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Tasouli-Drakou V, Ogurek I, Shaikh T, Ringor M, DiCaro MV, Lei K. Atherosclerosis: A Comprehensive Review of Molecular Factors and Mechanisms. Int J Mol Sci 2025; 26:1364. [PMID: 39941130 PMCID: PMC11818631 DOI: 10.3390/ijms26031364] [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: 01/13/2025] [Revised: 01/30/2025] [Accepted: 02/01/2025] [Indexed: 02/16/2025] Open
Abstract
Atherosclerosis, a condition characterized by the accumulation of lipids and a culprit behind cardiovascular events, has long been studied. However, in recent years, there has been an increase in interest in its initiation, with researchers shifting focus from traditional pathways involving the vascular infiltration of oxidized lipids and towards the novel presence of chronic inflammatory pathways. The accumulation of pro-inflammatory cytokines, in combination with the activation of transcription factors, creates a positive feedback loop that drives the creation and progression of atherosclerosis. From the upregulation of the nod-like receptor protein 3 (NLRP3) inflammasome and the Notch and Wnt pathways to the increased expression of VEGF-A and the downregulation of connexins Cx32, Cx37, and Cx40, these processes contribute further to endothelial dysfunction and plaque formation. Herein, we aim to provide insight into the molecular pathways and mechanisms implicated in the initiation and progression of atherosclerotic plaques, and to review the risk factors associated with their development.
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Affiliation(s)
- Vasiliki Tasouli-Drakou
- Department of Internal Medicine, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas, NV 89106, USA; (I.O.); (T.S.); (M.R.); (M.V.D.)
| | - Ian Ogurek
- Department of Internal Medicine, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas, NV 89106, USA; (I.O.); (T.S.); (M.R.); (M.V.D.)
| | - Taha Shaikh
- Department of Internal Medicine, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas, NV 89106, USA; (I.O.); (T.S.); (M.R.); (M.V.D.)
| | - Marc Ringor
- Department of Internal Medicine, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas, NV 89106, USA; (I.O.); (T.S.); (M.R.); (M.V.D.)
| | - Michael V. DiCaro
- Department of Internal Medicine, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas, NV 89106, USA; (I.O.); (T.S.); (M.R.); (M.V.D.)
| | - KaChon Lei
- Department of Cardiovascular Medicine, University of Nevada, Las Vegas, NV 89106, USA;
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Ardinal AP, Wiyono AV, Estiko RI. Unveiling the therapeutic potential of miR-146a: Targeting innate inflammation in atherosclerosis. J Cell Mol Med 2024; 28:e70121. [PMID: 39392102 PMCID: PMC11467738 DOI: 10.1111/jcmm.70121] [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: 05/20/2024] [Revised: 09/12/2024] [Accepted: 09/16/2024] [Indexed: 10/12/2024] Open
Abstract
Atherosclerosis is the foremost vascular disease, precipitating debilitating complications. Although therapeutic strategies have historically focused on reducing cholesterol deposition, recent insights emphasize the pivotal role of inflammation. Innate inflammation significantly contributes to plaque instability and rupture, underscoring the need for intervention across all disease stages. Numerous studies have highlighted the therapeutic potential of targeting innate immune pathways in atherosclerosis, revealing significant advancements in understanding the molecular mechanisms underlying inflammatory processes within arterial lesions. Notably, research has demonstrated that the modulation of microRNA-146a (miR-146a) expression impacts innate inflammation, effectively halts atherosclerosis progression, and enhances plaque stability by targeting interleukin-1 receptor-associated kinase (IRAK) and activating TNF receptor-associated factor 6 (TRAF6), a signalling pathway involving toll-like receptors (TLRs). Understanding the intricate mechanisms involved is crucial. This study provides a comprehensive analysis of the evidence and underlying mechanisms through which miR-146a exerts its effects. Integrating these findings into clinical practice may herald a transformative era in managing atherosclerotic cardiovascular disease.
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Ait-Oufella H, Libby P. Inflammation and Atherosclerosis: Prospects for Clinical Trials. Arterioscler Thromb Vasc Biol 2024; 44:1899-1905. [PMID: 39167675 PMCID: PMC11343092 DOI: 10.1161/atvbaha.124.320155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Affiliation(s)
- Hafid Ait-Oufella
- Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Sorbonne Université, Paris, France
- Medical Intensive Care Unit, Hôpital Saint-Antoine, AP-HP, Sorbonne Université, Paris, France
| | - Peter Libby
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
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Adams-Huet B, Jialal I. An Increasing Triglyceride-Glucose Index Is Associated with a Pro-Inflammatory and Pro-Oxidant Phenotype. J Clin Med 2024; 13:3941. [PMID: 38999506 PMCID: PMC11242814 DOI: 10.3390/jcm13133941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 06/21/2024] [Accepted: 07/02/2024] [Indexed: 07/14/2024] Open
Abstract
Background/Objectives: Insulin resistance is crucial in the pathogenesis of Metabolic Syndrome (MetS), type 2 diabetes mellitus (T2DM) and premature atherosclerotic cardiovascular disease (ASCVD). The triglyceride-glucose index (TyG index), a validated measure of insulin resistance, also predicts MetS, T2DM, the severity of albuminuria and ASCVD. There are scant data providing mechanistic insights into these sequalae. Accordingly, we investigated the relationship between the TyG index and biomarkers of inflammation, oxidative stress, free fatty acid (FFA) levels and adipokine dysregulation in a cohort comprising both controls and patients with nascent MetS. Methods: Participants (n = 102) included 59 patients with MetS and 43 controls. People with diabetes, ASCVD, smoking and macro-inflammation were excluded. Fasting blood was obtained for both plasma and monocyte isolation. Results: Receiver Operating Characteristic (ROC) curve analysis revealed that the TyG index was an excellent predictor of MetS with an area under the curve of 0.87, and it correlated with both hepatic and adipose tissue insulin resistance. Both serum RBP-4 levels and non-HDL cholesterol increased significantly over tertiles of the TyG index. Based on the TyG index tertiles and/or correlations, oxidized LDL, nitrotyrosine, C-reactive protein, endotoxin, chemerin, interleukin-6 levels and monocyte toll-like receptor (TLR)-4 and TLR-2 and their cellular signaling were significantly associated with the TyG index. Conclusions: Increased non-HDL-C and, most importantly, a pro-inflammatory and pro-oxidant state could be advanced as potential mechanisms explaining the increased risk for T2DM and ASCVD with an increasing TyG index.
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Affiliation(s)
| | - Ishwarlal Jialal
- UC Davis School of Medicine, 2616 Hepworth Drive, Davis, CA 95618, USA
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Alhamdan F, Bayarsaikhan G, Yuki K. Toll-like receptors and integrins crosstalk. Front Immunol 2024; 15:1403764. [PMID: 38915411 PMCID: PMC11194410 DOI: 10.3389/fimmu.2024.1403764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 05/24/2024] [Indexed: 06/26/2024] Open
Abstract
Immune system recognizes invading microbes at both pathogen and antigen levels. Toll-like receptors (TLRs) play a key role in the first-line defense against pathogens. Major functions of TLRs include cytokine and chemokine production. TLRs share common downstream signaling pathways with other receptors. The crosstalk revolving around TLRs is rather significant and complex, underscoring the intricate nature of immune system. The profiles of produced cytokines and chemokines via TLRs can be affected by other receptors. Integrins are critical heterodimeric adhesion molecules expressed on many different cells. There are studies describing synergetic or inhibitory interplay between TLRs and integrins. Thus, we reviewed the crosstalk between TLRs and integrins. Understanding the nature of the crosstalk could allow us to modulate TLR functions via integrins.
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Affiliation(s)
- Fahd Alhamdan
- Department of Anesthesiology, Critical Care and Pain Medicine, Cardiac Anesthesia, Boston Children’s Hospital, Boston, MA, United States
- Department of Anesthesia and Immunology, Harvard Medical School, Boston, MA, United States
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Ganchimeg Bayarsaikhan
- Department of Anesthesiology, Critical Care and Pain Medicine, Cardiac Anesthesia, Boston Children’s Hospital, Boston, MA, United States
- Department of Anesthesia and Immunology, Harvard Medical School, Boston, MA, United States
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Koichi Yuki
- Department of Anesthesiology, Critical Care and Pain Medicine, Cardiac Anesthesia, Boston Children’s Hospital, Boston, MA, United States
- Department of Anesthesia and Immunology, Harvard Medical School, Boston, MA, United States
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
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Zhang T, Pang C, Xu M, Zhao Q, Hu Z, Jiang X, Guo M. The role of immune system in atherosclerosis: Molecular mechanisms, controversies, and future possibilities. Hum Immunol 2024; 85:110765. [PMID: 38369442 DOI: 10.1016/j.humimm.2024.110765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 02/06/2024] [Accepted: 02/08/2024] [Indexed: 02/20/2024]
Abstract
Numerous cardiovascular disorders have atherosclerosis as their pathological underpinning. Numerous studies have demonstrated that, with the aid of pattern recognition receptors, cytokines, and immunoglobulins, innate immunity, represented by monocytes/macrophages, and adaptive immunity, primarily T/B cells, play a critical role in controlling inflammation and abnormal lipid metabolism in atherosclerosis. Additionally, the finding of numerous complement components in atherosclerotic plaques suggests yet again how heavily the immune system controls atherosclerosis. Therefore, it is essential to have a thorough grasp of how the immune system contributes to atherosclerosis. The specific molecular mechanisms involved in the activation of immune cells and immune molecules in atherosclerosis, the controversy surrounding some immune cells in atherosclerosis, and the limitations of extrapolating from relevant animal models to humans were all carefully reviewed in this review from the three perspectives of innate immunity, adaptive immunity, and complement system. This could provide fresh possibilities for atherosclerosis research and treatment in the future.
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Affiliation(s)
- Tianle Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, PR China
| | - Chenxu Pang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, PR China
| | - Mengxin Xu
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, PR China
| | - Qianqian Zhao
- School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin, PR China
| | - Zhijie Hu
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, PR China
| | - Xijuan Jiang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, PR China.
| | - Maojuan Guo
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, PR China.
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Schelemei P, Wagner E, Picard FSR, Winkels H. Macrophage mediators and mechanisms in cardiovascular disease. FASEB J 2024; 38:e23424. [PMID: 38275140 DOI: 10.1096/fj.202302001r] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 12/21/2023] [Accepted: 12/29/2023] [Indexed: 01/27/2024]
Abstract
Macrophages are major players in myocardial infarction (MI) and atherosclerosis, two major cardiovascular diseases (CVD). Atherosclerosis is caused by the buildup of cholesterol-rich lipoproteins in blood vessels, causing inflammation, vascular injury, and plaque formation. Plaque rupture or erosion can cause thrombus formation resulting in inadequate blood flow to the heart muscle and MI. Inflammation, particularly driven by macrophages, plays a central role in both atherosclerosis and MI. Recent integrative approaches of single-cell analysis-based classifications in both murine and human atherosclerosis as well as experimental MI showed overlap in origin, diversity, and function of macrophages in the aorta and the heart. We here discuss differences and communalities between macrophages in the heart and aorta at steady state and in atherosclerosis or upon MI. We focus on markers, mediators, and functional states of macrophage subpopulations. Recent trials testing anti-inflammatory agents show a major benefit in reducing the inflammatory burden of CVD patients, but highlight a necessity for a broader understanding of immune cell ontogeny and heterogeneity in CVD. The novel insights into macrophage biology in CVD represent exciting opportunities for the development of novel treatment strategies against CVD.
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Affiliation(s)
- Patrik Schelemei
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Elena Wagner
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Felix Simon Ruben Picard
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Holger Winkels
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
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Wu C, Li W, Li P, Niu X. Identification of a hub gene VCL for atherosclerotic plaques and discovery of potential therapeutic targets by molecular docking. BMC Med Genomics 2024; 17:42. [PMID: 38287421 PMCID: PMC10826019 DOI: 10.1186/s12920-024-01815-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 01/23/2024] [Indexed: 01/31/2024] Open
Abstract
BACKGROUND Atherosclerosis (AS) is a pathology factor for cardiovascular diseases and instability of atherosclerotic plaques contributes to acute coronary events. This study identified a hub gene VCL for atherosclerotic plaques and discovered its potential therapeutic targets for atherosclerotic plaques. METHODS Differential expressed genes (DEGs) were screened between unstable and stable plaques from GSE120521 dataset and then used for construction of a protein-protein interactions (PPI) network. Through topological analysis, hub genes were identified within this PPI network, followed by construction of a diagnostic model. GSE41571 dataset was utilized to validate the diagnostic model. A key hub gene was identified and its association with immune characteristics and pathways were further investigated. Molecular docking and molecular dynamics (MD) simulation were employed to discover potential therapeutic targets. RESULTS According to the PPI network, 3 tightly connected protein clusters were found. Topological analysis identified the top 5 hub genes, Vinculin (VCL), Dystrophin (DMD), Actin alpha 2 (ACTA2), Filamin A (FLNA), and transgelin (TAGLN). Among these hub genes, VCL had the highest diagnostic value. VCL was selected for further analysis and we found that VCL was negatively correlated with immune score and AS-related inflammatory pathways. Next, we identified 408 genes that were highly correlated with VCL and determined potential drug candidates. The results from molecular docking and MD simulation showed compound DB07117 combined with VCL protein stably, the binding energy is -7.7 kcal/mol, indicating that compound DB07117 was a potential inhibitor of VCL protein. CONCLUSION This study identified VCL as a key gene for atherosclerotic plaques and provides a potential therapeutic target of VCL for the treatment of atherosclerotic plaques.
