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1
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Hilgendorf I, Frantz S, Frangogiannis NG. Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities. Circ Res 2024; 134:1718-1751. [PMID: 38843294 PMCID: PMC11164543 DOI: 10.1161/circresaha.124.323658] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 05/08/2024] [Indexed: 06/12/2024]
Abstract
The adult mammalian heart has limited endogenous regenerative capacity and heals through the activation of inflammatory and fibrogenic cascades that ultimately result in the formation of a scar. After infarction, massive cardiomyocyte death releases a broad range of damage-associated molecular patterns that initiate both myocardial and systemic inflammatory responses. TLRs (toll-like receptors) and NLRs (NOD-like receptors) recognize damage-associated molecular patterns (DAMPs) and transduce downstream proinflammatory signals, leading to upregulation of cytokines (such as interleukin-1, TNF-α [tumor necrosis factor-α], and interleukin-6) and chemokines (such as CCL2 [CC chemokine ligand 2]) and recruitment of neutrophils, monocytes, and lymphocytes. Expansion and diversification of cardiac macrophages in the infarcted heart play a major role in the clearance of the infarct from dead cells and the subsequent stimulation of reparative pathways. Efferocytosis triggers the induction and release of anti-inflammatory mediators that restrain the inflammatory reaction and set the stage for the activation of reparative fibroblasts and vascular cells. Growth factor-mediated pathways, neurohumoral cascades, and matricellular proteins deposited in the provisional matrix stimulate fibroblast activation and proliferation and myofibroblast conversion. Deposition of a well-organized collagen-based extracellular matrix network protects the heart from catastrophic rupture and attenuates ventricular dilation. Scar maturation requires stimulation of endogenous signals that inhibit fibroblast activity and prevent excessive fibrosis. Moreover, in the mature scar, infarct neovessels acquire a mural cell coat that contributes to the stabilization of the microvascular network. Excessive, prolonged, or dysregulated inflammatory or fibrogenic cascades accentuate adverse remodeling and dysfunction. Moreover, inflammatory leukocytes and fibroblasts can contribute to arrhythmogenesis. Inflammatory and fibrogenic pathways may be promising therapeutic targets to attenuate heart failure progression and inhibit arrhythmia generation in patients surviving myocardial infarction.
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Affiliation(s)
- Ingo Hilgendorf
- Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine at the University of Freiburg, Freiburg, Germany
| | - Stefan Frantz
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Würzburg, Germany
| | - Nikolaos G Frangogiannis
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx NY
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2
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Li M, Wang Y, Qi Z, Yuan Z, Lv S, Zheng Y, Yan Z, Wang M, Fu H, Fan X, Ji N, Liu M, Fang Z. QishenYiqi dripping pill protects against myocardial ischemia/reperfusion injury via suppressing excessive autophagy and NLRP3 inflammasome based on network pharmacology and experimental pharmacology. Front Pharmacol 2022; 13:981206. [PMID: 36164369 PMCID: PMC9507923 DOI: 10.3389/fphar.2022.981206] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/12/2022] [Indexed: 11/21/2022] Open
Abstract
Background: Myocardial ischemia/reperfusion (I/R) injury is associated with multiple serious clinical manifestations. Autophagy is upregulated in a short period of ischemia and further enhanced during reperfusion phase, which was considered as a “double-edged sword” in the pathological process of myocardial I/R injury. In addition, NLRP3 inflammasome triggers myocardial inflammatory response, which leads to cardiomyocyte death via pyroptosis and promotes subsequent myocardial remodelling. Qishen Yiqi Dripping Pill (QSYQ) has been recognized as a potential protective agent of cardiovascular diseases. Objective: We predicted the bioactive compounds, targets and pathways of OSYQ intervening on myocardial I/R injury by network pharmacology. Furthermore, we investigated the effect of QSYQ on myocardial I/R injury and explored its underlying mechanism via autophagy and NLRP3 Inflammasome. Methods: Bioactive compounds, targets of QSYQ and relevant targets of myocardial I/R injury were collected from public databases. The protein-protein interaction network, Gene ontology and KEGG pathway enrichment analysis were carried out to screen the key compounds, target genes, functional annotation and pivotal pathways. Molecular docking was used to validate the binding association between target genes and key bioactive ingredients. Furthermore, sixty SD rats were randomized into four groups: 1) sham, 2) model, 3) captopril and 4) QSYQ pretreatment (14 days before and after surgery). Each arm was subjected to ischemia/reperfusion surgery except sham arm (30 min coronary ligation, then reperfusion). Left ventricular (LV) function were evaluated and the hearts were used to evaluate size of myocardial infarction, cardiomyocyte fibrosis, and myocardial autophagosomes. Results: The network pharmacology revealed the mechanism of QSYQ intervening on myocardial I/R injury might be related to NOD-like receptor signaling pathway, PI3K-Akt signaling pathway, autophagy-animal, etc., Molecular-docking suggested the core target proteins had good binding association with bioactive compounds of QSYQ. The experiment confirmed that QSYQ attenuated myocardial infarct size, decreased inflammatory infiltration and collagen fiber deposition and alleviated the autophagosome and myocardium ultrastructure injury, leading to LV systolic function improvement. The possible mechanism of cardioprotection was due to regulating autophagy-related proteins, activating PI3K/Akt-mTOR signaling pathway, and inhibiting activation and assembly of NLRP3 inflammasome. Conclusion: QSYQ ameliorated myocardial I/R injury via suppressing excessive autophagy and NLRP3 Inflammasome.
