). In this study, we investigated the potential association of lipoprotein particles and NETs in AAA in comparison to non-AAA control groups. The concentrations of neutrophil myeloperoxidase (MPO), the NET parameters citrullinated histone H3 (citH3) and circulating cell-free DNA (cfDNA), as well as of blood lipids were determined in plasma or serum of patients with AAA (n = 40), peripheral artery occlusive disease (PAD; n = 40) and healthy donors (n = 29). A sandwich ELISA detecting oxidized phosphatidylcholine in association with apolipoprotein B-100 (oxPL/apoB) was applied to measure oxidized phospholipids in circulation. The effect of lipoparticles on NET formation was tested using a DNA release assay with isolated human neutrophils. Plasma MPO, citH3 and cfDNA levels were significantly increased in AAA patients in comparison to healthy donors and PAD patients. Plasma concentrations of citH3 positively correlated with serum oxPL/apoB in AAA patients. In functional in vitro assays, the addition of oxLDL induced NET formation in pre-stimulated neutrophils. In conclusion, our data suggest a promoting role of oxLDL on NET formation in AAA patients.
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Affiliation(s)
- Annika Brandau
- Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, Vienna General Hospital, 1090 Vienna, Austria; (A.B.); (N.I.); (J.K.); (H.H.); (S.B.); (L.F.); (V.W.); (V.N.); (E.M.); (V.K.); (W.E.); (C.N.)
| | - Nahla Ibrahim
- Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, Vienna General Hospital, 1090 Vienna, Austria; (A.B.); (N.I.); (J.K.); (H.H.); (S.B.); (L.F.); (V.W.); (V.N.); (E.M.); (V.K.); (W.E.); (C.N.)
| | - Johannes Klopf
- Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, Vienna General Hospital, 1090 Vienna, Austria; (A.B.); (N.I.); (J.K.); (H.H.); (S.B.); (L.F.); (V.W.); (V.N.); (E.M.); (V.K.); (W.E.); (C.N.)
| | - Hubert Hayden
- Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, Vienna General Hospital, 1090 Vienna, Austria; (A.B.); (N.I.); (J.K.); (H.H.); (S.B.); (L.F.); (V.W.); (V.N.); (E.M.); (V.K.); (W.E.); (C.N.)
| | - Maria Ozsvar-Kozma
- Department of Laboratory Medicine, Medical University of Vienna, Vienna General Hospital, 1090 Vienna, Austria; (M.O.-K.); (T.A.)
| | - Taras Afonyushkin
- Department of Laboratory Medicine, Medical University of Vienna, Vienna General Hospital, 1090 Vienna, Austria; (M.O.-K.); (T.A.)
| | - Sonja Bleichert
- Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, Vienna General Hospital, 1090 Vienna, Austria; (A.B.); (N.I.); (J.K.); (H.H.); (S.B.); (L.F.); (V.W.); (V.N.); (E.M.); (V.K.); (W.E.); (C.N.)
| | - Lukas Fuchs
- Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, Vienna General Hospital, 1090 Vienna, Austria; (A.B.); (N.I.); (J.K.); (H.H.); (S.B.); (L.F.); (V.W.); (V.N.); (E.M.); (V.K.); (W.E.); (C.N.)
| | - Viktoria Watzinger
- Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, Vienna General Hospital, 1090 Vienna, Austria; (A.B.); (N.I.); (J.K.); (H.H.); (S.B.); (L.F.); (V.W.); (V.N.); (E.M.); (V.K.); (W.E.); (C.N.)
| | - Verena Nairz
- Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, Vienna General Hospital, 1090 Vienna, Austria; (A.B.); (N.I.); (J.K.); (H.H.); (S.B.); (L.F.); (V.W.); (V.N.); (E.M.); (V.K.); (W.E.); (C.N.)
| | - Emely Manville
- Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, Vienna General Hospital, 1090 Vienna, Austria; (A.B.); (N.I.); (J.K.); (H.H.); (S.B.); (L.F.); (V.W.); (V.N.); (E.M.); (V.K.); (W.E.); (C.N.)
| | - Veronika Kessler
- Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, Vienna General Hospital, 1090 Vienna, Austria; (A.B.); (N.I.); (J.K.); (H.H.); (S.B.); (L.F.); (V.W.); (V.N.); (E.M.); (V.K.); (W.E.); (C.N.)
| | - Herbert Stangl
- Center for Pathobiochemistry and Genetics, Department of Medical Chemistry, Medical University of Vienna, 1090 Vienna, Austria;
| | - Wolf Eilenberg
- Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, Vienna General Hospital, 1090 Vienna, Austria; (A.B.); (N.I.); (J.K.); (H.H.); (S.B.); (L.F.); (V.W.); (V.N.); (E.M.); (V.K.); (W.E.); (C.N.)
| | - Christoph Neumayer
- Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, Vienna General Hospital, 1090 Vienna, Austria; (A.B.); (N.I.); (J.K.); (H.H.); (S.B.); (L.F.); (V.W.); (V.N.); (E.M.); (V.K.); (W.E.); (C.N.)
| | - Christine Brostjan
- Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, Vienna General Hospital, 1090 Vienna, Austria; (A.B.); (N.I.); (J.K.); (H.H.); (S.B.); (L.F.); (V.W.); (V.N.); (E.M.); (V.K.); (W.E.); (C.N.)
- Correspondence: ; Tel.: +43-1-40400-73514
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15
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Sphingolipids and Cholesterol. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1372:1-14. [DOI: 10.1007/978-981-19-0394-6_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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16
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Libby P. Inflammation during the life cycle of the atherosclerotic plaque. Cardiovasc Res 2021; 117:2525-2536. [PMID: 34550337 PMCID: PMC8783385 DOI: 10.1093/cvr/cvab303] [Citation(s) in RCA: 143] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammation orchestrates each stage of the life cycle of atherosclerotic plaques. Indeed, inflammatory mediators likely link many traditional and emerging risk factors with atherogenesis. Atheroma initiation involves endothelial activation with recruitment of leucocytes to the arterial intima, where they interact with lipoproteins or their derivatives that have accumulated in this layer. The prolonged and usually clinically silent progression of atherosclerosis involves periods of smouldering inflammation, punctuated by episodes of acute activation that may arise from inflammatory mediators released from sites of extravascular injury or infection or from subclinical disruptions of the plaque. Smooth muscle cells and infiltrating leucocytes can proliferate but also undergo various forms of cell death that typically lead to formation of a lipid-rich 'necrotic' core within the evolving intimal lesion. Extracellular matrix synthesized by smooth muscle cells can form a fibrous cap that overlies the lesion's core. Thus, during progression of atheroma, cells not only procreate but perish. Inflammatory mediators participate in both processes. The ultimate clinical complication of atherosclerotic plaques involves disruption that provokes thrombosis, either by fracture of the plaque's fibrous cap or superficial erosion. The consequent clots can cause acute ischaemic syndromes if they embarrass perfusion. Incorporation of the thrombi can promote plaque healing and progressive intimal thickening that can aggravate stenosis and further limit downstream blood flow. Inflammatory mediators regulate many aspects of both plaque disruption and healing process. Thus, inflammatory processes contribute to all phases of the life cycle of atherosclerotic plaques, and represent ripe targets for mitigating the disease.
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Affiliation(s)
- Peter Libby
- Division of Cardiovascular Medicine, Department of Medicine, Harvard Medical School, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, Boston, MA, USA
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17
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Gurzeler E, Ruotsalainen AK, Laine A, Valkama T, Kettunen S, Laakso M, Ylä-Herttuala S. SUR1-E1506K mutation impairs glucose tolerance and promotes vulnerable atherosclerotic plaque phenotype in hypercholesterolemic mice. PLoS One 2021; 16:e0258408. [PMID: 34767557 PMCID: PMC8589160 DOI: 10.1371/journal.pone.0258408] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/24/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND AND AIMS Diabetes is a major risk factor of atherosclerosis and its complications. The loss-of-function mutation E1506K in the sulfonylurea receptor 1 (SUR1-E1506K) induces hyperinsulinemia in infancy, leading to impaired glucose tolerance and increased risk of type 2 diabetes. In this study, we investigate the effect of SUR1-E1506K mutation on atherogenesis in hypercholesterolemic LDLR-/- mice. METHODS SUR1-E1506K mutated mice were cross-bred with LDLR-/- mice (SUR1Δ/LDLR-/-), 6 months old mice were fed a western-diet (WD) for 6 months to induce advanced atherosclerotic plaques. At the age of 12 months, atherosclerosis and plaque morphology were analyzed and mRNA gene expression were measured from aortic sections and macrophages. Glucose metabolism was characterized before and after WD. Results were compared to age-matched LDLR-/- mice. RESULTS Advanced atherosclerotic plaques did not differ in size between the two strains. However, in SUR1Δ/LDLR-/- mice, plaque necrotic area was increased and smooth muscle cell number was reduced, resulting in higher plaque vulnerability index in SUR1Δ/LDLR-/- mice compared to LDLR-/- mice. SUR1Δ/LDLR-/- mice exhibited impaired glucose tolerance and elevated fasting glucose after WD. The positive staining area of IL-1β and NLRP3 inflammasome were increased in aortic sections in SUR1Δ/LDLR-/- mice compared to LDLR-/- mice, and IL-18 plasma level was elevated in SUR1Δ/LDLR-/- mice. Finally, the mRNA expression of IL-1β and IL-18 were increased in SUR1Δ/LDLR-/- bone marrow derived macrophages in comparison to LDLR-/- macrophages in response to LPS. CONCLUSIONS SUR1-E1506K mutation impairs glucose tolerance and increases arterial inflammation, which promotes a vulnerable atherosclerotic plaque phenotype in LDLR-/- mice.