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Affiliation(s)
- Chong Wu
- The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's Hospital), Zhengzhou, 450046, China.
| | - Wei Li
- Clinical Laboratory, Qingdao Women and Children's Hospital Affiliated, Qingdao University, Qingdao, 266034, China
| | - Panfeng Li
- Department of Vascular Surgery, Heart Center of Henan Provincial People's Hospital, Fuwai Central China Cardiovascular Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, 450000, China.
| | - Xiaoyang Niu
- Department of Vascular Surgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
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Huang H, Sun Z, Xu J, Wang L, Zhao J, Li J, Zhang S, Yuan F, Liu M, Fang Z. Yang-Xin-Shu-Mai granule alleviates atherosclerosis by regulating macrophage polarization via the TLR9/MyD88/NF-κB signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:116868. [PMID: 37454749 DOI: 10.1016/j.jep.2023.116868] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 06/04/2023] [Accepted: 06/27/2023] [Indexed: 07/18/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Previous studies have found that Yang-Xin-Shu-Mai granule (YXSMG) has certain advantages in the treatment of stable coronary heart disease. However, YXSMG can inhibit the progression of atherosclerotic plaque and stabilize vulnerable plaque needs to be further explored and studied. This research, mass spectrometry analysis, network pharmacology, in vivo and in vitro experimental studies were conducted to explore the mechanism of YXSMG on atherosclerosis. AIM OF THE STUDY To decipher the mechanism of atherosclerotic plaque, stabilization for YXSMG by analysis of its active ingredients and biological network and activity in whole animal and at cellular and molecular levels. METHODS The active components of YXSMG were determined using high performance liquid chromatography-mass spectrometry/mass spectrometry (HPLC-MS/MS) analysis. The 'Disease-Compound-Target-Pathway' network diagram was constructed using network pharmacology, and the stability of binding between core targets and core compounds was analyzed with molecular docking. After intervention with YXSMG, the pathology of aortic plaque, inflammation in the surrounding tissue, expression of TLR9/MyD88/NF-κB pathway protein in plaque and M1/M2 polarization of plaque macrophages were evaluated in vivo in apolipoprotein E-deficient (ApoE-/-) mice fed with high-fat diet. To verify whether it suppressed inflammation by inhibiting Toll-like receptor 9 (TLR9) reprogramming of macrophage polarization, we used RAW264.7 macrophages treated with specific TLR9 agonist (ODN1826) and inhibitor (ODN2088). RESULTS Five active compounds were identified in YXSMG: catechin, formononetin, tanshinone IIA, cryptotanshinone and glycitein. Network pharmacology studies revealed TLR9 as one of the core targets of YXSMG intervention in atherosclerosis. Computer simulation of molecular docking showed that TLR9 could interact with the core compound to form a stable complex. In vivo experiments confirmed that YXSMG could significantly inhibit atherosclerotic plaque, reduce levels of blood lipids and inflammatory factors, downregulate TLR9/MyD88/NF-κB pathway protein and inhibit aortic sinus macrophages polarization to M1, but promote their polarization to M2 to inhibit inflammation. In vitro experiments revealed that YXSMG could downregulate expression of TLR9 gene and protein in ODN1826-activated RAW264.7 macrophages. ODN2088 had a synergistic effect with YXSMG on the TLR9/MyD88/NF-κB signaling pathway, and reprogrammed macrophages polarization from M1 to M2 by inhibiting TLR9, thus reducing immuno-inflammatory response. CONCLUSION YXSMG can reduce the level of blood lipid and improve the size of atherosclerotic plaque and inflammatory infiltration in ApoE-/- mice fed with high fat. It is concluded that YXSMG can improve the mechanism of atherosclerotic plaque by inhibiting TLR9/MyD88/NF-κB pathway reprogramming macrophage M1/M2 polarization and reducing arterial inflammation.
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Affiliation(s)
- Hong Huang
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, PR China.
| | - Zeqi Sun
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, PR China.
| | - Junyao Xu
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, PR China
| | - Linjie Wang
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, PR China
| | - Jing Zhao
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, PR China
| | - Jie Li
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, PR China
| | - Siqi Zhang
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, PR China; Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, PR China
| | - Fang Yuan
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, PR China
| | - Ming Liu
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, PR China; Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, PR China.
| | - Zhuyuan Fang
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, PR China; Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, PR China.
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Velpuri P, Rai V, Agrawal DK. Role of sirtuins in attenuating plaque vulnerability in atherosclerosis. Mol Cell Biochem 2024; 479:51-62. [PMID: 36952068 PMCID: PMC10034899 DOI: 10.1007/s11010-023-04714-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 03/15/2023] [Indexed: 03/24/2023]
Abstract
Atherosclerosis is characterized by the development of intimal plaque, thrombosis, and stenosis of the vessel lumen causing decreased blood flow and hypoxia precipitating angina. Chronic inflammation in the stable plaque renders it unstable and rupture of unstable plaques results in the formation of emboli leading to hypoxia/ischemia to the organs by occluding the terminal branches and precipitate myocardial infarction and stroke. Such delibitating events could be controlled by the strategies that prevent plaque development or plaque stabilization. Despite the use of statins to stabilize plaques, there is a need for novel targets due to continuously increasing cases of cardiovascular events. Sirtuins (SIRTs), a family of signaling proteins, are involved in sustaining genome integrity, DNA damage response and repair, modulating oxidative stress, aging, inflammation, and energy metabolism. SIRTs play a critical role in modulating inflammation and involves in the development and progression of atherosclerosis. The role of SIRTs in relation to atherosclerosis and plaque vulnerability is scarcely discussed in the literature. Since SIRTs regulate oxidative stress, inflammation, and aging, they may also regulate plaque progression and vulnerability as these molecular mechanisms underlie the pathogenesis of plaque development, progression, and vulnerability. This review critically discusses the role of SIRTs in plaque progression and vulnerability and the possibility of targeting SIRTs to attenuate plaque rupture, focusing on the highlights in genomics, molecular pathways, and cell types involved in the underlying pathophysiology.
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Affiliation(s)
- Prathosh Velpuri
- Department of Translational Research, Western University of Health Sciences, 309 E. Second Street, Pomona, CA, 91766-1854, USA
| | - Vikrant Rai
- Department of Translational Research, Western University of Health Sciences, 309 E. Second Street, Pomona, CA, 91766-1854, USA
| | - Devendra K Agrawal
- Department of Translational Research, Western University of Health Sciences, 309 E. Second Street, Pomona, CA, 91766-1854, USA.
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Niu C, Zhang P, Zhang L, Lin D, Lai H, Xiao D, Liu Y, Zhuang R, Li M, Ma L, Ye J, Pan Y. Molecular targets and mechanisms of Guanxinning tablet in treating atherosclerosis: Network pharmacology and molecular docking analysis. Medicine (Baltimore) 2023; 102:e35106. [PMID: 37773840 PMCID: PMC10545342 DOI: 10.1097/md.0000000000035106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 08/16/2023] [Indexed: 10/01/2023] Open
Abstract
BACKGROUND Guanxinning tablet (GXNT), a Chinese patent medicine, is composed of salvia miltiorrhiza bunge and ligusticum striatum DC, which may play the role of endothelial protection through many pathways. We aimed to explore the molecular mechanisms of GXNT against atherosclerosis (AS) through network pharmacology and molecular docking verification. METHODS The active ingredients and their potential targets of GXNT were obtained in traditional Chinese medicine systems pharmacology database and analysis platform and bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine databases. DrugBank, TTD, DisGeNET, OMIM, and GeneCards databases were used to screen the targets of AS. The intersection targets gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis were performed in DAVID database. GXNT-AS protein-protein interaction network, ingredient-target network and herb-target-pathway network were constructed by Cytoscape. Finally, we used AutoDock for molecular docking. RESULTS We screened 65 active ingredients of GXNT and 70 GXNT-AS intersection targets. The key targets of protein-protein interaction network were AKT1, JUN, STAT3, TNF, TP53, IL6, EGFR, MAPK14, RELA, and CASP3. The Kyoto encyclopedia of genes and genomes pathway enrichment analysis showed that pathways in cancer, lipid and atherosclerosis, and PI3K-Akt signaling pathway were the main pathways. The ingredient-target network showed that the key ingredients were luteolin, tanshinone IIA, myricanone, dihydrotanshinlactone, dan-shexinkum d, 2-isopropyl-8-methylphenanthrene-3,4-dione, miltionone I, deoxyneocryptotanshinone, Isotanshinone II and 4-methylenemiltirone. The results of molecular docking showed that tanshinone IIA, dihydrotanshinlactone, dan-shexinkum d, 2-isopropyl-8-methylphenanthrene-3,4-dione, miltionone I, deoxyneocryptotanshinone, Isotanshinone II and 4-methylenemiltirone all had good binding interactions with AKT1, EGFR and MAPK14. CONCLUSION The results of network pharmacology and molecular docking showed that the multiple ingredients within GXNT may confer protective effects on the vascular endothelium against AS through multitarget and multichannel mechanisms. AKT1, EGFR and MAPK14 were the core potential targets of GXNT against AS.
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Affiliation(s)
- Chaofeng Niu
- Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Peiyu Zhang
- Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Lijing Zhang
- Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Dingfeng Lin
- Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Haixia Lai
- Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Di Xiao
- Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yong Liu
- Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Rui Zhuang
- Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Meng Li
- Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Liyong Ma
- Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jiaqi Ye
- Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yi Pan
- Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
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Shadisvaaran S, Chin KY, Mohd-Said S, Leong XF. Therapeutic potential of bixin on inflammation: a mini review. Front Nutr 2023; 10:1209248. [PMID: 37781110 PMCID: PMC10534043 DOI: 10.3389/fnut.2023.1209248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 08/28/2023] [Indexed: 10/03/2023] Open
Abstract
Chronic inflammation is the underlying mechanism for many diseases. Thus, inflammatory signaling pathways are valuable targets for new treatment modalities. Natural products have gained interest as a potential source of bioactive compounds which provide health benefits in combating inflammatory-related diseases. Recent reports have linked the medicinal values of Bixa orellana L. with its anti-inflammatory activities. Therefore, this review aims to examine the therapeutic potential of bixin, a major bioactive constituent found in the seeds of B. orellana, on inflammatory-related diseases based on existing in vitro and in vivo evidence. Additionally, the anti-inflammatory mechanism of bixin via signaling pathways is explored and possible toxic effects are addressed. The findings suggest that bixin may ameliorate inflammation via inhibition of toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and thioredoxin-interacting protein/NOD-like receptor protein 3 (TXNIP/NLRP3) inflammasome mechanisms. More well-planned clinical studies should be performed to verify its effectiveness and safety profile.
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Affiliation(s)
- Saminathan Shadisvaaran
- Department of Craniofacial Diagnostics and Biosciences, Faculty of Dentistry, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Kok-Yong Chin
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Malaysia
| | - Shahida Mohd-Said
- Department of Restorative Dentistry, Faculty of Dentistry, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Xin-Fang Leong
- Department of Craniofacial Diagnostics and Biosciences, Faculty of Dentistry, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Yeramilli V, Cheddadi R, Benjamin H, Martin C. The Impact of Stress, Microbial Dysbiosis, and Inflammation on Necrotizing Enterocolitis. Microorganisms 2023; 11:2206. [PMID: 37764050 PMCID: PMC10534571 DOI: 10.3390/microorganisms11092206] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/28/2023] [Accepted: 08/29/2023] [Indexed: 09/29/2023] Open
Abstract
Necrotizing enterocolitis (NEC) is the leading cause of intestinal morbidity and mortality in neonates. A large body of work exists; however, the pathogenesis of NEC remains poorly understood. Numerous predictors have been implicated in the development of NEC, with relatively less emphasis on maternal factors. Utilizing human tissue plays a crucial role in enhancing our comprehension of the underlying mechanisms accountable for this devastating disease. In this review, we will discuss how maternal stress affects the pathogenesis of NEC and how changes in the intestinal microbiome can influence the development of NEC. We will also discuss the results of transcriptomics-based studies and analyze the gene expression changes in NEC tissues and other molecular targets associated with the pathogenesis of NEC.
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Affiliation(s)
| | | | | | - Colin Martin
- Division of Pediatric, Department of Surgery, University of Alabama at Birmingham, 1600 7th Ave. S., Lowder Building Suite 300, Birmingham, AL 35233, USA
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14
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Díaz-García E, García-Sánchez A, Sánz-Rubio D, Alfaro E, López-Fernández C, Casitas R, Mañas Baena E, Cano-Pumarega I, Cubero P, Marin-Oto M, López-Collazo E, Marin JM, García-Río F, Cubillos-Zapata C. SMAD4 Expression in Monocytes as a Potential Biomarker for Atherosclerosis Risk in Patients with Obstructive Sleep Apnea. Int J Mol Sci 2023; 24:ijms24097900. [PMID: 37175608 PMCID: PMC10178665 DOI: 10.3390/ijms24097900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/14/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
Obstructive sleep apnea (OSA) patients are at special risk of suffering atherosclerosis, leading to major cardiovascular diseases. Notably, the transforming growth factor (TGF-β) plays a crucial role in the development and progression of atherosclerosis. In this context, the central regulator of TGF-β pathway, SMAD4 (small mother against decapentaplegic homolog 4), has been previously reported to be augmented in OSA patients, which levels were even higher in patients with concomitant cardiometabolic diseases. Here, we analyzed soluble and intracellular SMAD4 levels in plasma and monocytes from OSA patients and non-apneic subjects, with or without early subclinical atherosclerosis (eSA). In addition, we used in vitro and ex vivo models to explore the mechanisms underlying SMAD4 upregulation and release. Our study confirmed elevated sSMAD4 levels in OSA patients and identified that its levels were even higher in those OSA patients with eSA. Moreover, we demonstrated that SMAD4 is overexpressed in OSA monocytes and that intermittent hypoxia contributes to SMAD4 upregulation and release in a process mediated by NLRP3. In conclusion, this study highlights the potential role of sSMAD4 as a biomarker for atherosclerosis risk in OSA patients and provides new insights into the mechanisms underlying its upregulation and release to the extracellular space.