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Affiliation(s)
- Meng Li
- Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yueyao Wang
- The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhongwen Qi
- Institute of Gerontology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhuo Yuan
- Department of Psychosomatic Medicine, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Shichao Lv
- Geriatric Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yawei Zheng
- Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhipeng Yan
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Mingyang Wang
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Huanjie Fu
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xinbiao Fan
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Nan Ji
- School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Ming Liu
- Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Zhuyuan Fang, ; Ming Liu,
| | - Zhuyuan Fang
- Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Zhuyuan Fang, ; Ming Liu,
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3
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Penna C, Comità S, Tullio F, Alloatti G, Pagliaro P. Challenges facing the clinical translation of cardioprotection: 35 years after the discovery of ischemic preconditioning. Vascul Pharmacol 2022; 144:106995. [PMID: 35470102 DOI: 10.1016/j.vph.2022.106995] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/17/2022] [Accepted: 04/16/2022] [Indexed: 12/19/2022]
Abstract
Since coronary reperfusion was introduced into clinical practice in the late 1970s, the further translation of several successful animal experiments on cardioprotection into clinical practice has been disappointing to date. Animal experiments are often performed on young, healthy animals lacking the risk factors, co-morbidities and co-medications characteristic of acute myocardial infarction patients. Many hopes were kindled in 1986 when ischemic preconditioning was discovered. However, it is not yet known how long ischemia can last and what is the best modality for additional cardioprotection through conditioning to obtain benefits. There is a lack of experimental studies on the long-term effects of additional cardioprotection, in addition to the reduction in infarct size; in particular, there is a lack of studies on vessel protection, repair, inflammation, remodeling, and mortality. The reproducibility and robustness of experimental studies are often limited by species differences, the role of co-morbidities, vascular damage, inflammatory processes, and co-medications, which are not adequately considered. In particular, inflammatory processes, including NLRP3 inflammasome, play an important role in the long-term effects. Future studies should focus on interventions/agents with robust preclinical data and should recruit patients who truly have the potential to benefit from further cardioprotection. Here we focus on the main mechanisms and targets of cardioprotection during remote conditioning and their alteration by one of the most common co-morbidities, namely diabetes, in which microvascular lesions and inflammatory processes play extremely important roles.
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Affiliation(s)
- Claudia Penna
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano, 10043 Torino, TO, Italy; National Institute for Cardiovascular Research (INRC), Bologna, Italy
| | - Stefano Comità
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano, 10043 Torino, TO, Italy
| | - Francesca Tullio
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano, 10043 Torino, TO, Italy
| | | | - Pasquale Pagliaro
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano, 10043 Torino, TO, Italy; National Institute for Cardiovascular Research (INRC), Bologna, Italy.
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4
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Komal S, Komal N, Mujtaba A, Wang SH, Zhang LR, Han SN. Potential therapeutic strategies for myocardial infarction: the role of Toll-like receptors. Immunol Res 2022; 70:607-623. [PMID: 35608723 DOI: 10.1007/s12026-022-09290-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 05/06/2022] [Indexed: 11/27/2022]
Abstract
Myocardial infarction (MI) is a life-threatening condition among patients with cardiovascular diseases. MI increases the risk of stroke and heart failure and is a leading cause of morbidity and mortality worldwide. Several genetic and epigenetic factors contribute to the development of MI, suggesting that further understanding of the pathomechanism of MI might help in the early management and treatment of this disease. Toll-like receptors (TLRs) are well-known members of the pattern recognition receptor (PRR) family and contribute to both adaptive and innate immunity. Collectively, studies suggest that TLRs have a cardioprotective effect. However, prolonged TLR activation in the response to signals generated by damage-associated molecular patterns (DAMPs) results in the release of inflammatory cytokines and contributes to the development and exacerbation of myocardial inflammation, MI, ischemia-reperfusion injury, myocarditis, and heart failure. The objective of this review is to discuss and summarize the association of TLRs with MI, highlighting their therapeutic potential for the development of advanced TLR-targeted therapies for MI.