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MESH Headings
- Animals
- Aorta/pathology
- Aortic Diseases/blood
- Aortic Diseases/etiology
- Aortic Diseases/genetics
- Atherosclerosis/blood
- Atherosclerosis/etiology
- Atherosclerosis/genetics
- Blood Glucose/metabolism
- Cells, Cultured
- Diet, Western/adverse effects
- Disease Models, Animal
- Gene Expression
- Glucose Intolerance/genetics
- Hypercholesterolemia/blood
- Hypercholesterolemia/etiology
- Hypercholesterolemia/genetics
- Macrophages/metabolism
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mutation
- Myocytes, Smooth Muscle/metabolism
- Necrosis
- Phenotype
- Plaque, Atherosclerotic/blood
- Plaque, Atherosclerotic/etiology
- Plaque, Atherosclerotic/genetics
- RNA, Messenger/genetics
- Receptors, LDL/genetics
- Sulfonylurea Receptors/genetics
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Affiliation(s)
- Erika Gurzeler
- A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland
| | | | - Anssi Laine
- A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland
| | - Teemu Valkama
- A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland
| | - Sanna Kettunen
- A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland
| | - Markku Laakso
- Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Seppo Ylä-Herttuala
- A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland
- Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland
- Heart Center, Kuopio University Hospital, Kuopio, Finland
- * E-mail:
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18
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Shah AK, Dhalla NS. Effectiveness of Some Vitamins in the Prevention of Cardiovascular Disease: A Narrative Review. Front Physiol 2021; 12:729255. [PMID: 34690803 PMCID: PMC8531219 DOI: 10.3389/fphys.2021.729255] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 09/17/2021] [Indexed: 01/01/2023] Open
Abstract
By virtue of their regulatory role in various metabolic and biosynthetic pathways for energy status and cellular integrity, both hydro-soluble and lipo-soluble vitamins are considered to be involved in maintaining cardiovascular function in health and disease. Deficiency of some vitamins such as vitamin A, B6, folic acid, C, D, and E has been shown to be associated with cardiovascular abnormalities whereas supplementation with these vitamins has been claimed to reduce cardiovascular risk for hypertension, atherosclerosis, myocardial ischemia, arrhythmias, and heart failure. However, the data from several experimental and clinical studies for the pathogenesis of cardiovascular disease due to vitamin deficiency as well as therapy due to different vitamins are conflicting. In this article, we have attempted to review the existing literature on the role of different vitamins in cardiovascular disease with respect to their deficiency and supplementation in addition to examining some issues regarding their involvement in heart disease. Although both epidemiological and observational studies have shown some merit in the use of different antioxidant vitamins for the treatment of cardiovascular disorders, the results are not conclusive. Furthermore, in view of the complexities in the mechanisms of different cardiovascular disorders, no apparent involvement of any particular vitamin was seen in any specific cardiovascular disease. On the other hand, we have reviewed the evidence that deficiency of vitamin B6 promoted KCl-induced Ca2+ entry and reduced ATP-induced Ca2+-entry in cardiomyocytes in addition to decreasing sarcolemmal (SL) ATP binding. The active metabolite of vitamin B6, pyridoxal 5′-phosphate, attenuated arrhythmias due to myocardial infarction (MI) as well as cardiac dysfunction and defects in the sarcoplasmic reticulum (SR) Ca2+-transport in the ischemic-reperfused hearts. These observations indicate that both deficiency of some vitamins as well as pretreatments with different vitamins showing antioxidant activity affect cardiac function, metabolism and cation transport, and support the view that antioxidant vitamins or their metabolites may be involved in the prevention rather than the therapy of cardiovascular disease.
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Affiliation(s)
- Anureet K Shah
- School of Kinesiology, Nutrition and Food Science, California State University, Los Angeles, Los Angeles, CA, United States
| | - Naranjan S Dhalla
- Department of Physiology and Pathophysiology, St. Boniface Hospital Albrechtsen Research Centre, Max Rady College of Medicine, Institute of Cardiovascular Sciences, University of Manitoba, Winnipeg, MB, Canada
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19
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Ma S, Xia M, Gao X. Biomarker Discovery in Atherosclerotic Diseases Using Quantitative Nuclear Magnetic Resonance Metabolomics. Front Cardiovasc Med 2021; 8:681444. [PMID: 34395555 PMCID: PMC8356911 DOI: 10.3389/fcvm.2021.681444] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 07/02/2021] [Indexed: 12/23/2022] Open
Abstract
Despite great progress in the management of atherosclerosis (AS), its subsequent cardiovascular disease (CVD) remains the leading cause of morbidity and mortality. This is probably due to insufficient risk detection using routine lipid testing; thus, there is a need for more effective approaches relying on new biomarkers. Quantitative nuclear magnetic resonance (qNMR) metabolomics is able to phenotype holistic metabolic changes, with a unique advantage in regard to quantifying lipid-protein complexes. The rapidly increasing literature has indicated that qNMR-based lipoprotein particle number, particle size, lipid components, and some molecular metabolites can provide deeper insight into atherogenic diseases and could serve as novel promising determinants. Therefore, this article aims to offer an updated review of the qNMR biomarkers of AS and CVD found in epidemiological studies, with a special emphasis on lipoprotein-related parameters. As more researches are performed, we can envision more qNMR metabolite biomarkers being successfully translated into daily clinical practice to enhance the prevention, detection and intervention of atherosclerotic diseases.
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Affiliation(s)
- Shuai Ma
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
- Human Phenome Institute, Fudan University, Shanghai, China
| | - Mingfeng Xia
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
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20
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Pakzad B, Rajae E, Shahrabi S, Mansournezhad S, Davari N, Azizidoost S, Saki N. T-Cell Molecular Modulation Responses in Atherosclerosis Anergy. Lab Med 2021; 51:557-565. [PMID: 32106301 DOI: 10.1093/labmed/lmaa003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Atherosclerosis continues to be a major cause of death in patients with cardiovascular diseases. The cooperative role of immunity has been recently considered in atherosclerotic plaque inflammation, especially adaptive immune response by T cells. In this review, we examine the possible role of T cells in atherosclerosis-mediated inflammation and conceivable therapeutic strategies that can ameliorate complications of atherosclerosis. The cytokines secreted by T-lymphocyte subsets, different pathophysiological profiles of microRNAs (miRs), and the growth factor/receptor axis have diverse effects on the inflammatory cycle of atherosclerosis. Manipulation of miRNA expression and prominent growth factor receptors involved in inflammatory cytokine secretion in atherosclerosis can be considered diagnostic biomarkers in the induction of anergy and blockade of atherosclerotic development. This manuscript reviews immunomodulation of T cells responses in atherosclerosis anergy.
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Affiliation(s)
- Bahram Pakzad
- Internal Medicine Department, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Elham Rajae
- Department of Rheumatology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Saeid Shahrabi
- -Department of Biochemistry and Hematology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Somayeh Mansournezhad
- Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Nader Davari
- Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Shirin Azizidoost
- Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Najmaldin Saki
- Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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21
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Anti-inflammatory potential of simvastatin loaded nanoliposomes in 2D and 3D foam cell models. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2021; 37:102434. [PMID: 34214684 DOI: 10.1016/j.nano.2021.102434] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 05/10/2021] [Accepted: 05/31/2021] [Indexed: 12/17/2022]
Abstract
Atherosclerosis is a multifactorial disease triggered and sustained by risk factors such as high cholesterol, high blood pressure and unhealthy lifestyle. Inflammation plays a pivotal role in atherosclerosis pathogenesis. In this study, we developed a simvastatin (STAT) loaded nanoliposomal formulation (LIPOSTAT) which can deliver the drug into atherosclerotic plaque, when administered intravenously. This formulation is easily prepared, stable, and biocompatible with minimal burst release for effective drug delivery. 2D and 3D in vitro models were examined towards anti-inflammatory effects of STAT, both free and in combination with liposomes. LIPOSTAT induced greater cholesterol efflux in the 2D foam cells and significantly reduced inflammation in both 2D and 3D models. LIPOSTAT alleviated inflammation by reducing the secretion of early and late phase pro-inflammatory cytokines, monocyte adherence marker, and lipid accumulation cytokines. Additionally, the 3D foam cell spheroid model is a convenient and practical approach in testing various anti-atherosclerotic drugs without the need for human tissue.
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22
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Lin P, Ji HH, Li YJ, Guo SD. Macrophage Plasticity and Atherosclerosis Therapy. Front Mol Biosci 2021; 8:679797. [PMID: 34026849 PMCID: PMC8138136 DOI: 10.3389/fmolb.2021.679797] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 04/12/2021] [Indexed: 12/15/2022] Open
Abstract
Atherosclerosis is a chronic disease starting with the entry of monocytes into the subendothelium and the subsequent differentiation into macrophages. Macrophages are the major immune cells in atherosclerotic plaques and are involved in the dynamic progression of atherosclerotic plaques. The biological properties of atherosclerotic plaque macrophages determine lesion size, composition, and stability. The heterogenicity and plasticity of atherosclerotic macrophages have been a hotspot in recent years. Studies demonstrated that lipids, cytokines, chemokines, and other molecules in the atherosclerotic plaque microenvironment regulate macrophage phenotype, contributing to the switch of macrophages toward a pro- or anti-atherosclerosis state. Of note, M1/M2 classification is oversimplified and only represent two extreme states of macrophages. Moreover, M2 macrophages in atherosclerosis are not always protective. Understanding the phenotypic diversity and functions of macrophages can disclose their roles in atherosclerotic plaques. Given that lipid-lowering therapy cannot completely retard the progression of atherosclerosis, macrophages with high heterogeneity and plasticity raise the hope for atherosclerosis regression. This review will focus on the macrophage phenotypic diversity, its role in the progression of the dynamic atherosclerotic plaque, and finally discuss the possibility of treating atherosclerosis by targeting macrophage microenvironment.