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Affiliation(s)
- Elena Díaz-García
- Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain
- Respiratory Diseases Group, Respiratory Diseases Department, La Paz University Hospital, IdiPAZ, 28046 Madrid, Spain
| | - Aldara García-Sánchez
- Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain
- Servicio de Neumología, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - David Sánz-Rubio
- Precision Medicine in Respiratory Diseases Group, Miguel Servet University Hospital-IIS Aragon, 50009 Zaragoza, Spain
| | - Enrique Alfaro
- Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain
- Respiratory Diseases Group, Respiratory Diseases Department, La Paz University Hospital, IdiPAZ, 28046 Madrid, Spain
| | - Cristina López-Fernández
- Respiratory Diseases Group, Respiratory Diseases Department, La Paz University Hospital, IdiPAZ, 28046 Madrid, Spain
| | - Raquel Casitas
- Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain
- Respiratory Diseases Group, Respiratory Diseases Department, La Paz University Hospital, IdiPAZ, 28046 Madrid, Spain
| | - Eva Mañas Baena
- Servicio de Neumología, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Irene Cano-Pumarega
- Servicio de Neumología, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Pablo Cubero
- Precision Medicine in Respiratory Diseases Group, Miguel Servet University Hospital-IIS Aragon, 50009 Zaragoza, Spain
| | - Marta Marin-Oto
- Precision Medicine in Respiratory Diseases Group, Miguel Servet University Hospital-IIS Aragon, 50009 Zaragoza, Spain
| | - Eduardo López-Collazo
- Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain
- The Innate Immune Response Group, La Paz University Hospital, IdiPAZ, 28046 Madrid, Spain
| | - José María Marin
- Precision Medicine in Respiratory Diseases Group, Miguel Servet University Hospital-IIS Aragon, 50009 Zaragoza, Spain
- Department of Medicine, University of Zaragoza School of Medicine, 50009 Zaragoza, Spain
| | - Francisco García-Río
- Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain
- Respiratory Diseases Group, Respiratory Diseases Department, La Paz University Hospital, IdiPAZ, 28046 Madrid, Spain
- Faculty of Medicine, Autonomous University of Madrid, 28029 Madrid, Spain
| | - Carolina Cubillos-Zapata
- Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain
- Respiratory Diseases Group, Respiratory Diseases Department, La Paz University Hospital, IdiPAZ, 28046 Madrid, Spain
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15
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Gusev E, Sarapultsev A. Atherosclerosis and Inflammation: Insights from the Theory of General Pathological Processes. Int J Mol Sci 2023; 24:ijms24097910. [PMID: 37175617 PMCID: PMC10178362 DOI: 10.3390/ijms24097910] [Citation(s) in RCA: 80] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/24/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
Recent advances have greatly improved our understanding of the molecular mechanisms behind atherosclerosis pathogenesis. However, there is still a need to systematize this data from a general pathology perspective, particularly with regard to atherogenesis patterns in the context of both canonical and non-classical inflammation types. In this review, we analyze various typical phenomena and outcomes of cellular pro-inflammatory stress in atherosclerosis, as well as the role of endothelial dysfunction in local and systemic manifestations of low-grade inflammation. We also present the features of immune mechanisms in the development of productive inflammation in stable and unstable plaques, along with their similarities and differences compared to canonical inflammation. There are numerous factors that act as inducers of the inflammatory process in atherosclerosis, including vascular endothelium aging, metabolic dysfunctions, autoimmune, and in some cases, infectious damage factors. Life-critical complications of atherosclerosis, such as cardiogenic shock and severe strokes, are associated with the development of acute systemic hyperinflammation. Additionally, critical atherosclerotic ischemia of the lower extremities induces paracoagulation and the development of chronic systemic inflammation. Conversely, sepsis, other critical conditions, and severe systemic chronic diseases contribute to atherogenesis. In summary, atherosclerosis can be characterized as an independent form of inflammation, sharing similarities but also having fundamental differences from low-grade inflammation and various variants of canonical inflammation (classic vasculitis).
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Affiliation(s)
- Evgenii Gusev
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Science, 620049 Ekaterinburg, Russia
| | - Alexey Sarapultsev
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Science, 620049 Ekaterinburg, Russia
- Russian-Chinese Education and Research Center of System Pathology, South Ural State University, 454080 Chelyabinsk, Russia
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16
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Meyer-Lindemann U, Moggio A, Dutsch A, Kessler T, Sager HB. The Impact of Exercise on Immunity, Metabolism, and Atherosclerosis. Int J Mol Sci 2023; 24:3394. [PMID: 36834808 PMCID: PMC9967592 DOI: 10.3390/ijms24043394] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/29/2023] [Accepted: 02/06/2023] [Indexed: 02/11/2023] Open
Abstract
Physical exercise represents an effective preventive and therapeutic strategy beneficially modifying the course of multiple diseases. The protective mechanisms of exercise are manifold; primarily, they are elicited by alterations in metabolic and inflammatory pathways. Exercise intensity and duration strongly influence the provoked response. This narrative review aims to provide comprehensive up-to-date insights into the beneficial effects of physical exercise by illustrating the impact of moderate and vigorous exercise on innate and adaptive immunity. Specifically, we describe qualitative and quantitative changes in different leukocyte subsets while distinguishing between acute and chronic exercise effects. Further, we elaborate on how exercise modifies the progression of atherosclerosis, the leading cause of death worldwide, representing a prime example of a disease triggered by metabolic and inflammatory pathways. Here, we describe how exercise counteracts causal contributors and thereby improves outcomes. In addition, we identify gaps that still need to be addressed in the future.
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Affiliation(s)
- Ulrike Meyer-Lindemann
- Department of Cardiology, German Heart Center Munich, Technical University Munich, 80636 Munich, Germany
- DZHK e.V. (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, 80336 Munich, Germany
| | - Aldo Moggio
- Department of Cardiology, German Heart Center Munich, Technical University Munich, 80636 Munich, Germany
| | - Alexander Dutsch
- Department of Cardiology, German Heart Center Munich, Technical University Munich, 80636 Munich, Germany
- DZHK e.V. (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, 80336 Munich, Germany
| | - Thorsten Kessler
- Department of Cardiology, German Heart Center Munich, Technical University Munich, 80636 Munich, Germany
- DZHK e.V. (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, 80336 Munich, Germany
| | - Hendrik B. Sager
- Department of Cardiology, German Heart Center Munich, Technical University Munich, 80636 Munich, Germany
- DZHK e.V. (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, 80336 Munich, Germany
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17
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Zhao Q, Zhu L, Wang S, Gao Y, Jin F. Molecular mechanism of the anti-inflammatory effects of plant essential oils: A systematic review. JOURNAL OF ETHNOPHARMACOLOGY 2023; 301:115829. [PMID: 36252876 DOI: 10.1016/j.jep.2022.115829] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 10/05/2022] [Accepted: 10/08/2022] [Indexed: 06/16/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Plant essential oils (PEOs) extracted from aromatic compounds of the plant contain complex mixtures of volatile and lipophilic bioactive compounds. In ancient Egypt, Arabia, Greece, and China, PEOs were traditional used in aromatherapy for various health disorders, including pain and inflammation. AIM OF THE STUDY In this review, we provide an overview of the anti-inflammatory effects of PEOs and the underlying mechanisms associated with anti-inflammatory effects using in vitro and in vivo models. Further, clinical trials associated with PEOs were explored. MATERIALS AND METHODS The literature search was performed using various web-based tools and databases like Google Scholar, Web of Science, PubMed, CNKI and SCOPUS. The keywords used for conducting the literature review were general terms like "essential oils" followed by (AND) the subject of interest like "in vitro and/or in vivo anti-inflammatory models," "inflammatory response," "inflammatory indicators," "pro-inflammatory cytokines," "signaling pathway," "anti-inflammatory mechanism," "toxicology and side effects" and "clinical trials." The articles selected were published between 2017 and 2022. The articles prior to 2017 were only considered if they were associated with molecular mechanisms or signaling pathways involved in the inflammatory responses. RESULTS In vitro and in vivo inflammation models have been used to study the anti-inflammatory effects of 48 PEOs. Studies have reported that PEOs targets and inhibit multiple dysregulated signaling pathways associated with inflammation, including Toll-like receptors, nuclear transcription factor-κ B, mitogen-activated protein kinases, Nod-like receptor family pyrin domain containing 3, and auxiliary pathways like the nuclear factor erythroid 2-related factor 2/antioxidant response element and Janus kinase/signal transducers and activators of transcription) signaling pathways. CONCLUSION PEOs extracted from different plant materials had varied qualitative and quantitative compositions of biologically active compounds. Different anti-inflammatory potentials and different molecular signal transduction have been attributed to PEOs-derived bioactive compounds with different chemical structures. The data on therapeutic efficacy and the long-term side effects of PEOs as an anti-inflammatory drug are still unknown due to the lack of clinical trials on PEOs. There is still insufficient evidence to draw conclusions on anti-inflammatory properties of PEOs without promising outcomes from clinical trials.
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Affiliation(s)
- Qian Zhao
- College of Life Sciences, China Jiliang University, Aroma Engineering Technology Research and Development Center, Hangzhou, 310018, China.
| | - Liyun Zhu
- College of Life Sciences, China Jiliang University, Aroma Engineering Technology Research and Development Center, Hangzhou, 310018, China; Anhui Hanfang Biotechnology Co., Ltd, Huaibei, 23500, China.
| | - Sunan Wang
- Canadian Food and Wine Institute, Niagara College Canada, 135 Taylor Road, Niagara-on-the-Lake, Ontario, L0S1J0, Canada
| | - Yongsheng Gao
- College of Life Sciences, China Jiliang University, Aroma Engineering Technology Research and Development Center, Hangzhou, 310018, China; Anhui Hanfang Biotechnology Co., Ltd, Huaibei, 23500, China
| | - Fei Jin
- College of Life Sciences, China Jiliang University, Aroma Engineering Technology Research and Development Center, Hangzhou, 310018, China
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18
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Zhang H, Huang Y, Li X, Chen W, Lun Y, Zhang J. Identifying Hub Genes and Immune Cell Infiltration for the Progression of Carotid Atherosclerotic Plaques in the Context of Predictive and Preventive Using Integrative Bioinformatics Approaches and Machine-Learning Strategies. J Immunol Res 2022; 2022:7657379. [PMID: 36304068 PMCID: PMC9596267 DOI: 10.1155/2022/7657379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/10/2022] [Accepted: 10/11/2022] [Indexed: 12/03/2022] Open
Abstract
Emerging evidence shows that carotid atherosclerosis is related to the activation of immune-related pathways and inflammatory cell infiltration. However, the immune-linked pathways that helped in the advancement of the carotid atherosclerotic plaque and the association of such plaques with the infiltration status of the body's immune cells still unclear. Here, the expression profiles of the genes expressed during the progression of the carotid atherosclerotic plaques were retrieved from the Gene Expression Omnibus database and 178 differentially expressed genes were examined. The Weighted Gene Coexpression Network Analysis technique identified one of the brown modules showed the greatest correlation with carotid atherosclerotic plaques. In total, 66 intersecting genes could be detected after combining the DEGs. LASSO regression analysis was subsequently performed to obtain five hub genes as potential biomarkers for carotid atherosclerotic plaques. The functional analysis emphasized the vital roles played by the inflammation- and immune system-related pathways in this disease. The immune cell infiltration results highlighted the significant correlation among the CD4+ T cells, B cells, macrophages, and CD8+ T cells. Thereafter, the gene expression levels and the diagnostic values related to every hub gene were further validated. The above results indicated that macrophages, B cells, CD4+ T cells, and CD8 + T cells were closely related to the formation of the advanced-stage carotid atherosclerotic plaques. Based on the results, it could be hypothesized that the expression of hub genes (C3AR1, SLAMF8, TMEM176A, FERMT3, and GIMAP4) assisted in the advancement of the early-stage to advanced-stage carotid atherosclerotic plaque through immune-related signaling pathways. This may help to provide novel strategies for the treatment of carotid plaque in the context of predictive, preventive, and personalized medicine.
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Affiliation(s)
- Han Zhang
- Department of Vascular and Thyroid Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Yinde Huang
- Department of Vascular and Thyroid Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Xin Li
- Department of Vascular and Thyroid Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Wenbin Chen
- Department of Vascular and Thyroid Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Yu Lun
- Department of Vascular and Thyroid Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Jian Zhang
- Department of Vascular and Thyroid Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
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Mahdavi-Roshan M, Shoaibinobarian N, Noormohammadi M, Fakhr Mousavi A, Savar Rakhsh A, Salari A, Ghorbani Z. Inflammatory Markers and Atherogenic Coefficient: Early Markers of Metabolic Syndrome. Int J Endocrinol Metab 2022; 20:e127445. [PMID: 36714188 PMCID: PMC9871968 DOI: 10.5812/ijem-127445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 07/11/2022] [Accepted: 08/09/2022] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Considering the close link between metabolic syndrome (MetSyn) and cardiovascular diseases, considerable attention has been devoted to the identification of their shared underlying pathological mechanisms in recent decades. OBJECTIVES This study aimed to investigate the association between pro-inflammatory factors and newly-diagnosed MetSyn. METHODS This case-control study recruited obese and nonobese individuals who were newly diagnosed with MetSyn (cases, n = 84) and healthy individuals (controls, n = 83). The medical and sociodemographic data of the participants were collected on enrollment. Serum analysis was performed to ascertain the concentrations of tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), fasting blood sugar (FBS), total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and atherogenic coefficient (AC). Multiple regression analysis was carried out to explore the relationship between inflammatory markers and AC with MetSyn odds. The Pearson correlation test was also performed to investigate the correlations between metabolic and inflammatory parameters. RESULTS Positive relationships were observed between the serum levels of TNF-α and CRP with the odds of MetSyn following controlling for confounders (adjusted odds ratio [AOR] = 1.32; 95% confidence interval [CI]: 1.01 - 1.72; AOR = 1.29; 95% CI: 1.18 - 1.41; respectively, P ≤ 0.03). Additionally, higher AC was accompanied by increased odds of MetSyn (AOR = 1.98; 95% CI: 1.31 - 2.98; P = 0.001). The Pearson correlation analysis also showed positive correlations between TNF-α levels and serum metabolic abnormalities, including elevated LDL-C, FBS, and AC and lowered HDL-C levels (P ≤ 0.02). CONCLUSIONS The present results revealed that higher serum concentrations of pro-inflammatory and atherogenic indices, including CRP, TNF-α, and AC, might be associated with elevated odds of newly diagnosed MetSyn regardless of potential confounders, particularly body mass index. The obtained findings might be moderated by the positive correlations observed between serum TNF-α, as the chronic inflammatory state indicator, and impaired lipid and glycemic markers.