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Affiliation(s)
- Sumra Komal
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Nimrah Komal
- Department of Pharmacology, Mohi-Ud-Din Islamic Medical College, Azad Jammu & Kashmir, Mirpur, 10250, Pakistan
| | - Ali Mujtaba
- Department of Pharmacology, Mohi-Ud-Din Islamic Medical College, Azad Jammu & Kashmir, Mirpur, 10250, Pakistan
| | - Shu-Hui Wang
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Li-Rong Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Sheng-Na Han
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.
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5
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Chen E, Chang H, Gao R, Qiu Y, Chen H, Cheng X, Gan L, Ye-Lehmann S, Zhu T, Liu J, Chen G, Chen C. Poly(I:C) attenuates myocardial ischemia/reperfusion injury by restoring autophagic function. FASEB J 2022; 36:e22317. [PMID: 35438806 DOI: 10.1096/fj.202101220rr] [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: 07/30/2021] [Revised: 03/02/2022] [Accepted: 04/04/2022] [Indexed: 02/05/2023]
Abstract
Polyinosinic-polycytidylic acid (poly(I:C)) is the agonist of Toll-like receptor 3 (TLR3), which participates in innate immune responses under the condition of myocardial ischemia/reperfusion injury (MIRI). It has been shown that poly(I:C) exhibited cardioprotective activities through the PI3K/Akt pathway, which is the main signal transduction pathway during autophagy. However, the precise mechanism by whether poly(I:C) regulates autophagy remains poorly understood. Thus, this study was designed to investigate the therapeutic effect of poly(I:C) against MIRI and the underlying pathway connection with autophagy. We demonstrated that 1.25 and 5 mg/kg poly(I:C) preconditioning significantly reduced myocardial infarct size and cardiac dysfunction. Moreover, poly(I:C) significantly promoted cell survival by restoring autophagy flux and then regulating it to an adequate level Increased autophagy protein Beclin1 and LC3II together with p62 degradation after additional chloroquine. In addition, mRFP-GFP-LC3 adenoviruses exhibited autophagy activity in neonatal rat cardiac myocytes (NRCMs). Mechanistically, poly(I:C) activated the PI3K/AKT/mTOR pathway to induce autophagy, which was abolished by LY294002 (PI3K antagonist), rapamycin (autophagy activator and mTOR inhibitor), or 3-methyladenine (autophagy inhibitor), suggesting either inhibition of the PI3K/Akt/mTOR pathway or autophagy activity interrupt the beneficial effect of poly(I:C) preconditioning. In conclusion, poly(I:C) promotes cardiomyocyte survival from ischemia/reperfusion injury by regulating autophagy via the PI3K/Akt/mTOR pathway.
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Affiliation(s)
- Erya Chen
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
| | - Haiqing Chang
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
| | - Rui Gao
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
| | - Yanhua Qiu
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
| | - Hai Chen
- Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, China
| | - Xu Cheng
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
| | - Lu Gan
- Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Shixin Ye-Lehmann
- INSERM Tenured Researcher (CR)INSERM Research Unit U1195, Diseases and Hormones of the Nervous System, University of Paris-Scalay Bicêtre Hospital, Le Kremlin Bicêtre CEDEX, France
| | - Tao Zhu
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
| | - Jin Liu
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
| | - Guo Chen
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
| | - Chan Chen
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
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6
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Jin Z, Zheng E, Sareli C, Kolattukudy PE, Niu J. Monocyte Chemotactic Protein-Induced Protein 1 (MCPIP-1): A Key Player of Host Defense and Immune Regulation. Front Immunol 2021; 12:727861. [PMID: 34659213 PMCID: PMC8519509 DOI: 10.3389/fimmu.2021.727861] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 09/08/2021] [Indexed: 01/14/2023] Open
Abstract
Inflammatory response is a host-protective mechanism against tissue injury or infections, but also has the potential to cause extensive immunopathology and tissue damage, as seen in many diseases, such as cardiovascular diseases, neurodegenerative diseases, metabolic syndrome and many other infectious diseases with public health concerns, such as Coronavirus Disease 2019 (COVID-19), if failure to resolve in a timely manner. Recent studies have uncovered a superfamily of endogenous chemical molecules that tend to resolve inflammatory responses and re-establish homeostasis without causing excessive damage to healthy cells and tissues. Among these, the monocyte chemoattractant protein-induced protein (MCPIP) family consisting of four members (MCPIP-1, -2, -3, and -4) has emerged as a group of evolutionarily conserved molecules participating in the resolution of inflammation. The focus of this review highlights the biological functions of MCPIP-1 (also known as Regnase-1), the best-studied member of this family, in the resolution of inflammatory response. As outlined in this review, MCPIP-1 acts on specific signaling pathways, in particular NFκB, to blunt production of inflammatory mediators, while also acts as an endonuclease controlling the stability of mRNA and microRNA (miRNA), leading to the resolution of inflammation, clearance of virus and dead cells, and promotion of tissue regeneration via its pleiotropic effects. Evidence from transgenic and knock-out mouse models revealed an involvement of MCPIP-1 expression in immune functions and in the physiology of the cardiovascular system, indicating that MCPIP-1 is a key endogenous molecule that governs normal resolution of acute inflammation and infection. In this review, we also discuss the current evidence underlying the roles of other members of the MCPIP family in the regulation of inflammatory processes. Further understanding of the proteins from this family will provide new insights into the identification of novel targets for both host effectors and microbial factors and will lead to new therapeutic treatments for infections and other inflammatory diseases.