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Affiliation(s)
- Ping Lin
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang, China
| | - Hong-Hai Ji
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang, China
| | - Yan-Jie Li
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang, China
| | - Shou-Dong Guo
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang, China
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23
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Öörni K, Kovanen PT. Aggregation Susceptibility of Low-Density Lipoproteins-A Novel Modifiable Biomarker of Cardiovascular Risk. J Clin Med 2021; 10:1769. [PMID: 33921661 PMCID: PMC8074066 DOI: 10.3390/jcm10081769] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/31/2021] [Accepted: 04/13/2021] [Indexed: 01/07/2023] Open
Abstract
Circulating low-density lipoprotein (LDL) particles enter the arterial intima where they bind to the extracellular matrix and become modified by lipases, proteases, and oxidizing enzymes and agents. The modified LDL particles aggregate and fuse into larger matrix-bound lipid droplets and, upon generation of unesterified cholesterol, cholesterol crystals are also formed. Uptake of the aggregated/fused particles and cholesterol crystals by macrophages and smooth muscle cells induces their inflammatory activation and conversion into foam cells. In this review, we summarize the causes and consequences of LDL aggregation and describe the development and applications of an assay capable of determining the susceptibility of isolated LDL particles to aggregate when exposed to human recombinant sphingomyelinase enzyme ex vivo. Significant person-to-person differences in the aggregation susceptibility of LDL particles were observed, and such individual differences largely depended on particle lipid composition. The presence of aggregation-prone LDL in the circulation predicted future cardiovascular events in patients with atherosclerotic cardiovascular disease. We also discuss means capable of reducing LDL particles' aggregation susceptibility that could potentially inhibit LDL aggregation in the arterial wall. Whether reductions in LDL aggregation susceptibility are associated with attenuated atherogenesis and a reduced risk of atherosclerotic cardiovascular diseases remains to be studied.
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Affiliation(s)
- Katariina Öörni
- Wihuri Research Institute, 00290 Helsinki, Finland;
- Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, 00014 Helsinki, Finland
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24
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Niepolski L, Drzewiecka H, Warchoł W. Circulating vascular endothelial growth factor receptor 2 levels and their association with lipid abnormalities in patients on hemodialysis. Biomed Rep 2021; 14:37. [PMID: 33692900 PMCID: PMC7938296 DOI: 10.3892/br.2021.1413] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 02/08/2021] [Indexed: 12/22/2022] Open
Abstract
The aim of the present study was to examine the association between the levels of circulating vascular endothelial growth factor receptor (VEGFR)2 levels, serum lipid composition and plasma receptor for advanced glycation end-products (RAGE) expression in patients undergoing hemodialysis (HD). A total of 50 patients on HD (27 men and 23 women; median age, 66 years; age range 28-88 years; HD mean time, 29.0, 3.9-157.0 months) were enrolled. Age-matched healthy subjects (n=26) were used as the control group. Plasma VEGFR2 and RAGE levels were determined using ELISA. Dyslipidemia (D) in patients on HD was diagnosed according to the Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines for Managing Dyslipidemias in Chronic Kidney Disease. Circulating VEGFR2, RAGE and serum lipids were compared between dyslipidemic and non-dyslipidemic patients on HD and controls. In patients on HD, the plasma VEGFR2 levels were lower compared with those in the healthy population. D was associated with high plasma VEGFR2 levels. The triglyceride/HDL-cholesterol ratio was strongly associated with plasma VEGFR2 levels. The plasma VEGFR2 concentration was associated with circulating RAGE levels. Therefore, circulating VEGFR2 levels may be partly associated with lipid abnormalities and plasma RAGE levels in patients receiving HD.
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Affiliation(s)
- Leszek Niepolski
- Department of Physiology, Poznan University of Medical Sciences, Poznań 60-781, Poland
| | - Hanna Drzewiecka
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznań 60-781, Poland
| | - Wojciech Warchoł
- Department of Ophthalmology and Optometry, Poznan University of Medical Sciences, Poznań 60-781, Poland
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25
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Valanti EK, Dalakoura-Karagkouni K, Siasos G, Kardassis D, Eliopoulos AG, Sanoudou D. Advances in biological therapies for dyslipidemias and atherosclerosis. Metabolism 2021; 116:154461. [PMID: 33290761 DOI: 10.1016/j.metabol.2020.154461] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 12/02/2020] [Accepted: 12/03/2020] [Indexed: 12/22/2022]
Abstract
Atherosclerosis is a multifactorial disease influenced by genetics, lifestyle and environmental factors. Despite therapeutic advances that reduce the risk of cardiovascular events, atherosclerosis-related diseases remain the leading cause of mortality worldwide. Precise targeting of genes involved in lipoprotein metabolism is an emerging approach for atherosclerosis prevention and treatment. This article focuses on the latest developments, clinical potential and current challenges of monoclonal antibodies, vaccines and genome/transcriptome modification strategies, including antisense oligonucleotides, genome/base editing and gene therapy. Multiple lipid lowering biological therapies have already been approved by the FDA with impressive results to date, while many more promising targets are being pursued in clinical trials or pre-clinical animal models.
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Affiliation(s)
- Eftaxia-Konstantina Valanti
- 4th Department of Internal Medicine, Clinical Genomics and Pharmacogenomics Unit, 'Attikon' Hospital, Medical School, National and Kapodistrian University of Athens, Greece; Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, Greece; Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Gerasimos Siasos
- First Department of Cardiology, Hippokration Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitris Kardassis
- Laboratory of Biochemistry, University of Crete Medical School Heraklion, Greece; Division of Gene Regulation and Genomics, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, Greece
| | - Aristides G Eliopoulos
- Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, Greece; Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Department of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Despina Sanoudou
- 4th Department of Internal Medicine, Clinical Genomics and Pharmacogenomics Unit, 'Attikon' Hospital, Medical School, National and Kapodistrian University of Athens, Greece; Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, Greece; Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
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26
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Oxidatively Modified LDL Suppresses Lymphangiogenesis via CD36 Signaling. Antioxidants (Basel) 2021; 10:antiox10020331. [PMID: 33672291 PMCID: PMC7926875 DOI: 10.3390/antiox10020331] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 02/13/2021] [Accepted: 02/17/2021] [Indexed: 02/06/2023] Open
Abstract
Arterial accumulation of plasma-derived LDL and its subsequent oxidation contributes to atherosclerosis. Lymphatic vessel (LV)-mediated removal of arterial cholesterol has been shown to reduce atherosclerotic lesion formation. However, the precise mechanisms that regulate LV density and function in atherosclerotic vessels remain to be identified. The aim of this study was to investigate the role of native LDL (nLDL) and oxidized LDL (oxLDL) in modulating lymphangiogenesis and underlying molecular mechanisms. Western blotting and immunostaining experiments demonstrated increased oxLDL expression in human atherosclerotic arteries. Furthermore, elevated oxLDL levels were detected in the adventitial layer, where LV are primarily present. Treatment of human lymphatic endothelial cells (LEC) with oxLDL inhibited in vitro tube formation, while nLDL stimulated it. Similar results were observed with Matrigel plug assay in vivo. CD36 deletion in mice and its siRNA-mediated knockdown in LEC prevented oxLDL-induced inhibition of lymphangiogenesis. In addition, oxLDL via CD36 receptor suppressed cell cycle, downregulated AKT and eNOS expression, and increased levels of p27 in LEC. Collectively, these results indicate that oxLDL inhibits lymphangiogenesis via CD36-mediated regulation of AKT/eNOS pathway and cell cycle. These findings suggest that therapeutic blockade of LEC CD36 may promote arterial lymphangiogenesis, leading to increased cholesterol removal from the arterial wall and reduced atherosclerosis.
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27
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Mathew AV, Zeng L, Atkins KB, Sadri KN, Byun J, Fujiwara H, Reddy P, Pennathur S. Deletion of bone marrow myeloperoxidase attenuates chronic kidney disease accelerated atherosclerosis. J Biol Chem 2021; 296:100120. [PMID: 33234591 PMCID: PMC7948401 DOI: 10.1074/jbc.ra120.014095] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 10/28/2020] [Accepted: 11/24/2020] [Indexed: 12/14/2022] Open
Abstract
Increased myeloperoxidase (MPO) expression and activity are associated with atherosclerotic disease in patients with chronic kidney disease (CKD). However, the causal relationship between MPO and the development and progression of atherosclerosis in patients with CKD is unknown. Eight-week-old male low-density-lipoprotein-receptor-deficient mice were subjected to 5/6 nephrectomy, irradiated, and transplanted with bone marrow from MPO-deficient mice to induce bone marrow MPO deletion (CKD-bMPOKO) or bone marrow from WT mice as a control to maintain preserved bone marrow MPO(CKD-bMPOWT). The mice were maintained on a high-fat/high-cholesterol diet for 16 weeks. As anticipated, both groups of mice exhibited all features of moderate CKD, including elevated plasma creatinine, lower hematocrit, and increased intact parathyroid hormone but did not demonstrate any differences between the groups. Irradiation and bone marrow transplantation did not further affect body weight, blood pressure, creatinine, or hematocrit in either group. The absence of MPO expression in the bone marrow and atherosclerotic lesions of the aorta in the CKD-bMPOKO mice was confirmed by immunoblot and immunohistochemistry, respectively. Decreased MPO activity was substantiated by the absence of 3-chlorotyrosine, a specific by-product of MPO, in aortic atherosclerotic lesions as determined by both immunohistochemistry and highly sensitive LC-MS. Quantification of the aortic lesional area stained with oil red O revealed that CKD-bMPOKO mice had significantly decreased aortic plaque area as compared with CKD-bMPOWT mice. This study demonstrates the reduction of atherosclerosis in CKD mice with the deletion of MPO in bone marrow cells, strongly implicating bone-marrow-derived MPO in the pathogenesis of CKD atherosclerosis.