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Affiliation(s)
- Marjan Mahdavi-Roshan
- Cardiovascular Diseases Research Center, Department of Cardiology, Heshmat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Department of Clinical Nutrition, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Nargeskhatoon Shoaibinobarian
- Cardiovascular Diseases Research Center, Department of Cardiology, Heshmat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Morvarid Noormohammadi
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Aboozar Fakhr Mousavi
- Cardiovascular Diseases Research Center, Department of Cardiology, Heshmat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Amir Savar Rakhsh
- Cardiovascular Diseases Research Center, Department of Cardiology, Heshmat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Arsalan Salari
- Cardiovascular Diseases Research Center, Department of Cardiology, Heshmat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Zeinab Ghorbani
- Cardiovascular Diseases Research Center, Department of Cardiology, Heshmat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Department of Clinical Nutrition, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Corresponding Author: Cardiovascular Diseases Research Center, Department of Cardiology, Heshmat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
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Fang T, Sun S, Zhao B, Dong J, Cao K, Wang W. NLRC5 modulates phenotypic transition and inflammation of human venous smooth muscle cells by activating Wnt/β-catenin pathway via TLR4 in varicose veins. Microvasc Res 2022; 143:104405. [PMID: 35835172 DOI: 10.1016/j.mvr.2022.104405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 06/20/2022] [Accepted: 07/06/2022] [Indexed: 10/17/2022]
Abstract
In varicose veins, abnormal phenotypic transition and inflammatory response is commonly found in venous smooth muscle cells (VSMCs). We aimed to explore the potential role and mechanism of NLRC5 exerted on VSMCs phenotypic transition and inflammation. NLRC5 expression was detected in varicose veins and platelet-derived growth factor (PDGF)-induced VSMCs by RT-qPCR and Western bolt assays. A loss-of-function assay was performed to evaluate the effects of NLRC5 knockdown on VSMC proliferation, migration, and phenotypic transition. ELISA was used to detect the contents of pro-inflammatory cytokines in the supernatant. The modulation of NLRC5 on TLR4 expression and Wnt/β-catenin signaling was also evaluated. We found that the expressions of NLRC5 in varicose veins and PDGF-induced VSMCs were upregulated. NLRC5 knockdown inhibited VSMC proliferation and migration. Extracellular matrix transformation was blocked by downregulating NLRC5 with increasing SM-22α expression and MMP-1/TIMP-1 ratio, as well as decreasing OPN and collagen I expressions. Besides, NLRC5 silencing reduced the contents of inflammatory cytokines. Furthermore, we found that NLRC5 regulated TLR4 expression, as well as subsequently activation of Wnt/β-catenin pathway and nuclear translocation of β-catenin, which was involved in NLRC5-mediated phenotypic transition and inflammatory in VSMCs. In conclusion, silencing NLRC5 depressed VSMCs' phenotypic transition and inflammation by modulating Wnt/β-catenin pathway via TLR4. This may provide a theoretical basis for treatment of varicose veins.
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Affiliation(s)
- Tao Fang
- Department of Vascular Surgery, Yantaishan Hospital, Yantai city 264001, Shandong Province, China
| | - Shaojun Sun
- Department of Vascular Surgery, Yantaishan Hospital, Yantai city 264001, Shandong Province, China
| | - Bingjie Zhao
- Department of Vascular Surgery, Yantaishan Hospital, Yantai city 264001, Shandong Province, China
| | - Jianxin Dong
- Department of Vascular Surgery, Yantaishan Hospital, Yantai city 264001, Shandong Province, China
| | - Kai Cao
- Department of Vascular Surgery, Yantaishan Hospital, Yantai city 264001, Shandong Province, China
| | - Wenli Wang
- Department of Vascular Surgery, Yantaishan Hospital, Yantai city 264001, Shandong Province, China.
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21
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Zhuang C, Chen R, Zheng Z, Lu J, Hong C. Toll-Like Receptor 3 in Cardiovascular Diseases. Heart Lung Circ 2022; 31:e93-e109. [PMID: 35367134 DOI: 10.1016/j.hlc.2022.02.012] [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] [Received: 07/22/2021] [Revised: 02/08/2022] [Accepted: 02/17/2022] [Indexed: 02/06/2023]
Abstract
Toll-like receptor 3 (TLR3) is an important member of the innate immune response receptor toll-like receptors (TLRs) family, which plays a vital role in regulating immune response, promoting the maturation and differentiation of immune cells, and participating in the response of pro-inflammatory factors. TLR3 is activated by pathogen-associated molecular patterns and damage-associated molecular patterns, which support the pathophysiology of many diseases related to inflammation. An increasing number of studies have confirmed that TLR3, as a crucial medium of innate immunity, participates in the occurrence and development of cardiovascular diseases (CVDs) by regulating the transcription and translation of various cytokines, thus affecting the structure and physiological function of resident cells in the cardiovascular system, including vascular endothelial cells, vascular smooth muscle cells, cardiomyocytes, fibroblasts and macrophages. The dysfunction and structural damage of vascular endothelial cells and proliferation of vascular smooth muscle cells are the key factors in the occurrence of vascular diseases such as pulmonary arterial hypertension, atherosclerosis, myocardial hypertrophy, myocardial infarction, ischaemia/reperfusion injury, and heart failure. Meanwhile, cardiomyocytes, fibroblasts, and macrophages are involved in the development of CVDs. Therefore, the purpose of this review was to explore the latest research published on TLR3 in CVDs and discuss current understanding of potential mechanisms by which TLR3 contributes to CVDs. Even though TLR3 is a developing area, it has strong treatment potential as an immunomodulator and deserves further study for clinical translation.
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Affiliation(s)
- Chunying Zhuang
- China State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; First Clinical School, Guangzhou Medical University, Guangzhou, China
| | - Riken Chen
- China State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhenzhen Zheng
- Department of Respiration, The Second Affiliated Hospital of Guangdong Medical University, Guangzhou, China
| | - Jianmin Lu
- China State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Cheng Hong
- China State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
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22
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Malvandi AM, Shahba S, Mehrzad J, Lombardi G. Metabolic Disruption by Naturally Occurring Mycotoxins in Circulation: A Focus on Vascular and Bone Homeostasis Dysfunction. Front Nutr 2022; 9:915681. [PMID: 35811967 PMCID: PMC9263741 DOI: 10.3389/fnut.2022.915681] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 05/30/2022] [Indexed: 12/22/2022] Open
Abstract
Naturally occurring food/feed contaminants have become a significant global issue due to animal and human health implications. Despite risk assessments and legislation setpoints on the mycotoxins' levels, exposure to lower amounts occurs, and it might affect cell homeostasis. However, the inflammatory consequences of this possible everyday exposure to toxins on the vascular microenvironment and arterial dysfunction are unexplored in detail. Circulation is the most accessible path for food-borne toxins, and the consequent metabolic and immune shifts affect systemic health, both on vascular apparatus and bone homeostasis. Their oxidative nature makes mycotoxins a plausible underlying source of low-level toxicity in the bone marrow microenvironment and arterial dysfunction. Mycotoxins could also influence the function of cardiomyocytes with possible injury to the heart. Co-occurrence of mycotoxins can modulate the metabolic pathways favoring osteoblast dysfunction and bone health losses. This review provides a novel insight into understanding the complex events of coexposure to mixed (low levels) mycotoxicosis and subsequent metabolic/immune disruptions contributing to chronic alterations in circulation.
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Affiliation(s)
- Amir Mohammad Malvandi
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
- *Correspondence: Amir Mohammad Malvandi ; orcid.org/0000-0003-1243-2372
| | - Sara Shahba
- Department of Microbiology and Immunology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Jalil Mehrzad
- Department of Microbiology and Immunology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
- Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Poznań, Poland
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23
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Tetramethylpyrazine: A review on its mechanisms and functions. Biomed Pharmacother 2022; 150:113005. [PMID: 35483189 DOI: 10.1016/j.biopha.2022.113005] [Citation(s) in RCA: 100] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 04/15/2022] [Accepted: 04/19/2022] [Indexed: 11/21/2022] Open
Abstract
Ligusticum chuanxiong Hort (known as Chuanxiong in China, CX) is one of the most widely used and long-standing medicinal herbs in China. Tetramethylpyrazine (TMP) is an alkaloid and one of the active components of CX. Over the past few decades, TMP has been proven to possess several pharmacological properties. It has been used to treat a variety of diseases with excellent therapeutic effects. Here, the pharmacological characteristics and molecular mechanism of TMP in recent years are reviewed, with an emphasis on the signal-regulation mechanism of TMP. This review shows that TMP has many physiological functions, including anti-oxidant, anti-inflammatory, and anti-apoptosis properties; autophagy regulation; vasodilation; angiogenesis regulation; mitochondrial damage suppression; endothelial protection; reduction of proliferation and migration of vascular smooth muscle cells; and neuroprotection. At present, TMP is used in treating cardiovascular, nervous, and digestive system conditions, cancer, and other conditions and has achieved good curative effects. The therapeutic mechanism of TMP involves multiple targets, multiple pathways, and bidirectional regulation. TMP is, thus, a promising drug with great research potential.
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24
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The Effects of Probiotics on Inflammation, Endothelial Dysfunction, and Atherosclerosis Progression: A Mechanistic Overview. Heart Lung Circ 2022; 31:e45-e71. [PMID: 35153150 DOI: 10.1016/j.hlc.2021.09.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 06/07/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The relationship between the intestinal microbiota dysbiosis, inflammation, and cardiovascular disorders (CVDs) has become evident, based on a growing body of literature from animal models and human studies. On the other hand, probiotics are believed to have promising effects on modifying dysbiosis and protecting against CVDs. OBJECTIVE This narrative review provides an overview of the link between gut microbiota, inflammation, endothelial dysfunction, and atherosclerosis. The influences of probiotic supplementation on biomarkers contributing to these conditions as the primary underlying risk factors for developing CVDs are also discussed. METHODS An up-to-date review was performed of the available evidence from experimental studies, clinical trials, and meta-analyses, considering their challenges and limitations. It also aimed to provide mechanistic insight into the likely mechanisms of probiotics that could prevent atherosclerosis initiation and progression. RESULTS Probiotic supplementation seems to be associated with reduced levels of inflammation and oxidative stress biomarkers (C-reactive protein, tumour necrosis factor-α, interleukin (IL)-6, IL-12, and malondialdehyde). Further, these agents might enhance antioxidant factors (IL-10, total antioxidant status, total antioxidant capacity, glutathione, and nitric oxide). Probiotics also appear to improve intestinal barrier integrity, reduce leakage of harmful metabolites (e.g., lipopolysaccharides), inhibit pro-inflammatory signalling pathways, and possibly suppress the formation of trimethylamine/trimethylamine oxide. Probiotics have also been found to enhance endothelial function and halter thrombosis. CONCLUSION The current clinical evidence underlines belief that probiotics might be associated with reduced levels of inflammation biomarkers. Experimental evidence reports that the beneficial effects of probiotics seem to be mainly imposed by triggering the secretion of short-chain fatty acids and bile acids, in addition to suppressing the NF-κB signalling pathway. However, the current studies are still in their infancy and it is of high priority to design further research on the topic.
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25
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Bikomeye JC, Beyer AM, Kwarteng JL, Beyer KMM. Greenspace, Inflammation, Cardiovascular Health, and Cancer: A Review and Conceptual Framework for Greenspace in Cardio-Oncology Research. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:2426. [PMID: 35206610 PMCID: PMC8872601 DOI: 10.3390/ijerph19042426] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 02/12/2022] [Accepted: 02/17/2022] [Indexed: 02/04/2023]
Abstract
Cardiovascular disease (CVD) is a leading cause of global morbidity and mortality. Cancer survivors have significantly elevated risk of poor cardiovascular (CV) health outcomes due to close co-morbid linkages and shared risk factors between CVD and cancer, as well as adverse effects of cancer treatment-related cardiotoxicity. CVD and cancer-related outcomes are exacerbated by increased risk of inflammation. Results from different pharmacological interventions aimed at reducing inflammation and risk of major adverse cardiovascular events (MACEs) have been largely mixed to date. Greenspaces have been shown to reduce inflammation and have been associated with CV health benefits, including reduced CVD behavioral risk factors and overall improvement in CV outcomes. Greenspace may, thus, serve to alleviate the CVD burden among cancer survivors. To understand pathways through which greenspace can prevent or reduce adverse CV outcomes among cancer survivors, we review the state of knowledge on associations among inflammation, CVD, cancer, and existing pharmacological interventions. We then discuss greenspace benefits for CV health from ecological to multilevel studies and a few existing experimental studies. Furthermore, we review the relationship between greenspace and inflammation, and we highlight forest bathing in Asian-based studies while presenting existing research gaps in the US literature. Then, we use the socioecological model of health to present an expanded conceptual framework to help fill this US literature gap. Lastly, we present a way forward, including implications for translational science and a brief discussion on necessities for virtual nature and/or exposure to nature images due to the increasing human-nature disconnect; we also offer guidance for greenspace research in cardio-oncology to improve CV health outcomes among cancer survivors.
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Affiliation(s)
- Jean C. Bikomeye
- Institute for Health and Equity, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA; (J.C.B.); (J.L.K.)
- PhD Program in Public and Community Health, Division of Epidemiology & Social Sciences, Institute for Health and Equity, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA
| | - Andreas M. Beyer
- Department of Medicine, Division of Cardiology, Cardiovascular and Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA
| | - Jamila L. Kwarteng
- Institute for Health and Equity, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA; (J.C.B.); (J.L.K.)
- MCW Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA
| | - Kirsten M. M. Beyer
- Institute for Health and Equity, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA; (J.C.B.); (J.L.K.)
- PhD Program in Public and Community Health, Division of Epidemiology & Social Sciences, Institute for Health and Equity, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA
- MCW Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA
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26
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Gerhardt T, Haghikia A, Stapmanns P, Leistner DM. Immune Mechanisms of Plaque Instability. Front Cardiovasc Med 2022; 8:797046. [PMID: 35087883 PMCID: PMC8787133 DOI: 10.3389/fcvm.2021.797046] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/15/2021] [Indexed: 01/08/2023] Open
Abstract
Inflammation crucially drives atherosclerosis from disease initiation to the emergence of clinical complications. Targeting pivotal inflammatory pathways without compromising the host defense could compliment therapy with lipid-lowering agents, anti-hypertensive treatment, and lifestyle interventions to address the substantial residual cardiovascular risk that remains beyond classical risk factor control. Detailed understanding of the intricate immune mechanisms that propel plaque instability and disruption is indispensable for the development of novel therapeutic concepts. In this review, we provide an overview on the role of key immune cells in plaque inception and progression, and discuss recently identified maladaptive immune phenomena that contribute to plaque destabilization, including epigenetically programmed trained immunity in myeloid cells, pathogenic conversion of autoreactive regulatory T-cells and expansion of altered leukocytes due to clonal hematopoiesis. From a more global perspective, the article discusses how systemic crises such as acute mental stress or infection abruptly raise plaque vulnerability and summarizes recent advances in understanding the increased cardiovascular risk associated with COVID-19 disease. Stepping outside the box, we highlight the role of gut dysbiosis in atherosclerosis progression and plaque vulnerability. The emerging differential role of the immune system in plaque rupture and plaque erosion as well as the limitations of animal models in studying plaque disruption are reviewed.