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Affiliation(s)
- Zhuqing Jin
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - En Zheng
- Department of Chemistry, Zhejiang University, Hangzhou, China
| | - Candice Sareli
- Office of Human Research, Memorial Healthcare System, Hollywood, FL, United States
| | - Pappachan E Kolattukudy
- Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, United States
| | - Jianli Niu
- Office of Human Research, Memorial Healthcare System, Hollywood, FL, United States.,Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, United States
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7
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Chen E, Chen C, Niu Z, Gan L, Wang Q, Li M, Cai X, Gao R, Katakam S, Chen H, Zhang S, Zhou R, Cheng X, Qiu Y, Yu H, Zhu T, Liu J. Poly(I:C) preconditioning protects the heart against myocardial ischemia/reperfusion injury through TLR3/PI3K/Akt-dependent pathway. Signal Transduct Target Ther 2020; 5:216. [PMID: 33154351 PMCID: PMC7644758 DOI: 10.1038/s41392-020-00257-w] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 06/28/2020] [Accepted: 07/20/2020] [Indexed: 02/05/2023] Open
Abstract
Emerging evidence suggests that Toll-like receptors (TLRs) ligands pretreatment may play a vital role in the progress of myocardial ischemia/reperfusion (I/R) injury. As the ligand of TLR3, polyinosinic-polycytidylic acid (poly(I:C)), a synthetic double-stranded RNA, whether its preconditioning can exhibit a cardioprotective phenotype remains unknown. Here, we report the protective effect of poly(I:C) pretreatment in acute myocardial I/R injury by activating TLR3/PI3K/Akt signaling pathway. Poly(I:C) pretreatment leads to a significant reduction of infarct size, improvement of cardiac function, and downregulation of inflammatory cytokines and apoptotic molecules compared with controls. Subsequently, our data demonstrate that phosphorylation of TLR3 tyrosine residue and its interaction with PI3K is enhanced, and protein levels of phospho-PI3K and phospho-Akt are both increased after poly(I:C) pretreatment, while knock out of TLR3 suppresses the cardioprotection of poly(I:C) preconditioning through a decreased activation of PI3K/Akt signaling. Moreover, inhibition of p85 PI3K by the administration of LY294002 in vivo and knockdown of Akt by siRNA in vitro significantly abolish poly(I:C) preconditioning-induced cardioprotective effect. In conclusion, our results reveal that poly(I:C) preconditioning exhibits essential protection in myocardial I/R injury via its modulation of TLR3, and the downstream PI3K/Akt signaling, which may provide a potential pharmacologic target for perioperative cardioprotection.
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Affiliation(s)
- Erya Chen
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chan Chen
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Zhendong Niu
- Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lu Gan
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qiao Wang
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ming Li
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - XingWei Cai
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Rui Gao
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Sruthi Katakam
- Institute of Cell Engineering, Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Hai Chen
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Shu Zhang
- Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ronghua Zhou
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xu Cheng
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yanhua Qiu
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hai Yu
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Tao Zhu
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Jin Liu
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Rout A, Tantry US, Novakovic M, Sukhi A, Gurbel PA. Targeted pharmacotherapy for ischemia reperfusion injury in acute myocardial infarction. Expert Opin Pharmacother 2020; 21:1851-1865. [PMID: 32659185 DOI: 10.1080/14656566.2020.1787987] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
INTRODUCTION Achieving reperfusion immediately after acute myocardial infarction improves outcomes; despite this, patients remain at a high risk for mortality and morbidity at least for the first year after the event. Ischemia-reperfusion injury (IRI) has a complex pathophysiology and plays an important role in myocardial tissue injury, repair, and remodeling. AREAS COVERED In this review, the authors discuss the various mechanisms and their pharmacological agents currently available for reducing myocardial ischemia-reperfusion injury (IRI). They review important original investigations and trials in various clinical databases for treatments targeting IRI. EXPERT OPINION Encouraging results observed in many preclinical studies failed to show similar success in attenuating myocardial IRI in large-scale clinical trials. Identification of critical risk factors for IRI and targeting them individually rather than one size fits all approach should be the major focus of future research. Various newer therapies like tocilizumab, anakinra, colchicine, revacept, and therapies targeting the reperfusion injury salvage kinase pathway, survivor activating factor enhancement, mitochondrial pathways, and angiopoietin-like peptide 4 hold promise for the future.