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Affiliation(s)
- Anna V Mathew
- Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA.
| | - Lixia Zeng
- Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Kevin B Atkins
- Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Kiana N Sadri
- Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Jaeman Byun
- Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Hideaki Fujiwara
- Division of Hematology-Oncology, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Pavan Reddy
- Division of Hematology-Oncology, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Subramaniam Pennathur
- Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
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28
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Zhang S, Li L, Chen W, Xu S, Feng X, Zhang L. Natural products: The role and mechanism in low-density lipoprotein oxidation and atherosclerosis. Phytother Res 2020; 35:2945-2967. [PMID: 33368763 DOI: 10.1002/ptr.7002] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 10/30/2020] [Accepted: 12/13/2020] [Indexed: 12/11/2022]
Abstract
Atherosclerosis is a chronic inflammatory, metabolic, and epigenetic disease, which leads to the life-threatening coronary artery disease. Emerging studies from bench to bedside have demonstrated the pivotal role of low-density lipoprotein (LDL) oxidation in the initiation and progression of atherosclerosis. This article hereby reviews oxidation mechanism of LDL, and the pro-atherogenic and biomarker role of oxidized LDL in atherosclerosis. We also review the pharmacological effects of several representative natural products (vitamin E, resveratrol, quercetin, probucol, tanshinone IIA, epigallocatechin gallate, and Lycopene) in protecting against LDL oxidation and atherosclerosis. Clinical and basic research supports the beneficial effects of these natural products in inhibiting LDL oxidation and preventing atherosclerosis, but the data are still controversial. This may be related to factors such as the population and the dosage and time of taking natural products involved in different studies. Understanding the mechanism of LDL oxidation and effect of oxidized LDL help researchers to find novel therapies against atherosclerosis.
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Affiliation(s)
- Shengyu Zhang
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lingli Li
- Department of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, China
| | - Wenxu Chen
- Department of Pharmaceutics, College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
| | - Suowen Xu
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Xiaojun Feng
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lei Zhang
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.,Department of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, China
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29
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Yang X, Zhu K, Guo X, Pei Y, Zhao M, Song X, Li Y, Liu S, Li J. Constitutive expression of aldose reductase 1 from Zea mays exacerbates salt and drought sensitivity of transgenic Escherichia coli and Arabidopsis. PLANT PHYSIOLOGY AND BIOCHEMISTRY : PPB 2020; 156:436-444. [PMID: 33022480 DOI: 10.1016/j.plaphy.2020.09.029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 09/18/2020] [Indexed: 06/11/2023]
Abstract
Aldose reductases (ARs) have been considered to play important roles in sorbitol biosynthesis, cellular detoxification and stress response in some plants. ARs from maize are capable of catalyzing the oxidation of sorbitol to glucose. However, little is known how maize ARs response to abiotic stresses. In this work, we cloned one isoform of maize ARs (ZmAR1), and furthermore we analyzed the roles of ZmAR1 in response to salt and drought stresses at both prokaryotic and eukaryotic levels. ZmAR1 encodes a putative 35 kDa protein that contains 310 amino acids. Under normal growth conditions, ZmAR1 was expressed in maize seedlings, and the highest expression level was found in leaves. But when seedlings were subjected to drought or salt treatment, the expression levels of ZmAR1 were significantly reduced. The constitutive expression of ZmAR1 increased the sensitivity of recombinant E. coli cells to drought and salt stresses compared with the control. Under salt and drought stresses, transgenic Arabidopsis lines displayed lower seed germination rate, shorter seedling root length, lower chlorophyll content, lower survival rate and lower antioxidant enzyme activity than wild type (WT) plants, but transgenic Arabidopsis had higher relative conductivity, higher water loss rate, and more MDA content than WT. Meanwhile, the introduction of ZmAR1 into Arabidopsis changed the expression levels of some stress-related genes. Taken together, our results suggested that ZmAR1 might act as a negative regulator in response to salt and drought stresses in Arabidopsis by reducing the sorbitol content and modulating the expression levels of some stress-related genes.
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Affiliation(s)
- Xiaoying Yang
- College of Agronomy, Qingdao Agricultural University, Qingdao, 266109, China
| | - Kaili Zhu
- College of Agronomy, Qingdao Agricultural University, Qingdao, 266109, China
| | - Xinmei Guo
- College of Agronomy, Qingdao Agricultural University, Qingdao, 266109, China
| | - Yuhe Pei
- College of Agronomy, Qingdao Agricultural University, Qingdao, 266109, China
| | - Meiai Zhao
- College of Life Sciences, Qingdao Agricultural University, Qingdao, 266109, China
| | - Xiyun Song
- College of Agronomy, Qingdao Agricultural University, Qingdao, 266109, China.
| | - Yubin Li
- College of Agronomy, Qingdao Agricultural University, Qingdao, 266109, China
| | - Shutang Liu
- School of Resources and Environment, Qingdao Agricultural University, Qingdao, 266109, China
| | - Jun Li
- College of Agronomy, Qingdao Agricultural University, Qingdao, 266109, China.
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30
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Lian Z, Saeed A, Peng X, Perrard XD, Jia X, Hussain A, Ballantyne CM, Wu H. Monocyte phenotyping and management of lipoprotein X syndrome. J Clin Lipidol 2020; 14:850-858. [PMID: 33011137 DOI: 10.1016/j.jacl.2020.08.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 08/27/2020] [Accepted: 08/31/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Accumulation of lipoprotein X (LpX) in blood can cause severe hypercholesterolemia and cutaneous xanthomas. Monocytes sensitively sense lipid changes in circulation and contribute to inflammation. However, how monocytes respond to LpX is undefined. OBJECTIVE We examined the phenotype of monocytes from a patient, who had LpX, severe hypercholesterolemia, and extensive cutaneous xanthomas, and effects of semiselective plasmapheresis therapy (SPPT). METHOD Fluorescence-activated cell sorting and adhesion assays were used to examine monocyte phenotype and ex vivo oxidized low-density lipoprotein uptake and adhesion in the patient before and after treatment with SPPT. Effects of plasma from the patient on the phenotype and adhesion of monocytes from a healthy participant were determined. RESULTS SPPT improved hypercholesterolemia and cutaneous xanthomas. Before treatment, the patient had lower frequency of nonclassical monocytes but higher frequency of intermediate monocytes than the control participant. Before treatment, monocytes from the patient with LpX showed more intracellular lipid accumulation, alterations in several cell surface markers and intracellular cytokines, as well as enhanced oxidized low-density lipoprotein uptake and reduced adhesion compared with control. After SPPT, the phenotypes of monocytes from the patient with LpX were similar to control monocytes. Incubation with plasma from the patient before treatment as compared with plasma from the control participant or the patient after treatment increased CD11c expression and adhesion of monocytes from a healthy participant. CONCLUSION LpX-induced hypercholesterolemia increased lipid accumulation and altered the phenotype of monocytes, which may contribute to cutaneous xanthoma development. Removal of LpX by SPPT reduced lipid accumulation and improved monocyte phenotype, likely contributing to xanthoma resolution.
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Affiliation(s)
- Zeqin Lian
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Anum Saeed
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, TX, USA; Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Xueying Peng
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Department of Clinical Pharmacy, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | | | - Xiaoming Jia
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, TX, USA
| | - Aliza Hussain
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, TX, USA
| | - Christie M Ballantyne
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Huaizhu Wu
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
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31
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Zaric BL, Radovanovic JN, Gluvic Z, Stewart AJ, Essack M, Motwalli O, Gojobori T, Isenovic ER. Atherosclerosis Linked to Aberrant Amino Acid Metabolism and Immunosuppressive Amino Acid Catabolizing Enzymes. Front Immunol 2020; 11:551758. [PMID: 33117340 PMCID: PMC7549398 DOI: 10.3389/fimmu.2020.551758] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 08/25/2020] [Indexed: 02/05/2023] Open
Abstract
Cardiovascular disease is the leading global health concern and responsible for more deaths worldwide than any other type of disorder. Atherosclerosis is a chronic inflammatory disease in the arterial wall, which underpins several types of cardiovascular disease. It has emerged that a strong relationship exists between alterations in amino acid (AA) metabolism and the development of atherosclerosis. Recent studies have reported positive correlations between levels of branched-chain amino acids (BCAAs) such as leucine, valine, and isoleucine in plasma and the occurrence of metabolic disturbances. Elevated serum levels of BCAAs indicate a high cardiometabolic risk. Thus, BCAAs may also impact atherosclerosis prevention and offer a novel therapeutic strategy for specific individuals at risk of coronary events. The metabolism of AAs, such as L-arginine, homoarginine, and L-tryptophan, is recognized as a critical regulator of vascular homeostasis. Dietary intake of homoarginine, taurine, and glycine can improve atherosclerosis by endothelium remodeling. Available data also suggest that the regulation of AA metabolism by indoleamine 2,3-dioxygenase (IDO) and arginases 1 and 2 are mediated through various immunological signals and that immunosuppressive AA metabolizing enzymes are promising therapeutic targets against atherosclerosis. Further clinical studies and basic studies that make use of animal models are required. Here we review recent data examining links between AA metabolism and the development of atherosclerosis.