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Affiliation(s)
- Teresa Gerhardt
- Charité – Universitätsmedizin Berlin, Department of Cardiology, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Arash Haghikia
- Charité – Universitätsmedizin Berlin, Department of Cardiology, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Philip Stapmanns
- Charité – Universitätsmedizin Berlin, Department of Cardiology, Berlin, Germany
| | - David Manuel Leistner
- Charité – Universitätsmedizin Berlin, Department of Cardiology, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
- *Correspondence: David Manuel Leistner
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Razeghian-Jahromi I, Karimi Akhormeh A, Razmkhah M, Zibaeenezhad MJ. Immune system and atherosclerosis: Hostile or friendly relationship. Int J Immunopathol Pharmacol 2022; 36:3946320221092188. [PMID: 35410514 PMCID: PMC9009140 DOI: 10.1177/03946320221092188] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 03/16/2022] [Indexed: 11/21/2022] Open
Abstract
Coronary artery disease has remained a major health challenge despite enormous progress in prevention, diagnosis, and treatment strategies. Formation of atherosclerotic plaque is a chronic process that is developmentally influenced by intrinsic and extrinsic determinants. Inflammation triggers atherosclerosis, and the fundamental element of inflammation is the immune system. The immune system involves in the atherosclerosis process by a variety of immune cells and a cocktail of mediators. It is believed that almost all main components of this system possess a profound contribution to the atherosclerosis. However, they play contradictory roles, either protective or progressive, in different stages of atherosclerosis progression. It is evident that monocytes are the first immune cells appeared in the atherosclerotic lesion. With the plaque growth, other types of the immune cells such as mast cells, and T lymphocytes are gradually involved. Each cell releases several cytokines which cause the recruitment of other immune cells to the lesion site. This is followed by affecting the expression of other cytokines as well as altering certain signaling pathways. All in all, a mix of intertwined interactions determine the final outcome in terms of mild or severe manifestations, either clinical or subclinical. Therefore, it is of utmost importance to precisely understand the kind and degree of contribution which is made by each immune component in order to stop the growing burden of cardiovascular morbidity and mortality. In this review, we present a comprehensive appraisal on the role of immune cells in the atherosclerosis initiation and development.
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Affiliation(s)
| | - Ali Karimi Akhormeh
- Cardiovascular Research Center, Shiraz University of Medical
Sciences, Shiraz, Iran
| | - Mahboobeh Razmkhah
- Shiraz Institute for Cancer
Research, Shiraz University of Medical
Sciences, Shiraz, Iran
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28
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Page MJ, Kell DB, Pretorius E. The Role of Lipopolysaccharide-Induced Cell Signalling in Chronic Inflammation. CHRONIC STRESS (THOUSAND OAKS, CALIF.) 2022; 6:24705470221076390. [PMID: 35155966 PMCID: PMC8829728 DOI: 10.1177/24705470221076390] [Citation(s) in RCA: 121] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 01/11/2022] [Indexed: 12/20/2022]
Abstract
Lipopolysaccharide (LPS) is the main structural component of the outer membrane of most Gram-negative bacteria and has diverse immunostimulatory and procoagulant effects. Even though LPS is well described for its role in the pathology of sepsis, considerable evidence demonstrates that LPS-induced signalling and immune dysregulation are also relevant in the pathophysiology of many diseases, characteristically where endotoxaemia is less severe. These diseases are typically chronic and progressive in nature and span broad classifications, including neurodegenerative, metabolic, and cardiovascular diseases. This Review reappraises the mechanisms of LPS-induced signalling and emphasises the crucial contribution of LPS to the pathology of multiple chronic diseases, beyond conventional sepsis. This perspective asserts that new ways of approaching chronic diseases by targeting LPS-driven pathways may be of therapeutic benefit in a wide range of chronic inflammatory conditions.
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Affiliation(s)
| | - Douglas B Kell
- Stellenbosch University, Stellenbosch, South Africa.,Institute of Integrative Biology, University of Liverpool, Liverpool, UK.,The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby, Denmark
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29
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Wang P, Wang Y, Peng H, Wang J, Zheng Q, Wang P, Wang J, Zhang H, Huang Y, Xiong L, Zhang R, Xia Y, Wang QK, Xu C. Functional rare variant in a C/EBP beta binding site in NINJ2 gene increases the risk of coronary artery disease. Aging (Albany NY) 2021; 13:25393-25407. [PMID: 34897030 PMCID: PMC8714150 DOI: 10.18632/aging.203755] [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: 10/30/2021] [Accepted: 11/11/2021] [Indexed: 11/26/2022]
Abstract
Objective: NINJ2 regulates activation of vascular endothelial cells, and genome-wide association studies showed that variants in NINJ2 confer risk to stroke. However, whether variants in NINJ2 are associated with coronary artery disease (CAD) is unknown. Methods: We genotyped rs34166160 in NINJ2 in two independent Chinese GeneID populations which included 2,794 CAD cases and 4,131 controls, and performed genetics association studies. Functional studies were also performed to reveal the mechanisms. Results: Allele rs34166160 significantly confers risk to CAD in the GeneID Hubei population which contained 1,440 CAD cases and 2,660 CAD-free controls (observed P-obs = 6.39 × 10−3 with an odds ratio (OR) was 3.39, adjusted P-adj = 8.12 × 10−3 with an OR of 3.10). The association was replicated in another population, GeneID Shandong population contained 1,354 CAD cases and 1,471 controls (P-obs = 3.33 × 10−3 with an OR of 3.14, P-adj = 0.01 with an OR of 2.74). After combining the two populations, the association was more significant (P-obs = 1.57 × 10−5 with an OR of 3.58, P-adj = 3.41 × 10−4 with an OR of 2.80). In addition, we found that rs34166160 was associated with the mRNA expression level of NINJ2 and the flanking region of rs34166160 can directly bind with transcriptional factor CCAAT-box/enhancer-binding protein beta, and the risk A allele has more transcription activity than non-risk C allele with or without LPS in HUVEC cells. Conclusions: Our study demonstrates that the functional rare variant rs34166160 in NINJ2 confers risk to CAD for the first time, and these findings further expand the range of the pathology of CAD and atherosclerosis.
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Affiliation(s)
- Pengyun Wang
- Department of Clinical Laboratory, Liyuan Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Yifan Wang
- Human Genome Research Center, Cardio-X Institute, College of Life Science and Technology of Huazhong University of Science and Technology, Wuhan, PR China
| | - Huixin Peng
- Human Genome Research Center, Cardio-X Institute, College of Life Science and Technology of Huazhong University of Science and Technology, Wuhan, PR China
| | - Jingjing Wang
- State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, PR China
| | - Qian Zheng
- Human Genome Research Center, Cardio-X Institute, College of Life Science and Technology of Huazhong University of Science and Technology, Wuhan, PR China
| | - Pengxia Wang
- Human Genome Research Center, Cardio-X Institute, College of Life Science and Technology of Huazhong University of Science and Technology, Wuhan, PR China
| | - Jing Wang
- Human Genome Research Center, Cardio-X Institute, College of Life Science and Technology of Huazhong University of Science and Technology, Wuhan, PR China
| | - Hongfu Zhang
- Human Genome Research Center, Cardio-X Institute, College of Life Science and Technology of Huazhong University of Science and Technology, Wuhan, PR China
| | - Yufeng Huang
- Precision Medical Laboratory, Tongji Medical College, Wuhan Children's Hospital (Wuhan Maternal and Child Health Care Hospital), Huazhong University of Science and Technology, Wuhan, PR China
| | - Liang Xiong
- Department of Clinical Laboratory, Liyuan Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Rongfeng Zhang
- Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, PR China
| | - Yunlong Xia
- Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, PR China
| | - Qing K Wang
- Human Genome Research Center, Cardio-X Institute, College of Life Science and Technology of Huazhong University of Science and Technology, Wuhan, PR China
| | - Chengqi Xu
- Human Genome Research Center, Cardio-X Institute, College of Life Science and Technology of Huazhong University of Science and Technology, Wuhan, PR China
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30
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Hakhamaneshi MS, Abdolahi A, Vahabzadeh Z, Abdi M, Andalibi P. Toll-Like Receptor 4: A Macrophage Cell Surface Receptor Is Activated By Trimethylamine-N-Oxide. CELL JOURNAL 2021; 23:516-522. [PMID: 34837678 PMCID: PMC8588815 DOI: 10.22074/cellj.2021.7849] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 02/03/2021] [Indexed: 01/06/2023]
Abstract
OBJECTIVE Trimethylamine-N-Oxide (TMAO) is considered as a risk factor for atherosclerosis which further leads to inflammation during atherosclerosis. The exact mechanism(s) by which TMAO induces the inflammatory reactions remains to be determined. TMAO can cause the endoplasmic reticulum (ER) stress that triggers activation of Toll-Like Receptors (TLRs). In macrophages, this process stimulates the production of proinflammatory cytokines. This study designed to evaluate the expression level of TLR4 in TMAO-treated macrophages. MATERIALS AND METHODS In this experimental study, different concentrations of TMAO (37.5, 75, 150, and 300 μM) were exposed to murine macrophage (J774A.1 cell line) for 8, 18, 24, and 48 hours. The cells were also treated with 2.5 mM of 4-phenyl butyric acid as well as 2μg/ml of tunicamycin respectively as negative and positive controls for inducing ER-stress. We measured the viability of treated cells by the MTT test. Besides, the expression levels of TLR4 gene and protein were evaluated using western blotting and reverse transcription- quantitative polymerase chain reaction (RT-qPCR) analysis. One-Way ANOVA was used for statistical analysis. RESULTS No cell death was observed in treated cells. The cells treated with 150 and 300 μM doses of TMAO for 24 hours showed a significant elevation in the protein and/or mRNA levels of TLR4 when compared to normal control or tunicamycin-treated cells. CONCLUSION Our results may in part elucidate the mechanism by which TMAO induces the macrophage inflammatory reactions in response to the induction of ER stress, similar to what happens during atherosclerosis. It also provides documentation to support the direct contribution of TLR4 in TMAO-induced inflammation.
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Affiliation(s)
| | - Alina Abdolahi
- Department of Molecular Medicine and Genetics, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Zakaria Vahabzadeh
- Department of Biochemistry, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran. .,Liver and Digestive Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mohammad Abdi
- Cellular and Molecular Research Centre, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Pedram Andalibi
- Department of Biochemistry, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
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Miki S, Suzuki JI, Takashima M, Ishida M, Kokubo H, Yoshizumi M. S-1-Propenylcysteine promotes IL-10-induced M2c macrophage polarization through prolonged activation of IL-10R/STAT3 signaling. Sci Rep 2021; 11:22469. [PMID: 34789834 PMCID: PMC8599840 DOI: 10.1038/s41598-021-01866-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 11/02/2021] [Indexed: 12/15/2022] Open
Abstract
Atherosclerosis is a chronic inflammatory disease that may lead to the development of serious cardiovascular diseases. Aged garlic extract (AGE) has been reported to ameliorate atherosclerosis, although its mode of action remains unclear. We found that AGE increased the mRNA or protein levels of arginase1 (Arg1), interleukin-10 (IL-10), CD206 and hypoxia-inducible factor 2α (HIF2α) and decreased that of CD68, HIF1α and inducible nitric oxide synthase in the aorta and spleen of apolipoprotein E knockout mice. We also found that S-1-propenylcysteine (S1PC), a characteristic sulfur compound in AGE, increased the level of IL-10-induced Arg1 mRNA and the extent of M2c-like macrophage polarization in vitro. In addition, S1PC increased the population of M2c-like macrophages, resulting in suppressed the population of M1-like macrophages and decreased lipopolysaccharide-induced production of pro-inflammatory cytokines. These effects were accompanied by prolonged phosphorylation of the IL-10 receptor α (IL-10Rα) and signal transducer and activator of transcription 3 (STAT3) that inhibited the interaction between IL-10Rα and Src homology-2-containing inositol 5'-phosphatase 1 (SHIP1). In addition, administration of S1PC elevated the M2c/M1 macrophage ratio in senescence-accelerated mice. These findings suggest that S1PC may help improve atherosclerosis due to its anti-inflammatory effect to promote IL-10-induced M2c macrophage polarization.
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Affiliation(s)
- Satomi Miki
- Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima-shi, Hiroshima, 734-8551, Japan.
- Central Research Institute, Wakunaga Pharmaceutical Co., Ltd., 1624 Shimokotachi, Koda-cho, Akitakata-shi, Hiroshima, 739-1195, Japan.
| | - Jun-Ichiro Suzuki
- Central Research Institute, Wakunaga Pharmaceutical Co., Ltd., 1624 Shimokotachi, Koda-cho, Akitakata-shi, Hiroshima, 739-1195, Japan
| | - Miyuki Takashima
- Central Research Institute, Wakunaga Pharmaceutical Co., Ltd., 1624 Shimokotachi, Koda-cho, Akitakata-shi, Hiroshima, 739-1195, Japan
| | - Mari Ishida
- Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima-shi, Hiroshima, 734-8551, Japan
| | - Hiroki Kokubo
- Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima-shi, Hiroshima, 734-8551, Japan
| | - Masao Yoshizumi
- Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima-shi, Hiroshima, 734-8551, Japan.
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32
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Adhikarla SV, Jha NK, Goswami VK, Sharma A, Bhardwaj A, Dey A, Villa C, Kumar Y, Jha SK. TLR-Mediated Signal Transduction and Neurodegenerative Disorders. Brain Sci 2021; 11:brainsci11111373. [PMID: 34827372 PMCID: PMC8615980 DOI: 10.3390/brainsci11111373] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/16/2021] [Accepted: 10/16/2021] [Indexed: 11/16/2022] Open
Abstract
A special class of proteins called Toll-like receptors (TLRs) are an essential part of the innate immune system, connecting it to the adaptive immune system. There are 10 different Toll-Like Receptors that have been identified in human beings. TLRs are part of the central nervous system (CNS), showing that the CNS is capable of the immune response, breaking the long-held belief of the brain's "immune privilege" owing to the blood-brain barrier (BBB). These Toll-Like Receptors are present not just on the resident macrophages of the central nervous system but are also expressed by the neurons to allow them for the production of proinflammatory agents such as interferons, cytokines, and chemokines; the activation and recruitment of glial cells; and their participation in neuronal cell death by apoptosis. This study is focused on the potential roles of various TLRs in various neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD), namely TLR2, TLR3, TLR4, TLR7, and TLR9 in AD and PD in human beings and a mouse model.