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Affiliation(s)
- Amit Rout
- Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, Lifebridge Health , Baltimore, MD, USA
| | - Udaya S Tantry
- Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, Lifebridge Health , Baltimore, MD, USA
| | - Marko Novakovic
- Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, Lifebridge Health , Baltimore, MD, USA
| | - Ajaypaul Sukhi
- Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, Lifebridge Health , Baltimore, MD, USA
| | - Paul A Gurbel
- Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, Lifebridge Health , Baltimore, MD, USA
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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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10
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Abstract
The NLRP3 inflammasome may contribute to infarct development during acute cardiac ischemia-reperfusion (IR). Because infarct size strongly correlates with the degree of heart failure in the long term, therapies that reduce reperfusion injury are still needed as first primary care against heart failure development. Inhibition of the NLRP3 inflammasome is currently viewed as such a potential therapy. However, previous research studies directed at inhibition of various inflammatory pathways in acute cardiac IR injury were often disappointing. This is because inflammation is a double-edged sword, detrimental when hyperactive, but beneficial at lower activity, with activity critically dependent on time of reperfusion and cellular location. Moreover, several inflammatory mediators can also mediate cardioprotective signaling. It is reasonable that this also applies to the NLRP3 inflammasome, although current literature has mainly focused on its detrimental effects in the context of acute cardiac IR. Therefore, in this review, we focus on beneficial, cardioprotective properties of the NLRP3 inflammasome and its components NLRP3, ASC, and caspase-1. The results show that (1) NLRP3 deficiency prevents cardioprotection in isolated heart by ischemic preconditioning and in vivo heart by TLR2 activation, associated with impaired STAT3 or Akt signaling, respectively; (2) ASC deficiency also prevents in vivo TLR2-mediated protection; and (3) caspase-1 inhibition results in decreased infarction but impaired protection through the Akt pathway during mild ischemic insults. In conclusion, the NLRP3 inflammasome is not only detrimental, it can also be involved in cardioprotective signaling, thus fueling the future challenge to acquire a full understanding of NLRP3 inflammasome role in cardiac IR before embarking on clinical trials using NLRP3 inhibitors.
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11
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Zuurbier CJ, Abbate A, Cabrera-Fuentes HA, Cohen MV, Collino M, De Kleijn DPV, Downey JM, Pagliaro P, Preissner KT, Takahashi M, Davidson SM. Innate immunity as a target for acute cardioprotection. Cardiovasc Res 2020; 115:1131-1142. [PMID: 30576455 DOI: 10.1093/cvr/cvy304] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 11/07/2018] [Accepted: 12/14/2018] [Indexed: 12/18/2022] Open
Abstract
Acute obstruction of a coronary artery causes myocardial ischaemia and if prolonged, may result in an ST-segment elevation myocardial infarction (STEMI). First-line treatment involves rapid reperfusion. However, a highly dynamic and co-ordinated inflammatory response is rapidly mounted to repair and remove the injured cells which, paradoxically, can further exacerbate myocardial injury. Furthermore, although cardiac remodelling may initially preserve some function to the heart, it can lead over time to adverse remodelling and eventually heart failure. Since the size of the infarct corresponds to the subsequent risk of developing heart failure, it is important to find ways to limit initial infarct development. In this review, we focus on the role of the innate immune system in the acute response to ischaemia-reperfusion (IR) and specifically its contribution to cell death and myocardial infarction. Numerous danger-associated molecular patterns are released from dying cells in the myocardium, which can stimulate pattern recognition receptors including toll like receptors and NOD-like receptors (NLRs) in resident cardiac and immune cells. Activation of the NLRP3 inflammasome, caspase 1, and pyroptosis may ensue, particularly when the myocardium has been previously aggravated by the presence of comorbidities. Evidence will be discussed that suggests agents targeting innate immunity may be a promising means of protecting the hearts of STEMI patients against acute IR injury. However, the dosing and timing of such agents should be carefully determined because innate immunity pathways may also be involved in cardioprotection. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.