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Affiliation(s)
- Bozidarka L. Zaric
- Department of Radiobiology and Molecular Genetics, “VINČA” Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Jelena N. Radovanovic
- Department of Radiobiology and Molecular Genetics, “VINČA” Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Zoran Gluvic
- Department of Endocrinology and Diabetes, Faculty of Medicine, University Clinical-Hospital Centre Zemun-Belgrade, University of Belgrade, Belgrade, Serbia
| | - Alan J. Stewart
- School of Medicine, University of St Andrews, St Andrews, United Kingdom
| | - Magbubah Essack
- Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center, Computer (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Olaa Motwalli
- College of Computing and Informatics, Saudi Electronic University (SEU), Medina, Saudi Arabia
| | - Takashi Gojobori
- Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center, Computer (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
- Biological and Environmental Sciences and Engineering Division (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Esma R. Isenovic
- Department of Radiobiology and Molecular Genetics, “VINČA” Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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32
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Le Master E, Ahn SJ, Levitan I. Mechanisms of endothelial stiffening in dyslipidemia and aging: Oxidized lipids and shear stress. CURRENT TOPICS IN MEMBRANES 2020; 86:185-215. [PMID: 33837693 PMCID: PMC8168803 DOI: 10.1016/bs.ctm.2020.08.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Vascular stiffening of the arterial walls is well-known as a key factor in aging and the development of cardiovascular disease; however, the role of endothelial stiffness in vascular dysfunction is still an emerging topic. In this review, the authors discuss the impact of dyslipidemia, oxidized lipids, substrate stiffness, age and pro-atherogenic disturbed flow have on endothelial stiffness. Furthermore, we investigate several mechanistic pathways that are key contributors in endothelial stiffness and discuss their physiological effects in the onset of atherogenesis in the disturbed flow regions of the aortic vasculature. The findings in this chapter describe a novel paradigm of synergistic interaction of plasma dyslipidemia/oxidized lipids and pro-atherogenic disturbed shear stress, as well as aging has on endothelial stiffness and vascular dysfunction.
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Affiliation(s)
- Elizabeth Le Master
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Sang Joon Ahn
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Irena Levitan
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Illinois at Chicago, Chicago, IL, United States.
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Gorabi AM, Penson PE, Banach M, Motallebnezhad M, Jamialahmadi T, Sahebkar A. Epigenetic control of atherosclerosis via DNA methylation: A new therapeutic target? Life Sci 2020; 253:117682. [PMID: 32387418 DOI: 10.1016/j.lfs.2020.117682] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 04/01/2020] [Accepted: 04/15/2020] [Indexed: 02/07/2023]
Abstract
Atherosclerosis is a disease in which lipid-laden plaques are developed inside the vessel walls of arteries. The immune system is activated, resulting in inflammation and oxidative stress. Endothelial cells (ECs) are activated, arterial smooth muscle cells (SMCs) proliferate, macrophages are activated, and foam cells are developed, leading to dysfunctional ECs. Epigenetic regulatory mechanisms, including DNA methylation, histone modifications, and microRNAs are involved in the modulation of genes that play distinct roles in several aspects of cell biology and physiology, hence linking environmental stimuli to gene regulation. Recent research has investigated the involvement of DNA methylation in the etiopathogenesis of atherosclerosis, and several studies have documented the role of this mechanism in various aspects of the disease. Regulation of DNA methylation plays a critical role in the integrity of ECs, SMC proliferation and formation of atherosclerotic lesions. In this review, we seek to clarify the role of DNA methylation in the development of atherosclerosis through different mechanisms.
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Affiliation(s)
- Armita Mahdavi Gorabi
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Peter E Penson
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, Lodz, Poland; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
| | - Morteza Motallebnezhad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Tannaz Jamialahmadi
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Zhao TV, Li Y, Liu X, Xia S, Shi P, Li L, Chen Z, Yin C, Eriguchi M, Chen Y, Bernstein EA, Giani JF, Bernstein KE, Shen XZ. ATP release drives heightened immune responses associated with hypertension. Sci Immunol 2020; 4:4/36/eaau6426. [PMID: 31253642 DOI: 10.1126/sciimmunol.aau6426] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 05/30/2019] [Indexed: 12/12/2022]
Abstract
The cause of most hypertensive disease is unclear, but inflammation appears critical in disease progression. However, how elevated blood pressure initiates inflammation is unknown, as are the effects of high blood pressure on innate and adaptive immune responses. We now report that hypertensive mice have increased T cell responses to antigenic challenge and develop more severe T cell-mediated immunopathology. A root cause for this is hypertension-induced erythrocyte adenosine 5'-triphosphate (ATP) release, leading to an increase in plasma ATP levels, which begins soon after the onset of hypertension and stimulates P2X7 receptors on antigen-presenting cells (APCs), increasing APC expression of CD86. Hydrolyzing ATP or blocking the P2X7 receptor eliminated hypertension-induced T cell hyperactivation. In addition, pharmacologic or genetic blockade of P2X7 receptor activity suppressed the progression of hypertension. Consistent with the results in mice, we also found that untreated human hypertensive patients have significantly elevated plasma ATP levels compared with treated hypertensive patients or normotensive controls. Thus, a hypertension-induced increase in extracellular ATP triggers augmented APC and T cell function and contributes to the immune-mediated pathologic changes associated with hypertensive disease.
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Affiliation(s)
- Tuantuan V Zhao
- Department of Physiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yu Li
- Department of Physiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xiaoli Liu
- Department of Neurology, Zhejiang Hospital, Hangzhou, Zhejiang, China
| | - Shudong Xia
- Department of Cardiology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Peng Shi
- Department of Cardiology of the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Li Li
- Department of Pharmacy, Zhejiang Hospital, Hangzhou, Zhejiang, China
| | - Zexin Chen
- Center of Clinical Epidemiology & Biostatistics, Department of Science and Education, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Chunyou Yin
- Department of Physiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Masahiro Eriguchi
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.,Department of Nephrology, Nara Medical University, Kashihara, Nara, Japan
| | - Yayu Chen
- Department of Cardiology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Ellen A Bernstein
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jorge F Giani
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.,Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Kenneth E Bernstein
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.,Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Xiao Z Shen
- Department of Physiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
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Ruan Z, Chu T, Wu L, Zhang M, Zheng M, Zhang Q, Zhou M, Zhu G. miR-155 inhibits oxidized low-density lipoprotein-induced apoptosis in different cell models by targeting the p85α/AKT pathway. J Physiol Biochem 2020; 76:329-343. [PMID: 32277342 DOI: 10.1007/s13105-020-00738-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 03/26/2020] [Indexed: 12/17/2022]
Abstract
The apoptosis of vascular endothelial cells (VECs), vascular smooth muscle cells (VSMCs), and macrophages directly causes the instability or rupture of atherosclerotic plaques. Accumulating evidence suggests that oxidized low-density lipoprotein (OxLDL) could induce apoptosis via endogenous or exogenous pathways. Interestingly, it has been reported that microRNA155 (miR-155) plays a pivotal role in the regulation of apoptosis. Here, we hypothesized that overexpression of miR-155 could inhibit OxLDL-induced apoptosis by targeting the p85α/AKT pathway. In this study, we established models of OxLDL-induced apoptosis in mouse VECs, VSMCs, and macrophages. Furthermore, we explored the effects of miR-155 expression on the apoptosis of different cells, and ultimately revealed whether miR-155 regulated apoptosis by targeting the p85α/AKT pathway. The results demonstrated that miR-155 inhibited p85α expression and attenuated VEC, VSMC, and macrophage apoptosis, at least in part by suppressing the expression of p85α-activated AKT to inhibit apoptosis. Our findings collectively suggested that miR-155 attenuated OxLDL-mediated apoptosis in different cells by targeting p85α, supporting its possible therapeutic role in atherosclerosis.
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Affiliation(s)
- Zhimin Ruan
- Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650101, China
| | - Tianshu Chu
- Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650101, China
| | - Liyong Wu
- Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650101, China
| | - Mingguo Zhang
- Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650101, China
| | - Mei Zheng
- Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650101, China
| | - Qian Zhang
- Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650101, China
| | - Mingli Zhou
- Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650101, China
| | - Guofu Zhu
- Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650101, China.
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Abstract
PURPOSE OF REVIEW Atherosclerosis is characterized by accumulation of lipids and chronic inflammation in medium size to large arteries. Recently, RNA-based antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are being developed, along with small molecule-based drugs and monoclonal antibodies, for the treatment of risk factors associated with atherosclerosis.. The purpose of this review is to describe nucleic acid-based therapeutics and introduce novel RNAs that might become future tools for treatment of atherosclerosis. RECENT FINDINGS RNA-based inhibitors for PCSK9, Lp(a), ApoCIII, and ANGPTL3 have been successfully tested in phase II-III clinical trials. Moreover, multiple microRNA and long non-coding RNAs have been found to reduce atherogenesis in preclinical animal models. Clinical trials especially with ASOs and siRNAs directed to liver, targeting cholesterol and lipoprotein metabolism, have shown promising results. Additional research in larger patient cohorts is needed to fully evaluate the therapeutic potential of these new drugs.