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Affiliation(s)
- Shashank Vishwanath Adhikarla
- Department of Biological Sciences and Engineering, Netaji Subhas University of Technology (Formerly NSIT, University of Delhi), New Delhi 110078, India;
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida 201310, India; (N.K.J.); (A.B.)
| | - Vineet Kumar Goswami
- Department of Biotechnology, Delhi Technological University, Delhi 110042, India;
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham 2770, Australia;
| | - Ankur Sharma
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham 2770, Australia;
- Department of Life Science, School of Basic Science & Research (SBSR), Sharda University, Greater Noida 201310, India
| | - Anuradha Bhardwaj
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida 201310, India; (N.K.J.); (A.B.)
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata 700073, India;
| | - Chiara Villa
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy;
| | - Yatender Kumar
- Department of Biological Sciences and Engineering, Netaji Subhas University of Technology (Formerly NSIT, University of Delhi), New Delhi 110078, India;
- Correspondence: (Y.K.); (S.K.J.)
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida 201310, India; (N.K.J.); (A.B.)
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham 2770, Australia;
- Correspondence: (Y.K.); (S.K.J.)
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Coronary atherosclerosis severity is closely associated with decreased GLP-1R positivity among CD16 + pro-inflammatory and patrolling monocyte subsets. ATHEROSCLEROSIS PLUS 2021; 46:15-19. [PMID: 36643724 PMCID: PMC9833237 DOI: 10.1016/j.athplu.2021.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 09/30/2021] [Accepted: 10/05/2021] [Indexed: 01/18/2023]
Abstract
Background and aims Glucagon Like Peptide-1 Receptor (GLP-1R) activation reduces pro-inflammatory responses of human monocytes, their accumulation in the vascular wall and foam cell formation inhibiting atherosclerogenesis. This suggests that reduction of circulating GLP-1-1R positive monocytes may have pro-atherogenic effects. It is unknown whether different CD14/CD16 monocytes subsets display GLP-1R and whether their relative proportions correlate with atherosclerosis severity. We evaluated the association between GLP-1R positivity in different CD14/CD16 monocyte subsets and coronary atherosclerosis severity. Methods Relative amounts of classical (CD14+/CD16-), intermediate pro-inflammatory (CD14+/CD16+) and non-classical patrolling (CD14-/CD16+) subsets of total circulating monocytes and the proportions of GLP-1R positive monocytes in these subsets were determined in 13 control subjects and 10 dyslipidemic ischemic heart disease (IHD) patients with severe angiographic proven coronary atherosclerosis using flow cytometry analysis. Atherosclerosis severity was calculated by SYNTAX score. Results In univariable analysis, severe atherosclerosis was associated with decreased proportion of classical monocytes and two fold increased CD16+ pro-inflammatory and patrolling subsets as compared with controls (p = 0.01, p = 0.02 and p = 0.01, respectively). Frequency of GLP-1R positive monocytes was decreased in both CD16+ subsets (p = 0.02 and p = 0.05, respectively) and negatively correlated with atherosclerosis severity (r = -0.65, p = 0.005 and r = -0.44, p = 0.05, respectively). Conclusions Increased skewing of the classical monocyte population toward CD16+ pro-inflammatory and patrolling subsets accompanied by decreased in GLP-1R positivity are associated with coronary atherosclerosis severity in IHD patients with dyslipidemia. Although the effect of potential confounders cannot be ruled out, our data suggest that failure of GLP-1R-dependent anti-inflammatory/anti-atherogenic control results in innate immune system dysfunction and can promote atherosclerogenesis.
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Li D, Wu M. Pattern recognition receptors in health and diseases. Signal Transduct Target Ther 2021; 6:291. [PMID: 34344870 PMCID: PMC8333067 DOI: 10.1038/s41392-021-00687-0] [Citation(s) in RCA: 842] [Impact Index Per Article: 210.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 05/23/2021] [Accepted: 06/22/2021] [Indexed: 02/07/2023] Open
Abstract
Pattern recognition receptors (PRRs) are a class of receptors that can directly recognize the specific molecular structures on the surface of pathogens, apoptotic host cells, and damaged senescent cells. PRRs bridge nonspecific immunity and specific immunity. Through the recognition and binding of ligands, PRRs can produce nonspecific anti-infection, antitumor, and other immunoprotective effects. Most PRRs in the innate immune system of vertebrates can be classified into the following five types based on protein domain homology: Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), C-type lectin receptors (CLRs), and absent in melanoma-2 (AIM2)-like receptors (ALRs). PRRs are basically composed of ligand recognition domains, intermediate domains, and effector domains. PRRs recognize and bind their respective ligands and recruit adaptor molecules with the same structure through their effector domains, initiating downstream signaling pathways to exert effects. In recent years, the increased researches on the recognition and binding of PRRs and their ligands have greatly promoted the understanding of different PRRs signaling pathways and provided ideas for the treatment of immune-related diseases and even tumors. This review describes in detail the history, the structural characteristics, ligand recognition mechanism, the signaling pathway, the related disease, new drugs in clinical trials and clinical therapy of different types of PRRs, and discusses the significance of the research on pattern recognition mechanism for the treatment of PRR-related diseases.
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Affiliation(s)
- Danyang Li
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Minghua Wu
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan, China.
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.
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Overexpression of TOLLIP Protects against Acute Kidney Injury after Paraquat Intoxication through Inhibiting NLRP3 Inflammasome Activation Modulated by Toll-Like Receptor 2/4 Signaling. Mediators Inflamm 2021; 2021:5571272. [PMID: 34335089 PMCID: PMC8298172 DOI: 10.1155/2021/5571272] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/10/2021] [Accepted: 06/09/2021] [Indexed: 01/22/2023] Open
Abstract
Paraquat (PQ) can cause multiorgan failure including acute kidney injury (AKI). Our prior study showed that Toll-interacting protein (TOLLIP) protected against PQ-induced acute lung injury. However, the role of TOLLIP in PQ-induced AKI remains undefined. This study was aimed at understanding the role and mechanism of TOLLIP in AKI. Six-eight-week-old male Wistar rats were intraperitoneally injected with 25 mg/kg PQ to induce AKI for 24 h in vivo. HK-2 cells were treated with 300 μM PQ for 24 h to induce cellular injury in vitro or 300 μM PQ and 5 μM nuclear factor-κB (NF-κB) inhibitor BAY11-7082 for 24 h. Rats were infected with adenovirus carrying TOLLIP shRNA via tail vein injection and HK-2 cells with adenovirus carrying TOLLIP shRNA or TOLLIP 48 h before PQ exposure. Results showed that TOLLIP and Toll-like receptor 2/4 (TLR2/4) expressions were boosted in the kidney after PQ intoxication. The toxic effect of PQ on the kidney and HK-2 cells was exacerbated by TOLLIP knockdown, as evidenced by aggravated glomerulus and tubule injury, inflammatory infiltration, and cell apoptosis in the kidney and increased loss of cell viability and apoptotic cells in HK-2 cells. TOLLIP knockdown also enhanced PQ-induced NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation in vivo and in vitro and TLR2/4-NF-κB signaling in vitro, reflected by increased contents of proinflammatory cytokines and expressions of NLRP3 inflammasome-related proteins in the kidney and HK-2 cells and expressions of TLR2, TLR4, and nuclear NF-κB p65 in HK-2 cells. However, TOLLIP overexpression inhibited PQ-induced loss of cell viability, cell apoptosis, NLRP3 inflammasome activation, and TLR2/4-NF-κB signaling in vitro. Additionally, BAY11-7082 abolished TOLLIP knockdown-induced NLRP3 inflammasome activation in vitro, indicating that TOLLIP protected against NLRP3 inflammasome activation in PQ-induced AKI through inhibiting TLR2/4-NF-κB signaling. This study highlights the importance of TOLLIP in AKI after PQ intoxication.
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Ahmadi A, Vahabzadeh Z, Moloudi M, Farhadi L, Shirahmadi S. Contribution of toll-like receptor 2 and nicotinamide adenine dinucleotide phosphate oxidase to the trimethylamine N-oxide-induced inflammatory reactions in U937-derived macrophages. ARYA ATHEROSCLEROSIS 2021; 17:1-7. [PMID: 35685229 PMCID: PMC9137230 DOI: 10.22122/arya.v17i0.2096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/24/2021] [Indexed: 11/09/2022]
Abstract
BACKGROUND Trimethylamine N-oxide (TMAO) is emerging as a new generation of metabolites related to the activation of inflammatory reactions in the macrophages during atherosclerosis. Stress-activation of cell surface toll-like receptors (TLRs) as well as nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) is also assumed to be involved in TMAO-induced inflammatory reaction in the macrophages. To elucidate the possible contribution of TLRs and NOX to the mentioned signaling pathway, we aimed to simultaneously evaluate the expression level of TLR2, TLR6, and NOX2 in TMAO-treated macrophages. METHODS 2.5 × 106 cells of U937-derived macrophages were treated in triplicates with different concentrations (37.5, 75, 150, and 300 μM) of TMAO for 24 hours. The cells were also treated with tunicamycin (TUN), as a positive control of stress. Normal control group (CTR) cells received no treatment. The viability of treated cells was checked by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole (MTT) assay. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was also used to evaluate the relative expression (fold change) of TLR2, TLR6, and NOX2 at messenger ribonucleic acid (mRNA) levels. One-way analysis of variance (ANOVA) with post-hoc Dunnett's test was performed to compare every mean with that of the control. RESULTS No cell death occurred because of treatments. Dose of 300 μM of TMAO significantly increased the relative expression of both TLR2 and NOX2 compared to the CTR cells (P < 0.001 for both). The elevation of TLR6 was not statistically significant in all groups of TMAO-treated cells (P > 0.050). CONCLUSION Our results provide documentation supporting contribution of TLR2 and NOX2 to previously described inflammatory reactions induced by TMAO in macrophages. In addition, they may clarify the proatherogenic role of TMAO in foam cell formation as well as abnormal activation of macrophages during atherosclerosis.
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Affiliation(s)
- Abbas Ahmadi
- Assistant Professor, Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Zakaria Vahabzadeh
- Assistant Professor, Liver and Digestive Research Center, Research Institute for Health Development AND Department of Clinical Biochemistry, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mohammadraman Moloudi
- Assistant Professor, Liver and Digestive Research Center, Research Institute for Health Development AND Department of Medical Physiology and Pharmacology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Leila Farhadi
- PhD Candidate, Department of Molecular Medicine and Genetics, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Sara Shirahmadi
- Medical Student, Department of Clinical Biochemistry, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
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Tutunchi H, Naeini F, Ebrahimi-Mameghani M, Mobasseri M, Naghshi S, Ostadrahimi A. The association of the steatosis severity, NAFLD fibrosis score and FIB-4 index with atherogenic dyslipidaemia in adult patients with NAFLD: A cross-sectional study. Int J Clin Pract 2021; 75:e14131. [PMID: 33683797 DOI: 10.1111/ijcp.14131] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 02/26/2021] [Accepted: 03/02/2021] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES Obesity and dyslipidaemia are the major risk factors for non-alcoholic fatty liver disease (NAFLD), and are known to increase cardiovascular disease (CVD), which is the leading cause of death in NAFLD patients. The present cross-sectional study aimed to investigate associations among severity of hepatic steatosis, NAFLD fibrosis score and atherogenic lipid profile. METHODS A total of 265 patients with NAFLD confirmed by ultrasonographic findings were included. The NAFLD fibrosis score and the fibrosis-4 (FIB-4) index were used to classify the probability of fibrosis as low, intermediate and high probability. Serum lipids including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured, and then TC/HDL-C, LDL-C/HDL-C, TG/HDL-C and non HDL-C/HDL-C ratios were determined. Fasting blood sugar (FBS), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were also assessed. The homeostatic model assessment for insulin resistance (HOMA-IR) was calculated. RESULTS The severity of hepatic steatosis was positively correlated with TC/HDL-C (r = 0.29, P = .002), LDL-C/HDL-C (r = 0.32, P < .001), TG/HDL-C (r = 0.36, P < .001) and non-HDL-C/HDL-C (r = 0.24, P = .001) ratios. Similarly, these parameters were positively correlated with NAFLD fibrosis score and FIB-4 index (P < .05). In addition, alanine aminotransferase and aspartate aminotransferase levels were positively correlated with TG/HDL-C ratio (r = 0.31, P = .003; and r = 0.27, P = .001 respectively). With increasing the severity of hepatic steatosis and NAFLD fibrosis score, the mean of all lipid ratios increased significantly (P < .01 and P < .05, respectively). Importantly, after controlling for potential confounders including age, gender, physical activity level, body mass index, waist circumference and HOMA-IR, the severity of steatosis, NAFLD fibrosis score and FIB-4 index remained independent predictors of atherogenic lipid profile. CONCLUSIONS Severity of hepatic steatosis, NAFLD fibrosis score and FIB-4 index were significantly correlated with atherogenic lipid profile. As NAFLD is high among patients with metabolic risk factors for CVD, their dyslipidaemia should be aggressively managed.
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Affiliation(s)
- Helda Tutunchi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Naeini
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran university of medical science, Tehran, Iran
| | - Mehrangiz Ebrahimi-Mameghani
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Mobasseri
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sina Naghshi
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran university of medical science, Tehran, Iran
| | - Alireza Ostadrahimi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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Mettu PS, Allingham MJ, Cousins SW. Incomplete response to Anti-VEGF therapy in neovascular AMD: Exploring disease mechanisms and therapeutic opportunities. Prog Retin Eye Res 2021; 82:100906. [PMID: 33022379 PMCID: PMC10368393 DOI: 10.1016/j.preteyeres.2020.100906] [Citation(s) in RCA: 201] [Impact Index Per Article: 50.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 09/18/2020] [Accepted: 09/22/2020] [Indexed: 12/13/2022]
Abstract
Intravitreal anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular age-related macular degeneration (NVAMD). However, many patients suffer from incomplete response to anti-VEGF therapy (IRT), which is defined as (1) persistent (plasma) fluid exudation; (2) unresolved or new hemorrhage; (3) progressive lesion fibrosis; and/or (4) suboptimal vision recovery. The first three of these collectively comprise the problem of persistent disease activity (PDA) in spite of anti-VEGF therapy. Meanwhile, the problem of suboptimal vision recovery (SVR) is defined as a failure to achieve excellent functional visual acuity of 20/40 or better in spite of sufficient anti-VEGF treatment. Thus, incomplete response to anti-VEGF therapy, and specifically PDA and SVR, represent significant clinical unmet needs. In this review, we will explore PDA and SVR in NVAMD, characterizing the clinical manifestations and exploring the pathobiology of each. We will demonstrate that PDA occurs most frequently in NVAMD patients who develop high-flow CNV lesions with arteriolarization, in contrast to patients with capillary CNV who are highly responsive to anti-VEGF therapy. We will review investigations of experimental CNV and demonstrate that both types of CNV can be modeled in mice. We will present and consider a provocative hypothesis: formation of arteriolar CNV occurs via a distinct pathobiology, termed neovascular remodeling (NVR), wherein blood-derived macrophages infiltrate the incipient CNV lesion, recruit bone marrow-derived mesenchymal precursor cells (MPCs) from the circulation, and activate MPCs to become vascular smooth muscle cells (VSMCs) and myofibroblasts, driving the development of high-flow CNV with arteriolarization and perivascular fibrosis. In considering SVR, we will discuss the concept that limited or poor vision in spite of anti-VEGF may not be caused simply by photoreceptor degeneration but instead may be associated with photoreceptor synaptic dysfunction in the neurosensory retina overlying CNV, triggered by infiltrating blood-derived macrophages and mediated by Müller cell activation Finally, for each of PDA and SVR, we will discuss current approaches to disease management and treatment and consider novel avenues for potential future therapies.