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Affiliation(s)
- Coert J Zuurbier
- Laboratory of Experimental Intensive Care and Anesthesiology, Department of Anesthesiology, Amsterdam UMC, University of Amsterdam, Amsterdam Cardiovascular Sciences, 1081 HV Amsterdam, The Netherlands
| | - Antonio Abbate
- VCU Pauley Heart Center and Wright Center for Clinical and Translational Research, Richmond, VA, USA
| | - Hector A Cabrera-Fuentes
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore.,National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.,Escuela de Ingeniería y Ciencias, Tecnologico de Monterrey, Centro de Biotecnología-FEMSA, Monterrey, Nuevo León, México.,Department of Microbiology, Kazan Federal University, Kazan, Russian Federation.,Institute of Biochemistry, Medical School, Justus-Liebig-University, Giessen, Germany
| | - Michael V Cohen
- Department of Medicine, University of South Alabama College of Medicine, Mobile, AL, USA.,Department of Physiology and Cell Biology, University of South Alabama College of Medicine, Mobile, AL, USA
| | - Massimo Collino
- Department of Drug Science and Technology, University of Turin, Torino, Italy
| | - Dominique P V De Kleijn
- Department of Vascular Surgery, UMC Utrecht, Utrecht University, Utrecht, the Netherlands.,Netherlands Heart Institute, Utrecht, the Netherlands
| | - James M Downey
- Department of Physiology and Cell Biology, University of South Alabama College of Medicine, Mobile, AL, USA
| | - Pasquale Pagliaro
- Department of Biological and Clinical Sciences, University of Turin, Torino, Italy.,National Institute for Cardiovascular Research, Bologna, Italy
| | - Klaus T Preissner
- Department of Biochemistry, Medical School, Justus-Liebig-University, Giessen, Germany
| | - Masafumi Takahashi
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
| | - Sean M Davidson
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, UK
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12
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Zhang XY, Huang Z, Li QJ, Zhong GQ, Meng JJ, Wang DX, Tu RH. Ischemic postconditioning attenuates the inflammatory response in ischemia/reperfusion myocardium by upregulating miR‑499 and inhibiting TLR2 activation. Mol Med Rep 2020; 22:209-218. [PMID: 32377693 PMCID: PMC7248531 DOI: 10.3892/mmr.2020.11104] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 03/25/2020] [Indexed: 12/18/2022] Open
Abstract
Toll-like receptor 2 (TLR2)-mediated myocardial inflammation serves an important role in promoting myocardial ischemic/reperfusion (I/R) injury. Previous studies have shown that miR-499 is critical for cardioprotection after ischemic postconditioning (IPostC). Therefore, the present study evaluated the protective effect of IPostC on the myocardium by inhibiting TLR2, and also assessed the involvement of microRNA (miR)-499. Rat hearts were subjected to 30 min of ischemia and 2 h of reperfusion. The IPostC was 3 cycles of 30 sec of reperfusion and 30 sec of re-occlusion prior to reperfusion. In total, 90 rats were randomly divided into six groups (n=15 per group): Sham; I/R; IPostC; miR-499 negative control adeno-associated virus (AAV) vectors + IPostC; miR-499 inhibitor AAV vectors + IPostC; and miR-499 mimic AAV vectors + IPostC. It was identified that IPostC significantly decreased the I/R-induced cardiomyocyte apoptotic index (29.4±2.03% in IPostC vs. 42.64±2.27% in I/R; P<0.05) and myocardial infarct size (48.53±2.49% in IPostC vs. 66.52±3.1% in I/R; P<0.05). Moreover, these beneficial effects were accompanied by increased miR-499 expression levels (as demonstrated by reverse transcription-quantitative PCR) in the myocardial tissue and decreased TLR2, protein kinase C (PKC), interleukin (IL)-1β and IL-6 expression levels (as demonstrated by western blotting and ELISA) in the myocardium and serum. The results indicated that IPostC + miR-499 mimics significantly inhibited inflammation and the PKC signaling pathway and enhanced the anti-inflammatory and anti-apoptotic effects of IPostC. However, IPostC + miR-499 inhibitors had the opposite effect. Therefore, it was speculated that IPostC may have a miR-499-dependent cardioprotective effect. The present results suggested that miR-499 may be involved in IPostC-mediated ischemic cardioprotection, which may occur via local and systemic TLR2 inhibition, subsequent inhibition of the PKC signaling pathway and a decrease in inflammatory cytokine release, including IL-1β and IL-6. Moreover, these effects will ultimately lead to a decrease in the myocardial apoptotic index and myocardial infarct size via the induction of the anti-apoptotic protein Bcl-2, and inhibition of the pro-apoptotic protein Bax in myocardium.
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Affiliation(s)
- Xin-Yue Zhang
- Department of Cardiology, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Zheng Huang
- Department of Cardiology, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Qing-Jie Li
- Department of Cardiology, Second Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Guo-Qiang Zhong
- Department of Cardiology, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Jian-Jun Meng
- Department of Geriatric Health Care Center, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Dong-Xiao Wang
- Department of Cardiology, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Rong-Hui Tu
- Guangxi Key Laboratory of Precision Medicine in Cardio‑Cerebrovascular Diseases Control and Prevention, Nanning, Guangxi 530021, P.R. China
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13
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Walsh TG, Poole AW. Do platelets promote cardiac recovery after myocardial infarction: roles beyond occlusive ischemic damage. Am J Physiol Heart Circ Physiol 2018; 314:H1043-H1048. [PMID: 29547023 PMCID: PMC6008147 DOI: 10.1152/ajpheart.00134.2018] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Our understanding of platelet function has traditionally focused on their roles in physiological hemostasis and pathological thrombosis, with the latter being causative of vessel occlusion and subsequent ischemic damage to various tissues. In particular, numerous in vivo studies have implicated causative roles for platelets in the pathogenesis of ischemia-reperfusion (I/R) injury to the myocardium. However, platelets clearly have more complex pathophysiological roles, particularly as a result of the heterogeneous nature of biologically active cargo secreted from their granules or contained within released microparticles or exosomes. While some of these released mediators amplify platelet activation and thrombosis through autocrine or paracrine amplification pathways, they can also regulate diverse cellular functions within the localized microenvironment and recruit progenitor cells to the damage site to facilitate repair processes. Notably, there is evidence to support cardioprotective roles for platelet mediators during I/R injury. As such, it is becoming more widely appreciated that platelets fulfill a host of physiological and pathological roles beyond our basic understanding. Therefore, the purpose of this perspective is to consider whether platelets, through their released mediators, can assume a paradoxically beneficial role to promote cardiac recovery after I/R injury.