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Affiliation(s)
- Petri Mäkinen
- A.I. Virtanen Institute, University of Eastern Finland, Neulaniementie 2, P.O. Box 1627, 70211, Kuopio, Finland
| | - Anna-Kaisa Ruotsalainen
- A.I. Virtanen Institute, University of Eastern Finland, Neulaniementie 2, P.O. Box 1627, 70211, Kuopio, Finland
| | - Seppo Ylä-Herttuala
- A.I. Virtanen Institute, University of Eastern Finland, Neulaniementie 2, P.O. Box 1627, 70211, Kuopio, Finland.
- Heart Center and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland.
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Rosenfeld ME, Palinski W, Ylä-Herttuala S, Carew TE. Macrophages, Endothelial Cells, and Lipoprotein Oxidation in the Pathogenesis of Atherosclerosis*. Toxicol Pathol 2020. [DOI: 10.1177/019262339001804a06] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
One of the earliest phenomena in the atherogenic process in cholesterol-fed rabbits appears to be the trapping of low density lipoproteins (LDL) at lesion-prone sites in the aorta. The resulting increase in residence time may facilitate oxidation of the lipoproteins, which, in turn, may be a chemotactic signal for monocytes to enter the intima. Oxidized lipoproteins may also be the major source of the cholesterol that the cells accumulate during their transformation into macrophage-derived foam cells (MFC). Adherent monocytes appear to cluster over small groups of subendothelial foam cells, perhaps in response to the enhanced expression of specific adhesion molecules on the surface of endothelial cells and/or monocytes following activation by oxidized lipoproteins. Lipoproteins oxidized by MFC may also injure endothelial cells causing them to retract or rupture. The resulting exposure of the MFC facilitates the formation of mural thrombi. MFC contain oxidation-specific lipid-protein adducts and specifically express the mRNA for 15-lipoxygenase, an enzyme potentially involved in lipoprotein oxidation. MFC isolated from atherosclerotic lesions and containing up to 600 μg cholesterol/mg protein are still capable of binding and degrading modified lipoproteins and affecting the oxidation of LDL.
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Affiliation(s)
- Michael E. Rosenfeld
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California 92093
| | - Wulf Palinski
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California 92093
| | - Seppo Ylä-Herttuala
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California 92093
| | - Thomas E. Carew
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California 92093
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Mastrogiovanni M, Trostchansky A, Rubbo H. Fatty acid nitration in human low-density lipoprotein. Arch Biochem Biophys 2020; 679:108190. [PMID: 31738891 DOI: 10.1016/j.abb.2019.108190] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 11/05/2019] [Accepted: 11/12/2019] [Indexed: 10/25/2022]
Abstract
Lipid nitration occurs during physiological and pathophysiological conditions, generating a variety of biomolecules capable to modulate inflammatory cell responses. Low-density lipoprotein (LDL) oxidation has been extensively related to atherosclerotic lesion development while oxidative modifications confer the particle pro-atherogenic features. Herein, we reviewed the oxidation versus nitration of human LDL protein and lipid fractions. We propose that unsaturated fatty acids present in LDL can be nitrated under mild nitration conditions, suggesting an anti-atherogenic role for LDL carrying nitro-fatty acids (NFA).
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Affiliation(s)
- Mauricio Mastrogiovanni
- Departamento de Bioquímica, Facultad de Medicina and Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay
| | - Andrés Trostchansky
- Departamento de Bioquímica, Facultad de Medicina and Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay
| | - Homero Rubbo
- Departamento de Bioquímica, Facultad de Medicina and Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay.
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Caiati C, Pollice P, Favale S, Lepera ME. The Herbicide Glyphosate and Its Apparently Controversial Effect on Human Health: An Updated Clinical Perspective. Endocr Metab Immune Disord Drug Targets 2020; 20:489-505. [PMID: 31613732 DOI: 10.2174/1871530319666191015191614] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 09/03/2019] [Accepted: 09/04/2019] [Indexed: 01/18/2023]
Abstract
BACKGROUND Glyphosate (G) is the most common weed-killer in the world. Every year tons and tons of G are applied on crop fields. G was first introduced in the mid 1970s and since then its usage has gradually increased to reach a peak since 2005. Now G usage is approximately 100 -fold what it was in 1970. Its impact on human health was considered benign at the beginning. But over the years, evidence of a pervasive negative effect of this pesticide on humans has been mounting. Nonetheless, G usage is allowed by government health control agencies (both in the United States and Europe), that rely upon the evidence produced by the G producer. However, the IARC (International Agency for Research on Cancer) in 2015 has stated that G is probable carcinogenic (class 2A), the second highest class in terms of risk. OBJECTIVE In this review, we explore the effect of G on human health, focusing in particular on more recent knowledge. RESULTS We have attempted to untangle the controversy about the dangers of the product for human beings in view of a very recent development, when the so -called Monsanto Papers, consisting of Emails and memos from Monsanto came to light, revealing a coordinated strategy to manipulate the debate about the safety of glyphosate to the company's advantage. CONCLUSION The story of G is a recurrent one (see the tobacco story), that seriously jeopardizes the credibility of the scientific study in the modern era.
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Affiliation(s)
- Carlo Caiati
- Department of Emergency and Organ Transplantation, Unit of Cardiovascular Diseases, University of Bari, Bari, Italy
| | - Paolo Pollice
- Department of Emergency and Organ Transplantation, Unit of Cardiovascular Diseases, University of Bari, Bari, Italy
| | - Stefano Favale
- Department of Emergency and Organ Transplantation, Unit of Cardiovascular Diseases, University of Bari, Bari, Italy
| | - Mario Erminio Lepera
- Department of Emergency and Organ Transplantation, Unit of Cardiovascular Diseases, University of Bari, Bari, Italy
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Couto NF, Rezende L, Fernandes-Braga W, Alves AP, Agero U, Alvarez-Leite J, Damasceno NRT, Castro-Gomes T, Andrade LO. OxLDL alterations in endothelial cell membrane dynamics leads to changes in vesicle trafficking and increases cell susceptibility to injury. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2019; 1862:183139. [PMID: 31812625 DOI: 10.1016/j.bbamem.2019.183139] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 11/14/2019] [Accepted: 11/27/2019] [Indexed: 02/07/2023]
Abstract
Plasma membrane repair (PMR) is an important process for cell homeostasis, especially for cells under constant physical stress. Repair involves a sequence of Ca2+-dependent events, including lysosomal exocytosis and subsequent compensatory endocytosis. Cholesterol sequestration from plasma membrane causes actin cytoskeleton reorganization and polymerization, increasing cell stiffness, which leads to exocytosis and reduction of a peripheral pool of lysosomes involved in PMR. These changes in mechanical properties are similar to those observed in cells exposed to oxidized Low Density Lipoprotein (oxLDL), a key molecule during atherosclerosis development. Using a human umbilical vein endothelial cell line (EAhY926) we evaluated the influence of mechanical modulation induced by oxLDL in PMR and its effect in endothelial fragility. Similar to MβCD (a drug capable of sequestering cholesterol) treatment, oxLDL exposure led to actin reorganization and de novo polymerization, as well as an increase in cell rigidity and lysosomal exocytosis. Additionally, for both MβCD and oxLDL treated cells, there was an initial increase in endocytic events, likely triggered by the peak of exocytosis induced by both treatments. However, no further endocytic events were observed, suggesting that constitutive endocytosis is blocked upon treatment and that the reorganized cytoskeleton function as a mechanical barrier to membrane traffic. Finally, the increase in cell rigidity renders cells more prone to mechanical injury. Together, these data show that mechanical modulation induced by oxLDL exposure not only alters membrane traffic in cells, but also makes them more susceptible to mechanical injury, which may likely contribute to the initial steps of atherosclerosis development.
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Affiliation(s)
- Natália Fernanda Couto
- Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Luisa Rezende
- Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Weslley Fernandes-Braga
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Ana Paula Alves
- Department of Physics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Ubirajara Agero
- Department of Physics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Jacqueline Alvarez-Leite
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | | | - Thiago Castro-Gomes
- Department of Parasitology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Luciana O Andrade
- Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
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Clemens DL, Duryee MJ, Hall JH, Thiele GM, Mikuls TR, Klassen LW, Zimmerman MC, Anderson DR. Relevance of the antioxidant properties of methotrexate and doxycycline to their treatment of cardiovascular disease. Pharmacol Ther 2019; 205:107413. [PMID: 31626869 DOI: 10.1016/j.pharmthera.2019.107413] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 09/15/2019] [Indexed: 12/21/2022]
Abstract
Many medications exhibit clinical benefits that are unrelated to their primary therapeutic uses. In many cases, the mechanisms underpinning these pleotropic effects are unknown. Two commonly prescribed medications that exhibit pleotropic benefits in cardiovascular disease and other diseases associated with chronic inflammation are methotrexate (MTX) and doxycycline (DOX). The vast majority of cardiovascular disease is associated with atherosclerosis. Because atherosclerosis is a chronic inflammatory disease, possible mechanisms by which MTX and DOX reduce inflammation have been investigated. Interestingly, the primary structure of both of these medications contain aromatic phenolic rings, which resemble polyphenols that are known to possess antioxidant activity. Inflammation and oxidative stress are intimately related. Inflammation promotes oxidative stress, which in turn leads to further inflammation; in this way, oxidative stress and inflammation can establish a self-perpetuating cycle. It has been shown that MTX and DOX act as antioxidants and are capable of scavenging free radicals and the reactive oxygen species (ROS) superoxide (O2-). Furthermore, both MTX and DOX inhibit the formation of malondialdehyde acetaldehyde (MAA) adducts, products of oxidative stress and lipid peroxidation. Importantly, MAA-adducts are highly immunogenic and initiate inflammatory responses; thereby, fueling the cycle of inflammation and oxidative stress that results in chronic inflammation. Thus, reducing the formation of MAA-adducts may ameliorate inflammation that leads to ROS production and in this way, break the self-sustaining cycle of oxidative stress and inflammation. It is possible that the under-recognized antioxidant properties of these medications may be a mechanism by which they and other medications provide pleotropic benefit in the treatment of chronic inflammatory disease.