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Affiliation(s)
- Priyatham S Mettu
- Duke Center for Macular Diseases, Department of Ophthalmology, Duke University School of Medicine, Durham, NC, NC.
| | - Michael J Allingham
- Duke Center for Macular Diseases, Department of Ophthalmology, Duke University School of Medicine, Durham, NC, NC
| | - Scott W Cousins
- Duke Center for Macular Diseases, Department of Ophthalmology, Duke University School of Medicine, Durham, NC, NC; Department of Immunology, Duke University School of Medicine, Durham, NC, USA
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Lazaridis A, Gavriilaki E, Douma S, Gkaliagkousi E. Toll-Like Receptors in the Pathogenesis of Essential Hypertension. A Forthcoming Immune-Driven Theory in Full Effect. Int J Mol Sci 2021; 22:3451. [PMID: 33810594 PMCID: PMC8037648 DOI: 10.3390/ijms22073451] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/18/2021] [Accepted: 03/23/2021] [Indexed: 12/15/2022] Open
Abstract
Essential hypertension (EH) is a highly heterogenous disease with a complex etiology. Recent evidence highlights the significant contribution of subclinical inflammation, triggered and sustained by excessive innate immune system activation in the pathogenesis of the disease. Toll-like receptors (TLRs) have been implied as novel effectors in this inflammatory environment since they can significantly stimulate the production of pro-inflammatory cytokines, the migration and proliferation of smooth muscle cells and the generation of reactive oxygen species (ROS), facilitating a low-intensity inflammatory background that is evident from the very early stages of hypertension. Furthermore, the net result of their activation is oxidative stress, endothelial dysfunction, vascular remodeling, and finally, vascular target organ damage, which forms the pathogenetic basis of EH. Importantly, evidence of augmented TLR expression and activation in hypertension has been documented not only in immune but also in several non-immune cells located in the central nervous system, the kidneys, and the vasculature which form the pathogenetic core systems operating in hypertensive disease. In this review, we will try to highlight the contribution of innate immunity in the pathogenesis of hypertension by clarifying the deleterious role of TLR signaling in promoting inflammation and facilitating hypertensive vascular damage.
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Affiliation(s)
- Antonios Lazaridis
- 3rd Department of Internal Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece; (A.L.); (S.D.); (E.G.)
| | - Eleni Gavriilaki
- Hematology Department, Bone Marrow Transplantation Unit, G. Papanicolaou Hospital, 57010 Thessaloniki, Greece
| | - Stella Douma
- 3rd Department of Internal Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece; (A.L.); (S.D.); (E.G.)
| | - Eugenia Gkaliagkousi
- 3rd Department of Internal Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece; (A.L.); (S.D.); (E.G.)
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Chang R, Mamun A, Dominic A, Le NT. SARS-CoV-2 Mediated Endothelial Dysfunction: The Potential Role of Chronic Oxidative Stress. Front Physiol 2021; 11:605908. [PMID: 33519510 PMCID: PMC7844210 DOI: 10.3389/fphys.2020.605908] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 12/09/2020] [Indexed: 01/08/2023] Open
Abstract
Endothelial cells have emerged as key players in SARS-CoV-2 infection and COVID-19 inflammatory pathologies. Dysfunctional endothelial cells can promote chronic inflammation and disease processes like thrombosis, atherosclerosis, and lung injury. In endothelial cells, mitochondria regulate these inflammatory pathways via redox signaling, which is primarily achieved through mitochondrial reactive oxygen species (mtROS). Excess mtROS causes oxidative stress that can initiate and exacerbate senescence, a state that promotes inflammation and chronic endothelial dysfunction. Oxidative stress can also activate feedback loops that perpetuate mitochondrial dysfunction, mtROS overproduction, and inflammation. In this review, we provide an overview of phenotypes mediated by mtROS in endothelial cells - such as mitochondrial dysfunction, inflammation, and senescence - as well as how these chronic states may be initiated by SARS-CoV-2 infection of endothelial cells. We also propose that SARS-CoV-2 activates mtROS-mediated feedback loops that cause long-term changes in host redox status and endothelial function, promoting cardiovascular disease and lung injury after recovery from COVID-19. Finally, we discuss the implications of these proposed pathways on long-term vascular health and potential treatments to address these chronic conditions.
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Affiliation(s)
- Ryan Chang
- College of Arts & Sciences, Washington University in St. Louis, St. Louis, MO, United States
| | - Abrar Mamun
- Wiess School of Natural Sciences, Rice University, Houston, TX, United States
| | - Abishai Dominic
- Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University, College Station, TX, United States
- Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, United States
| | - Nhat-Tu Le
- Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, United States
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Li J, Huynh L, Cornwell WD, Tang MS, Simborio H, Huang J, Kosmider B, Rogers TJ, Zhao H, Steinberg MB, Thu Thi Le L, Zhang L, Pham K, Liu C, Wang H. Electronic Cigarettes Induce Mitochondrial DNA Damage and Trigger TLR9 (Toll-Like Receptor 9)-Mediated Atherosclerosis. Arterioscler Thromb Vasc Biol 2020; 41:839-853. [PMID: 33380174 DOI: 10.1161/atvbaha.120.315556] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Electronic cigarette (e-cig) use has recently been implicated in promoting atherosclerosis. In this study, we aimed to investigate the mechanism of e-cig exposure accelerated atherosclerotic lesion development. Approach and Results: Eight-week-old ApoE-/- mice fed normal laboratory diet were exposed to e-cig vapor (ECV) for 2 hours/day, 5 days/week for 16 weeks. We found that ECV exposure significantly induced atherosclerotic lesions as examined by Oil Red O staining and greatly upregulated TLR9 (toll-like receptor 9) expression in classical monocytes and in the atherosclerotic plaques, which the latter was corroborated by enhanced TLR9 expression in human femoral artery atherosclerotic plaques from e-cig smokers. Intriguingly, we found a significant increase of oxidative mitochondria DNA lesion in the plasma of ECV-exposed mice. Administration of TLR9 antagonist before ECV exposure not only alleviated atherosclerosis and the upregulation of TLR9 in plaques but also attenuated the increase of plasma levels of inflammatory cytokines, reduced the plaque accumulation of lipid and macrophages, and decreased the frequency of blood CCR2+ (C-C chemokine receptor type 2) classical monocytes. Surprisingly, we found that cytoplasmic mitochondrial DNA isolated from ECV extract-treated macrophages can enhance TLR9 activation in reporter cells and the induction of inflammatory cytokine could be suppressed by TLR9 inhibitor in macrophages. CONCLUSIONS E-cig increases level of damaged mitochondrial DNA in circulating blood and induces the expression of TLR9, which elevate the expression of proinflammatory cytokines in monocyte/macrophage and consequently lead to atherosclerosis. Our results raise the possibility that intervention of TLR9 activation is a potential pharmacological target of ECV-related inflammation and cardiovascular diseases.
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Affiliation(s)
- Jieliang Li
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ (J.L., L.H., J.H., L.T.T.L., H.W.)
| | - Luong Huynh
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ (J.L., L.H., J.H., L.T.T.L., H.W.)
| | - William D Cornwell
- Department of Physiology (W.D.C.), Temple University School of Medicine, Philadelphia, PA
| | - Moon-Shong Tang
- Department of Environment Medicine, New York University School of Medicine, Tuxedo Park (M.-S.T.)
| | - Hannah Simborio
- Center for Inflammation, Translational and Clinical Lung Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA (H.S., B.K., T.J.R.)
| | - Jing Huang
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ (J.L., L.H., J.H., L.T.T.L., H.W.)
| | - Beata Kosmider
- Center for Inflammation, Translational and Clinical Lung Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA (H.S., B.K., T.J.R.).,Department of Thoracic Medicine and Surgery (B.K.), Temple University School of Medicine, Philadelphia, PA
| | - Thomas J Rogers
- Center for Inflammation, Translational and Clinical Lung Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA (H.S., B.K., T.J.R.)
| | - Huaqing Zhao
- Department of Clinical Sciences (H.Z.), Temple University School of Medicine, Philadelphia, PA
| | - Michael B Steinberg
- Division of General Internal Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ (M.B.S.)
| | - Le Thu Thi Le
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ (J.L., L.H., J.H., L.T.T.L., H.W.)
| | - Lanjing Zhang
- Gastrointestinal and Liver Pathology, Penn Medicine Princeton Medical Center, Plainsboro, New Jersey (L.Z.)
| | - Kien Pham
- Department of Pathology, Yale University School of Medicine, New Haven, CT (K.P., C.L.)
| | - Chen Liu
- Department of Pathology, Yale University School of Medicine, New Haven, CT (K.P., C.L.)
| | - He Wang
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ (J.L., L.H., J.H., L.T.T.L., H.W.)
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Identification of Yak's TLR4 Alternative Spliceosomes and Bioinformatic Analysis of TLR4 Protein Structure and Function. Animals (Basel) 2020; 11:ani11010032. [PMID: 33375267 PMCID: PMC7823342 DOI: 10.3390/ani11010032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/15/2020] [Accepted: 12/23/2020] [Indexed: 12/28/2022] Open
Abstract
Simple Summary In this study, yak’s TLR4 gene alternative spliceosomes were investigated using PCR amplification and cloning with an aim to improve disease-resistance in yaks and promote efficient utilization of yak’s resources. qRT-PCR was used to evaluate the expression levels of two alternatively spliced TLR4 transcripts in seven distinct yak tissues. To predict the function of proteins expressed by each TLR4 spliceosome, TLR4 protein structure and function were analyzed bioinformatically. Besides, two alternative spliceosomes of yak’s TLR4 gene were also identified, which were in line with predicted variants of the TLR4 gene in NCBI. These two alternative spliceosomes of the TLR4 gene were expressed in each tissue; however, the expression levels of these spliceosomes were significantly different in different tissue. We also observed that deletion of exon-2 in TLR4 affected the function of the corresponding protein. This study will lay a theoretical foundation for future studies on the role of two variants of yak’s TLR4 gene in disease resistance. Besides, data from this study could be analyzed further to explore the molecular mechanism associated with disease-resistance in the yak. Abstract In this study, the yak’s TLR4 gene alternative spliceosomes were investigated using PCR amplification and cloning to improve disease-resistance in yak and promote efficient utilization of yak’s resources. qRT-PCR was used to determine the expression levels of two alternatively spliced transcripts of the TLR4 gene in seven distinct tissues. To predict the function of proteins expressed by each TLR4 spliceosome, bioinformatic analysis of yak’s TLR4 protein structure and function was performed, which led to the identification of two alternative spliceosomes of yak’s TLR4 gene. The TLR4-X1 sequence length was 2526 bp, and it encoded full-length TLR4 protein (841 amino acids). The sequence length of the exon-2 deleted TLR4-X2 sequence was 1926 bp, and it encoded truncated TLR4 protein (641 amino acids). TLR4-X2 sequence was consistent with the predicted sequence of the TLR4 gene in GenBank. Each tissue showed significantly different expression levels of these two alternative spliceosomes. As per the bioinformatic analysis of the structure and function of TLR4 protein, deletion of exon-2 in the TLR4 gene resulted in frameshift mutations of the reading frame in the corresponding protein, which altered its ligand-binding and active sites. Besides, biological property such as substrate specificity of truncated TLR4 protein was also altered, leading to altered protein function. This study has laid a theoretical foundation for exploring the role of two variants of the TLR4 gene in yak’s disease resistance. Besides, this study’s data could be analyzed further to explore the molecular mechanism associated with disease-resistance in the yak.
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Toshchakov VY, Javmen A. Targeting the TLR signalosome with TIR domain-derived cell-permeable decoy peptides: the current state and perspectives. Innate Immun 2020; 26:35-47. [PMID: 31955621 PMCID: PMC6974878 DOI: 10.1177/1753425919844310] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The ability to engineer pharmaceuticals that target the signal-dependent
interactions of signaling proteins should revolutionize drug development. One
approach to the rational design of protein interaction inhibitors uses decoy
peptides, i.e. segments of protein primary sequence, which are derived from
interfaces that mediate functional protein interactions. Decoy peptides often
retain the ability of the full-length prototype to bind the docking site of the
folded protein and thereby block the signal transduction. This review summarizes
advances made in the last decade in the development of cell-permeable decoy
peptide (CPDP) inhibitors to target the Toll/IL-1R resistance (TIR)
domain-mediated protein interactions in TLR signaling, in connection with the
recent progress in understanding of the TLR signalosome assembly mechanisms. We
present a large collection of currently available, TIR-targeting CPDPs and
propose their classification based on the types of TIR–TIR interactions they
target. The binding behavior of different CPDP-TIR pairs, studied in cell-based
assays and in binary in vitro systems using recombinant TIR
domains, is also reviewed. The available affinity data provide benchmarks for
rapid preliminary evaluation of future inhibitors. We review literature that
evaluates the in vivo potency of select CPDPs and attempt to
outline the areas of forthcoming progress, towards the development of CPDP-based
TLR inhibitors of pharmaceutical grade.