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Affiliation(s)
- Tony G Walsh
- School of Physiology, Pharmacology and Neuroscience, University of Bristol , Bristol , United Kingdom
| | - Alastair W Poole
- School of Physiology, Pharmacology and Neuroscience, University of Bristol , Bristol , United Kingdom
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14
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Zhang P, Shao L, Ma J. Toll-Like Receptors 2 and 4 Predict New-Onset Atrial Fibrillation in Acute Myocardial Infarction Patients. Int Heart J 2018; 59:64-70. [PMID: 29375116 DOI: 10.1536/ihj.17-084] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Myocardial infarction (MI) can cause new-onset atrial fibrillation (AF) due to cardiac remodeling. As a recent study has shown, inflammatory factors are closely tied to cell death and survival in myocardial ischemia injury. Toll-like receptors (TLRs) have been shown to participate in the process of myocardial infarction as innate immune factors.The subjects were divided into 3 groups: healthy controls (n = 82), MI patients (n = 84), and AFMI (new-onset atrial fibrillation after myocardial infarction) patients (n = 85). Peripheral blood mononuclear cell (PBMC) TLR mRNA expression was detected by rt-PCR. Western blot was used to analyze PBMC TLRs and their downstream signal protein expression. PBMCs were presented as TLR2 expression or TLR4 expression using flow cytometry.From mRNA to protein detection, PBMC TLR2 and TLR4 were significantly higher in the AFMI group than in the control group and MI group. A similar tendency was also observed in the expression of downstream signaling proteins. When further analyzed with TLR2 and TLR4 antibodies by flow cytometry, PBMC levels also appeared to be higher in AFMI patients than those in MI patients and the healthy control group.In our study, PBMC TLRs and their downstream signaling proteins were significantly higher in the acute myocardial infarction patients with new-onset atrial fibrillation compared with healthy people and acute myocardial infarction patients without new-onset atrial fibrillation. They have the potential to be novel biomarkers for new-onset atrial fibrillation after acute myocardial infarction.
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Affiliation(s)
- Ping Zhang
- Department of Geriatrics & Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
| | - Liang Shao
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
| | - Jun Ma
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
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15
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de Preux Charles AS, Bise T, Baier F, Marro J, Jaźwińska A. Distinct effects of inflammation on preconditioning and regeneration of the adult zebrafish heart. Open Biol 2017; 6:rsob.160102. [PMID: 27440424 PMCID: PMC4967830 DOI: 10.1098/rsob.160102] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 05/17/2016] [Indexed: 12/19/2022] Open
Abstract
The adult heart is able to activate cardioprotective programmes and modifies its architecture in response to physiological or pathological changes. While mammalian cardiac remodelling often involves hypertrophic expansion, the adult zebrafish heart exploits hyperplastic growth. This capacity depends on the responsiveness of zebrafish cardiomyocytes to mitogenic signals throughout their entire life. Here, we have examined the role of inflammation on the stimulation of cell cycle activity in the context of heart preconditioning and regeneration. We used thoracotomy as a cardiac preconditioning model and cryoinjury as a model of cardiac infarction in the adult zebrafish. First, we performed a spatio-temporal characterization of leucocytes and cycling cardiac cells after thoracotomy. This analysis revealed a concomitance between the infiltration of inflammatory cells and the stimulation of the mitotic activity. However, decreasing the immune response using clodronate liposome injection, PLX3397 treatment or anti-inflammatory drugs surprisingly had no effect on the re-entry of cardiac cells into the cell cycle. In contrast, reducing inflammation using the same strategies after cryoinjury strongly impaired cardiac cell mitotic activity and the regenerative process. Taken together, our results show that, while the immune response is not necessary to induce cell-cycle activity in intact preconditioned hearts, inflammation is required for the regeneration of injured hearts in zebrafish.