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Affiliation(s)
- Dahn L Clemens
- Department of Internal Medicine, University of Nebraska Medical Center, 982650 Nebraska Medical Center, Omaha, NE, 68198-2265, United States; Veterans Affairs (VA) Nebraska-Western Iowa Health Care System, 4101 Woolworth Ave., Omaha, NE, 68105, United States; Fred and Pamela Buffet Cancer Center, Nebraska Medical Center, Omaha, NE, 68114, United States
| | - Michael J Duryee
- Department of Internal Medicine, University of Nebraska Medical Center, 982650 Nebraska Medical Center, Omaha, NE, 68198-2265, United States; Veterans Affairs (VA) Nebraska-Western Iowa Health Care System, 4101 Woolworth Ave., Omaha, NE, 68105, United States
| | - Johnathan H Hall
- Department of Internal Medicine, University of Nebraska Medical Center, 982650 Nebraska Medical Center, Omaha, NE, 68198-2265, United States
| | - Geoffrey M Thiele
- Department of Internal Medicine, University of Nebraska Medical Center, 982650 Nebraska Medical Center, Omaha, NE, 68198-2265, United States; Veterans Affairs (VA) Nebraska-Western Iowa Health Care System, 4101 Woolworth Ave., Omaha, NE, 68105, United States
| | - Ted R Mikuls
- Department of Internal Medicine, University of Nebraska Medical Center, 982650 Nebraska Medical Center, Omaha, NE, 68198-2265, United States; Veterans Affairs (VA) Nebraska-Western Iowa Health Care System, 4101 Woolworth Ave., Omaha, NE, 68105, United States
| | - Lynell W Klassen
- Department of Internal Medicine, University of Nebraska Medical Center, 982650 Nebraska Medical Center, Omaha, NE, 68198-2265, United States
| | - Matthew C Zimmerman
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 982650 Nebraska Medical Center, Omaha, NE, 68198-2265, United States
| | - Daniel R Anderson
- Department of Internal Medicine, University of Nebraska Medical Center, 982650 Nebraska Medical Center, Omaha, NE, 68198-2265, United States.
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Hokkanen K, Tirronen A, Ylä-Herttuala S. Intestinal lymphatic vessels and their role in chylomicron absorption and lipid homeostasis. Curr Opin Lipidol 2019; 30:370-376. [PMID: 31361624 DOI: 10.1097/mol.0000000000000626] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW In this review, we describe novel findings related to intestinal lipid transport in lymphatic vessels. RECENT FINDINGS Studies have shown that chylomicron entry to lacteals and lymph movement in intestinal lymphatic capillaries is an active process. Regulators of this intestinal chylomicron transport include among others the autonomous nervous system, transcription factors like PLAGL2, and molecular regulators, such as VEGF-A/Nrp1/VEGFR1, VEGF-C/VEGFR3, DLL4, CALCRL and GLP-2. Chylomicron transport in intestinal lymphatics is now emerging not only as an option for drug delivery but also as a new candidate for drug targeting in lipid-related disorders. SUMMARY Dysfunctions of lymphatic lipid transport can result in conditions such as dyslipidaemia. Intestinal lymphatics also provide several potential therapeutic possibilities: molecular regulation of lacteal cell-to-cell junctioning and lymph flow could provide new ways of treating conditions like hyperlipidaemia and associated diseases, such as atherosclerosis and other cardiovascular diseases, obesity, diabetes and fatty-liver disease. The intestinal lymphatic system can also be employed to deliver lipid nanoparticles as drug carriers to the venous circulation for improved treatment outcome. These findings highlight the importance and need for research on the different players of intestinal lymphatics in dietary lipid handling and therapeutic applications.
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Affiliation(s)
- Krista Hokkanen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland
| | - Annakaisa Tirronen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland
| | - Seppo Ylä-Herttuala
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland
- Heart Center and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland
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Surendran A, Zhang H, Winter T, Edel A, Aukema H, Ravandi A. Oxylipin profile of human low-density lipoprotein is dependent on its extent of oxidation. Atherosclerosis 2019; 288:101-111. [DOI: 10.1016/j.atherosclerosis.2019.07.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 07/02/2019] [Accepted: 07/17/2019] [Indexed: 11/16/2022]
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Lopes-Virella MF, Bebu I, Hunt KJ, Virella G, Baker NL, Braffett B, Gao X, Lachin JM. Immune Complexes and the Risk of CVD in Type 1 Diabetes. Diabetes 2019; 68:1853-1860. [PMID: 31217176 PMCID: PMC6702641 DOI: 10.2337/db19-0358] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 06/17/2019] [Indexed: 12/15/2022]
Abstract
We investigated whether the composition of modified forms of LDL in circulating immune complexes (LDL-ICs) was associated with cardiovascular disease (CVD) outcomes, including any CVD, major adverse cardiac and cerebrovascular events (MACCE), myocardial infarction (MI), and coronary artery disease, in type 1 diabetes (T1D). Our results demonstrate that the baseline levels of oxidized LDL (oxLDL), MDA-modified LDL (MDA-LDL), and advanced glycosylation-modified LDL (AGE-LDL) in circulating ICs were associated with the four CVD outcomes in unadjusted models, and adjustment by age and mean HbA1c only resulted in minimal reduction of these associations. After adjustments were made for other cardiovascular risk factors, particularly LDL cholesterol, oxLDL-IC and MDA-LDL-IC remained independently associated with the risk of CVD, and oxLDL-IC was independently associated with the risk of MACCE and MI. In the majority of cases, the baseline levels of modified LDL-IC (measured many years before the occurrence of any CVD event) were associated with the risk of CVD over a 25-year period even after adjustment for other risk factors (including LDL cholesterol). Therefore, modified LDL biomarkers may help identify patients with T1D at high risk for MACCE and CVD events very early in the evolution of the disease, before other signals of disease are apparent.
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Affiliation(s)
| | - Ionut Bebu
- Biostatistics Center, The George Washington University, Rockville, MD
| | - Kelly J Hunt
- Medical University of South Carolina, Charleston, SC
| | | | | | - Barbara Braffett
- Biostatistics Center, The George Washington University, Rockville, MD
| | - Xiaoyu Gao
- Biostatistics Center, The George Washington University, Rockville, MD
| | - John M Lachin
- Biostatistics Center, The George Washington University, Rockville, MD
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Fan C, Huang T, Kong X, Zhang X, Zou Z, Xiao J. Circulating vitamin E and cardiometabolic measures: a Mendelian randomization analysis. J Clin Biochem Nutr 2019; 65:160-169. [PMID: 31592210 DOI: 10.3164/jcbn.19-12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 04/25/2019] [Indexed: 12/14/2022] Open
Abstract
Although a large body of literature reported that high intake of vitamin E played a possible role in reducing risk of cardiometabolic diseases, conflicting results were also found in some observational studies due to confounding factors. Hence, we used a Mendelian randomization study as an alternative way to examine the causality between circulating vitamin E and cardiometabolic diseases. Summary-level data were extracted from consortia and three single nucleotide polymorphisms were used as instrumental variables. Our study showed that a one-SD increase in circulating vitamin E levels was causally associated with an increased risk of coronary artery disease [odds ratio (OR) 3.16 (95%CI 1.74, 5.73); p = 1.91 × 10-3] at the Bonferroni-adjusted level of significance (p<0.005). Moreover, a one-SD increase in circulating vitamin E levels was associated with a 0.572-SD increase in low density lipoprotein cholesterol (mg/dl), a 0.693-SD increase in total cholesterol (mg/dl), and a 1.45-SD increase in triglyceride (mg/dl), but a 0.502-SD decrease in high density lipoprotein cholesterol (mg/dl) at the Bonferroni-adjusted level of significance (p<0.0028). Our findings indicated that genetically elevated vitamin E was associated with increased risk of coronary artery disease, suggesting an adverse causality between circulating vitamin E and coronary artery disease.