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Affiliation(s)
- Vladimir Y Toshchakov
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Artur Javmen
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
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van der Heijden CDCC, Keating ST, Groh L, Joosten LAB, Netea MG, Riksen NP. Aldosterone induces trained immunity: the role of fatty acid synthesis. Cardiovasc Res 2020; 116:317-328. [PMID: 31119285 DOI: 10.1093/cvr/cvz137] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 03/09/2019] [Accepted: 05/16/2019] [Indexed: 12/26/2022] Open
Abstract
AIMS Supranormal levels of aldosterone are associated with an increased cardiovascular risk in humans, and with accelerated atherosclerosis in animal models. Atherosclerosis is a low-grade inflammatory disorder, with monocyte-derived macrophages as major drivers of plaque formation. Monocytes can adopt a long-term pro-inflammatory phenotype after brief stimulation with microbial pathogens or endogenous atherogenic lipoproteins via a process termed trained immunity. In this study, we aimed to investigate whether aldosterone can induce trained immunity in primary human monocytes in vitro and explored the underlying mechanism. METHODS AND RESULTS We exposed human monocytes to aldosterone for 24 h, after which they were rested to differentiate into monocyte-derived macrophages for 5 days, and re-stimulated with toll-like receptor 2 and 4 ligands on day 6. We demonstrated that aldosterone augments pro-inflammatory cytokine production and reactive oxygen species production in monocyte-derived macrophages after re-stimulation, via the mineralocorticoid receptor. Fatty acid synthesis was identified as a crucial pathway necessary for this induction of trained immunity and pharmacological inhibition of this pathway blunted aldosterone-induced trained immunity. At the level of gene regulation, aldosterone promoted enrichment of the transcriptionally permissive H3K4me3 modification at promoters of genes central to the fatty acid synthesis pathway. CONCLUSION Aldosterone induces trained immunity in vitro, which is dependent on epigenetically mediated up-regulation of fatty acid synthesis. These data provide mechanistic insight into the contribution of aldosterone to inflammation, atherosclerosis, and cardiovascular disease.
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Affiliation(s)
- Charlotte D C C van der Heijden
- Department of Internal Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 8, 6525 GA, Nijmegen, The Netherlands
| | - Samuel T Keating
- Department of Internal Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 8, 6525 GA, Nijmegen, The Netherlands
| | - Laszlo Groh
- Department of Internal Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 8, 6525 GA, Nijmegen, The Netherlands
| | - Leo A B Joosten
- Department of Internal Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 8, 6525 GA, Nijmegen, The Netherlands
| | - Mihai G Netea
- Department of Internal Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 8, 6525 GA, Nijmegen, The Netherlands.,Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Niels P Riksen
- Department of Internal Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 8, 6525 GA, Nijmegen, The Netherlands
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Nishimoto S, Fukuda D, Sata M. Emerging roles of Toll-like receptor 9 in cardiometabolic disorders. Inflamm Regen 2020; 40:18. [PMID: 32714475 PMCID: PMC7374824 DOI: 10.1186/s41232-020-00118-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 05/21/2020] [Indexed: 02/08/2023] Open
Abstract
Growing evidence suggests that damage-associated molecule patterns (DAMPs) and their receptors, pattern recognition receptors (PRRs), are associated with the progression of cardiometabolic disorders, including obesity-related insulin resistance and atherosclerosis. Cardiometabolic disorders share sterile chronic inflammation as a major cause; however, the exact mechanisms are still obscure. Toll-like receptor 9 (TLR9), one of the nucleic acid-sensing TLRs, recognizes DNA fragments derived from pathogens and contributes to self-defense by activation of the innate immune system. In addition, previous studies demonstrated that TLR9 recognizes DNA fragments released from host cells, accelerating sterile inflammation, which is associated with inflammatory diseases such as autoimmune diseases. In obese adipose tissue and atherosclerotic vascular tissue, various stresses release DNA fragments and/or nuclear proteins as DAMPs from degenerated adipocytes and vascular cells. Recent studies indicated that the activation of TLR9 in immune cells including macrophages and dendritic cells by recognition of these DAMPs promotes inflammation in these tissues, which causes cardiometabolic disorders. This review discusses recent advances in understanding the role of sterile inflammation associated with TLR9 and its endogenous ligands in cardiometabolic disorders. New insights into innate immunity may provide better understanding of cardiometabolic disorders and new therapeutic options for these major health threats in recent decades.
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Affiliation(s)
- Sachiko Nishimoto
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503 Japan
| | - Daiju Fukuda
- Department of Cardio-Diabetes Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8503 Japan
| | - Masataka Sata
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503 Japan
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The Association of rs1898830 in Toll-Like Receptor 2 with Lipids and Blood Pressure. J Cardiovasc Dev Dis 2020; 7:jcdd7030024. [PMID: 32650372 PMCID: PMC7569770 DOI: 10.3390/jcdd7030024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 06/29/2020] [Accepted: 07/06/2020] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Toll-like receptors (TLRs) are important components of the innate immune system, involved in establishing immunity to infections. Apart from being implicated in immunity, numerous studies have reported that many TLRs, including TLR2, are involved in the pathogenesis of cardiovascular diseases and their risk factors. Since rs1898830 is associated with TLR2-mediated cellular activation, we aimed to study its association with CVD risk factors, such as lipid levels and hypertension. METHODS A cross-sectional study was conducted on 460 individuals free from chronic diseases. Clinical and biological data were collected and DNA was extracted and genotyped using Kompetitive allele specific PCR (KASP™). Multiple logistic regression models, adjusted for six covariates, were used. A power calculation analysis was also performed. RESULTS We found that rs1898830 in TLR2 was positively associated with hypertension (OR = 2.18, p = 0.03) and negatively associated with high-density lipoprotein cholesterol (OR = 0.66, p = 0.05). In contrast, no relation was found with total cholesterol and low-density lipoprotein cholesterol. CONCLUSION The present results provide additional evidence supporting the implication of TLR2 in CVD risk factors.
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Jaén RI, Val-Blasco A, Prieto P, Gil-Fernández M, Smani T, López-Sendón JL, Delgado C, Boscá L, Fernández-Velasco M. Innate Immune Receptors, Key Actors in Cardiovascular Diseases. JACC Basic Transl Sci 2020; 5:735-749. [PMID: 32760860 PMCID: PMC7393405 DOI: 10.1016/j.jacbts.2020.03.015] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/19/2020] [Accepted: 03/19/2020] [Indexed: 02/07/2023]
Abstract
Cardiovascular diseases (CVDs) are the leading cause of death in the industrialized world. Most CVDs are associated with increased inflammation that arises mainly from innate immune system activation related to cardiac damage. Sustained activation of the innate immune system frequently results in maladaptive inflammatory responses that promote cardiovascular dysfunction and remodeling. Much research has focused on determining whether some mediators of the innate immune system are potential targets for CVD therapy. The innate immune system has specific receptors-termed pattern recognition receptors (PRRs)-that not only recognize pathogen-associated molecular patterns, but also sense danger-associated molecular signals. Activation of PRRs triggers the inflammatory response in different physiological systems, including the cardiovascular system. The classic PRRs, toll-like receptors (TLRs), and the more recently discovered nucleotide-binding oligomerization domain-like receptors (NLRs), have been recently proposed as key partners in the progression of several CVDs (e.g., atherosclerosis and heart failure). The present review discusses the key findings related to the involvement of TLRs and NLRs in the progression of several vascular and cardiac diseases, with a focus on whether some NLR subtypes (nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing receptor 3 and nucleotide-binding oligomerization domain-containing protein 1) can be candidates for the development of new therapeutic strategies for several CVDs.
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Key Words
- AMI, acute myocardial infarction
- CARD, caspase activation and recruitment domain
- CVD, cardiovascular disease
- Ca2+, calcium ion
- DAMPs, danger-associated molecular patterns
- DAP, D-glutamyl-meso-diaminopimelic acid
- ER, endoplasmic reticulum
- HF, heart failure
- I/R, ischemia/reperfusion
- IL, interleukin
- MAPK, mitogen-activated protein kinase
- NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells
- NLR, nucleotide-binding oligomerization domain-like receptors
- NLRP, nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing receptor
- NLRP3
- NOD, Nucleotide-binding oligomerization domain-containing protein
- NOD1
- PAMP, pathogen-associated molecular pattern
- ROS, reactive oxygen species
- SR, sarcoplasmic reticulum
- TLR, toll-like receptor
- cardiovascular disease
- innate immune system
- nucleotide-binding oligomerization domain-like receptors
- toll-like receptors
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Affiliation(s)
- Rafael I. Jaén
- Biomedical Research Institute “Alberto Sols” CSIC-UAM, Madrid, Spain
- CIBER Cardiovascular (CIBER-CV, ISCIII), Madrid, Spain
| | - Almudena Val-Blasco
- Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Patricia Prieto
- Biomedical Research Institute “Alberto Sols” CSIC-UAM, Madrid, Spain
- CIBER Cardiovascular (CIBER-CV, ISCIII), Madrid, Spain
- Pharmacology, Pharmacognosy and Botany department, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain
| | - Marta Gil-Fernández
- CIBER Cardiovascular (CIBER-CV, ISCIII), Madrid, Spain
- Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Tarik Smani
- CIBER Cardiovascular (CIBER-CV, ISCIII), Madrid, Spain
- Department of Medical Physiology and Biophysics, Institute of Biomedicine of Seville, University of Seville, Sevilla, Spain
| | - José Luis López-Sendón
- CIBER Cardiovascular (CIBER-CV, ISCIII), Madrid, Spain
- Servicio de Cardiología, Hospital Universitario La Paz, Madrid, Spain
| | - Carmen Delgado
- Biomedical Research Institute “Alberto Sols” CSIC-UAM, Madrid, Spain
- CIBER Cardiovascular (CIBER-CV, ISCIII), Madrid, Spain
| | - Lisardo Boscá
- Biomedical Research Institute “Alberto Sols” CSIC-UAM, Madrid, Spain
- CIBER Cardiovascular (CIBER-CV, ISCIII), Madrid, Spain
| | - María Fernández-Velasco
- CIBER Cardiovascular (CIBER-CV, ISCIII), Madrid, Spain
- Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
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Truncated Pneumolysin from Streptococcus pneumoniae as a TLR4-Antagonizing New Drug for Chronic Inflammatory Conditions. Cells 2020; 9:cells9051183. [PMID: 32397494 PMCID: PMC7290803 DOI: 10.3390/cells9051183] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/05/2020] [Accepted: 05/07/2020] [Indexed: 11/17/2022] Open
Abstract
Microbial proteins have recently been found to have more benefits in clinical disease treatment because of their better-developed strategy and properties than traditional medicine. In this study, we investigated the effectiveness of a truncated peptide synthesized from the C-terminal sequence of pneumolysin, i.e., C70PLY4, in Streptococcus pneumoniae, in treating chronic inflammatory conditions. It has been shown that C70PLY4 significantly blocks the transendothelial migration of neutrophils and attenuates the formation of atherosclerotic plaque and the secretion of soluble forms of the intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule 1 (VCAM-1), and E-selectin in high-fat-diet/streptozotocin-induced inflammatory rats. The mechanism and the docking simulation analysis further indicated that C70PLY4 might serve as a Toll-like receptor 4 (TLR4) antagonist by competing for the binding site of MD2, an indispensable protein for lipopolysaccharide (LPS)–TLR4 interaction signaling, on the TLR4 structure. Moreover, compared to the full-length PLY, C70PLY4 seems to have no cytotoxicity in human vascular endothelial cells. Our study elucidated a possible therapeutic efficacy of C70PLY4 in reducing chronic inflammatory conditions and clarified the underlying mechanism. Thus, our findings identify a new drug candidate that, by blocking TLR4 activity, could be an effective treatment for patients with chronic inflammatory diseases.
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Li X, Zhou H, Guo D, Hu Y, Fang X, Chen Y, Zhang F. Oxidative stress and inflammation: Early predictive indicators of multiple recurrent coronary in‐stent chronic total occlusions in elderly patients after coronary stenting. IUBMB Life 2020; 72:1023-1033. [PMID: 32022379 DOI: 10.1002/iub.2239] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 01/23/2020] [Indexed: 11/07/2022]
Affiliation(s)
- Xia Li
- Department of GeriatricsThe Affiliated Huai'an Hospital of Xuzhou Medical University Huai'an China
| | - Hualan Zhou
- Department of GeriatricsThe Affiliated Huai'an Hospital of Xuzhou Medical University Huai'an China
| | - Dianxuan Guo
- Department of GeriatricsThe Affiliated Huai'an Hospital of Xuzhou Medical University Huai'an China
| | - Youdong Hu
- Department of GeriatricsThe Affiliated Huai'an Hospital of Xuzhou Medical University Huai'an China
| | - Xiang Fang
- Department of GeriatricsThe Affiliated Huai'an Hospital of Xuzhou Medical University Huai'an China
| | - Ying Chen
- Department of GeriatricsThe Affiliated Huai'an Hospital of Xuzhou Medical University Huai'an China
| | - Fenglin Zhang
- Department of GeriatricsThe Affiliated Huai'an Hospital of Xuzhou Medical University Huai'an China
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Kwon MY, Hwang N, Lee SJ, Chung SW. Nucleotide-binding oligomerization domain protein 2 attenuates ER stress-induced cell death in vascular smooth muscle cells. BMB Rep 2020. [PMID: 31619316 PMCID: PMC6889894 DOI: 10.5483/bmbrep.2019.52.11.176] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Nucleotide-binding oligomerization domain protein 2 (NOD2), an intracellular pattern recognition receptor, plays important roles in inflammation and cell death. Previously, we have shown that NOD2 is expressed in vascular smooth muscle cells (VSMCs) and that NOD2 deficiency promotes VSMC proliferation, migration, and neointimal formation after vascular injury. However, its role in endoplasmic reticulum (ER) stress-induced cell death in VSMCs remains unclear. Thus, the objective of this study was to evaluate ER stress-induced viability of mouse primary VSMCs. NOD2 deficiency increased ER stress-induced cell death and expression levels of apoptosis mediators (cleaved caspase-3, Bax, and Bak) in VSMCs in the presence of tunicamycin (TM), an ER stress inducer. In contrast, ER stress-induced cell death and expression levels of apoptosis mediators (cleaved caspase-3, Bax, and Bak) were decreased in NOD2-overexpressed VSMCs. We found that the IRE-1α-XBP1 pathway, one of unfolded protein response branches, was decreased in NOD2-deficient VSMCs and reversed in NOD2-overexpressed VSMCs in the presence of TM. Furthermore, NOD2 deficiency reduced the expression of XBP1 target genes such as GRP78, PDI-1, and Herpud1, thus improving cell survival. Taken together, these data suggest that the induction of ER stress through NOD2 expression can protect against TM-induced cell death in VSMCs. These results may contribute to a new paradigm in vascular homeostasis. [BMB Reports 2019; 52(11): 665-670].
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Affiliation(s)
- Min-Young Kwon
- School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea
| | - Narae Hwang
- School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea
| | - Seon-Jin Lee
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Su Wol Chung
- School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea
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