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Affiliation(s)
- Chuanlong Fan
- Medical School, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang 315211, China
| | - Tao Huang
- Department of Epidemiology & Biostatistics, School of Public Health, Peking University, 5 Summer Palace Road, Haidian District, Beijing 100000, China.,Department of Global Health, School of Public Health, Peking University, 5 Summer Palace Road, Haidian District, Beijing 100000, China.,Key Laboratory of Molecular Cardiovascular Sciences Ministry of Education, 5 Summer Palace Road, Haidian District, Beijing 100000, China
| | - Xuejun Kong
- Synapse program/Martinos Center, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129, USA
| | - Xiaohong Zhang
- Medical School, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang 315211, China
| | - Zuquan Zou
- Medical School, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang 315211, China
| | - Jing Xiao
- Beijing Friendship Hospital, Capital Medical University, 95 Yongan Road, Xuanwu District, Beijing 100000, China
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Tirronen A, Vuorio T, Kettunen S, Hokkanen K, Ramms B, Niskanen H, Laakso H, Kaikkonen MU, Jauhiainen M, Gordts PLSM, Ylä-Herttuala S. Deletion of Lymphangiogenic and Angiogenic Growth Factor VEGF-D Leads to Severe Hyperlipidemia and Delayed Clearance of Chylomicron Remnants. Arterioscler Thromb Vasc Biol 2019; 38:2327-2337. [PMID: 30354205 DOI: 10.1161/atvbaha.118.311549] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Objective- Dyslipidemia is one of the key factors behind coronary heart disease. Blood and lymphatic vessels play pivotal roles in both lipoprotein metabolism and development of atherosclerotic plaques. Recent studies have linked members of VEGF (vascular endothelial growth factor) family to lipid metabolism, but the function of VEGF-D has remained unexplored. Here, we investigated how the deletion of VEGF-D affects lipid and lipoprotein metabolism in atherogenic LDLR-/- ApoB100/100 mice. Approach and Results- Deletion of VEGF-D (VEGF-D-/-LDLR-/-ApoB100/100) led to markedly elevated plasma cholesterol and triglyceride levels without an increase in atherogenesis. Size distribution and hepatic lipid uptake studies confirmed a delayed clearance of large chylomicron remnant particles that cannot easily penetrate through the vascular endothelium. Mechanistically, the inhibition of VEGF-D signaling significantly decreased the hepatic expression of SDC1 (syndecan 1), which is one of the main receptors for chylomicron remnant uptake when LDLR is absent. Immunohistochemical staining confirmed reduced expression of SDC1 in the sinusoidal surface of hepatocytes in VEGF-D deficient mice. Furthermore, hepatic RNA-sequencing revealed that VEGF-D is also an important regulator of genes related to lipid metabolism and inflammation. The lack of VEGF-D signaling via VEGFR3 (VEGF receptor 3) led to lowered expression of genes regulating triglyceride and cholesterol production, as well as downregulation of peroxisomal β-oxidation pathway. Conclusions- These results demonstrate that VEGF-D, a powerful lymphangiogenic and angiogenic growth factor, is also a major regulator of chylomicron metabolism in mice.
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Affiliation(s)
- Annakaisa Tirronen
- From the A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (A.T., T.V., S.K., K.H., H.N., H.L., M.U.K., S.Y.-H.)
| | - Taina Vuorio
- From the A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (A.T., T.V., S.K., K.H., H.N., H.L., M.U.K., S.Y.-H.)
| | - Sanna Kettunen
- From the A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (A.T., T.V., S.K., K.H., H.N., H.L., M.U.K., S.Y.-H.)
| | - Krista Hokkanen
- From the A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (A.T., T.V., S.K., K.H., H.N., H.L., M.U.K., S.Y.-H.)
| | - Bastian Ramms
- Division of Endocrinology and Metabolism, Department of Medicine (B.R., P.L.S.M.G.), University of California San Diego, La Jolla, CA.,Department of Chemistry, Biochemistry I, Bielefeld University, Germany (B.R.)
| | - Henri Niskanen
- From the A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (A.T., T.V., S.K., K.H., H.N., H.L., M.U.K., S.Y.-H.)
| | - Hanne Laakso
- From the A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (A.T., T.V., S.K., K.H., H.N., H.L., M.U.K., S.Y.-H.)
| | - Minna U Kaikkonen
- From the A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (A.T., T.V., S.K., K.H., H.N., H.L., M.U.K., S.Y.-H.)
| | - Matti Jauhiainen
- Genomics and Biomarkers Unit, National Institute for Health and Welfare, Biomedicum, Helsinki, Finland (M.J.)
| | - Philip L S M Gordts
- Division of Endocrinology and Metabolism, Department of Medicine (B.R., P.L.S.M.G.), University of California San Diego, La Jolla, CA.,Glycobiology Research and Training Center (P.L.S.M.G.), University of California San Diego, La Jolla, CA
| | - Seppo Ylä-Herttuala
- From the A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (A.T., T.V., S.K., K.H., H.N., H.L., M.U.K., S.Y.-H.).,Heart Center and Gene Therapy Unit, Kuopio University Hospital, Finland (S.Y.-H.)
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Rahman M, Steuer J, Gillgren P, Végvári Á, Liu A, Frostegård J. Malondialdehyde Conjugated With Albumin Induces Pro-Inflammatory Activation of T Cells Isolated From Human Atherosclerotic Plaques Both Directly and Via Dendritic Cell-Mediated Mechanism. JACC Basic Transl Sci 2019; 4:480-494. [PMID: 31468003 PMCID: PMC6712057 DOI: 10.1016/j.jacbts.2019.03.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 03/11/2019] [Accepted: 03/13/2019] [Indexed: 12/14/2022]
Abstract
Human dendritic cells were differentiated from blood monocytes and treated with malondialdehyde (MDA) conjugated with human serum albumin (HSA). Autologous T cells from human plaques or blood were co-cultured with the pre-treated dendritic cells or treated directly. MDA modifications were studied by mass spectrometry. MDA-HSA induced a pro-inflammatory DC-mediated T-cell activation and also a strong direct effect on T cells, inhibited by an inhibitor of oxidative stress and antibodies against MDA. Atherogenic heat shock protein-60 was strongly induced in T cells activated by MDA-HSA. Two peptide modifications in atherosclerotic patients' HSA were similar to those present in in vitro MDA-modified HSA.
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Key Words
- ATP, adenosine triphosphate
- CVD, cardiovascular disease
- DC, dendritic cell
- GM-CSF, granulocyte-macrophage colony-stimulating factor
- HLA, human leukocyte antigen
- HSA, human serum albumin
- HSP, heat shock protein
- IFN, interferon
- IL, interleukin
- IgM, immunoglobulin M
- LDL, low-density lipoprotein
- MDA, malondialdehyde
- MS, mass spectrometry
- OxLDL, oxidized low-density lipoprotein
- PCR, polymerase chain reaction
- T cells
- TCR, T-cell receptor
- TGF, transforming growth factor
- TLR, Toll-like receptor
- TNF, tumor necrosis factor
- atherosclerosis
- dendritic cells
- malondialdehyde
- oxidized low-density lipoprotein
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Affiliation(s)
- Mizanur Rahman
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Johnny Steuer
- Section of Vascular Surgery, Department of Surgery, Södersjukhuset, Institution of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden
| | - Peter Gillgren
- Section of Vascular Surgery, Department of Surgery, Södersjukhuset, Institution of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden
| | - Ákos Végvári
- Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Biomedicum, Karolinska Institutet, Stockholm, Sweden
| | - Anquan Liu
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Johan Frostegård
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
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Affiliation(s)
- James J DiNicolantonio
- Preventive cardiology, University of Missouri-Kansas City, Saint Lukes Mid America Heart Institute, Kansas City, Missouri, USA
| | - James OKeefe
- Preventive cardiology, University of Missouri-Kansas City, Saint Lukes Mid America Heart Institute, Kansas City, Missouri, USA
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Pietiäinen M, Liljestrand JM, Kopra E, Pussinen PJ. Mediators between oral dysbiosis and cardiovascular diseases. Eur J Oral Sci 2019; 126 Suppl 1:26-36. [PMID: 30178551 DOI: 10.1111/eos.12423] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/22/2018] [Indexed: 12/11/2022]
Abstract
Clinical periodontitis is associated with an increased risk for cardiovascular diseases (CVDs) through systemic inflammation as the etiopathogenic link. Whether the oral microbiota, especially its quality, quantity, serology, and virulence factors, plays a role in atherogenesis is not clarified. Patients with periodontitis are exposed to bacteria and their products, which have access to the circulation directly through inflamed oral tissues and indirectly (via saliva) through the gastrointestinal tract, resulting in systemic inflammatory and immunologic responses. Periodontitis is associated with persistent endotoxemia, which has been identified as a notable cardiometabolic risk factor. The serology of bacterial biomarkers for oral dysbiosis is associated with an increased risk for subclinical atherosclerosis, prevalent and future coronary artery disease, and incident and recurrent stroke. In addition to species-specific antibodies, the immunologic response includes persistent, cross-reactive, proatherogenic antibodies against host-derived antigens. Periodontitis may affect lipoprotein metabolism at all levels, and all lipoprotein classes are affected. Periodontitis or its bacterial signatures may be involved not only in increased storage of proatherogenic lipids but also in attenuation of the anti-atherogenic processes, thereby putatively increasing the net risk of atherosclerosis. In this review we summarize possible molecular mediators between the dysbiotic oral microbiota and atherosclerotic processes.
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Affiliation(s)
- Milla Pietiäinen
- Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - John M Liljestrand
- Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Elisa Kopra
- Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Pirkko J Pussinen
- Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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50
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Aavik E, Babu M, Ylä-Herttuala S. DNA methylation processes in atherosclerotic plaque. Atherosclerosis 2019; 281:168-179. [DOI: 10.1016/j.atherosclerosis.2018.12.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 11/09/2018] [Accepted: 12/14/2018] [Indexed: 12/18/2022]
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