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Affiliation(s)
| | - Thomas Bise
- Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland
| | - Felix Baier
- Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland
| | - Jan Marro
- Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland
| | - Anna Jaźwińska
- Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland
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16
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Prabhu SD, Frangogiannis NG. The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis. Circ Res 2017; 119:91-112. [PMID: 27340270 DOI: 10.1161/circresaha.116.303577] [Citation(s) in RCA: 1546] [Impact Index Per Article: 193.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Accepted: 04/15/2016] [Indexed: 12/14/2022]
Abstract
In adult mammals, massive sudden loss of cardiomyocytes after infarction overwhelms the limited regenerative capacity of the myocardium, resulting in the formation of a collagen-based scar. Necrotic cells release danger signals, activating innate immune pathways and triggering an intense inflammatory response. Stimulation of toll-like receptor signaling and complement activation induces expression of proinflammatory cytokines (such as interleukin-1 and tumor necrosis factor-α) and chemokines (such as monocyte chemoattractant protein-1/ chemokine (C-C motif) ligand 2 [CCL2]). Inflammatory signals promote adhesive interactions between leukocytes and endothelial cells, leading to extravasation of neutrophils and monocytes. As infiltrating leukocytes clear the infarct from dead cells, mediators repressing inflammation are released, and anti-inflammatory mononuclear cell subsets predominate. Suppression of the inflammatory response is associated with activation of reparative cells. Fibroblasts proliferate, undergo myofibroblast transdifferentiation, and deposit large amounts of extracellular matrix proteins maintaining the structural integrity of the infarcted ventricle. The renin-angiotensin-aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts. Maturation of the scar follows, as a network of cross-linked collagenous matrix is formed and granulation tissue cells become apoptotic. This review discusses the cellular effectors and molecular signals regulating the inflammatory and reparative response after myocardial infarction. Dysregulation of immune pathways, impaired suppression of postinfarction inflammation, perturbed spatial containment of the inflammatory response, and overactive fibrosis may cause adverse remodeling in patients with infarction contributing to the pathogenesis of heart failure. Therapeutic modulation of the inflammatory and reparative response may hold promise for the prevention of postinfarction heart failure.
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Affiliation(s)
- Sumanth D Prabhu
- From the Division of Cardiovascular Disease, University of Alabama at Birmingham, and Medical Service, Birmingham VAMC (S.D.P.); and Department of Medicine, The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (N.G.F.)
| | - Nikolaos G Frangogiannis
- From the Division of Cardiovascular Disease, University of Alabama at Birmingham, and Medical Service, Birmingham VAMC (S.D.P.); and Department of Medicine, The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (N.G.F.).
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17
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Sandanger Ø, Gao E, Ranheim T, Bliksøen M, Kaasbøll OJ, Alfsnes K, Nymo SH, Rashidi A, Ohm IK, Attramadal H, Aukrust P, Vinge LE, Yndestad A. NLRP3 inflammasome activation during myocardial ischemia reperfusion is cardioprotective. Biochem Biophys Res Commun 2015; 469:1012-20. [PMID: 26706279 DOI: 10.1016/j.bbrc.2015.12.051] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2015] [Accepted: 12/13/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND The innate immune receptor NLRP3 recognizes tissue damage and initiates inflammatory processes through formation multiprotein complexes with the adaptor protein ASC and caspase-1, i.e. NLRP3 inflammasomes, which through cleavage of pro-IL-1β mediates release of bioactive IL-1β. We hypothesized that NLRP3 mediates tissue damage during acute myocardial infarction (MI) and sought to investigate the mechanisms herein in an experimental MI model in mice. METHODS AND RESULTS The left coronary artery (LCA) of WT, NLRP3(-/-) and ASC(-/-) mice of both genders was ligated for 30 min followed by 3 or 24 h reperfusion. For pre-conditioning studies, the TLR2 agonist Pam3CSK4 or PBS was injected intraperitoneally 60 min prior to LCA ligation. For mechanistic investigations, blood plasmas and left ventricle tissues were collected, and a hypothesis-driven selection of protein or mRNA targets was investigated. Surprisingly, hearts from NLRP3-deficient mice featured larger infarct size than WT mice (p = 0.0048). In general, there were only modest changes with no significant pattern in myocardial infiltration of neutrophils and macrophages and systemic and myocardial cytokine expression between the three genotypes. Preconditioning with the TLR2 agonist Pam3CSK4 induced Akt phosphorylation and reduced infarct size in WT but not NLRP3 -or ASC -deficient hearts. CONCLUSION Absence of NLRP3 results in increased myocardial infarct size after in vivo ischemia reperfusion, seemingly due to dysfunction of the cardioprotective RISK pathway. Our data imply that NLRP3 contributes to cardio-protection during I/R and do not support a role for NLRP3 or ASC inhibition in the management of acute MI including revascularization therapy.
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Affiliation(s)
- Ø Sandanger
- Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Centre for Heart Failure Research, University of Oslo, Oslo, Norway; K.G.Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
| | - E Gao
- Temple University School of Medicine, Philadelphia, United States
| | - T Ranheim
- Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Centre for Heart Failure Research, University of Oslo, Oslo, Norway; K.G.Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
| | - M Bliksøen
- Institute of Basic Medical Sciences, Department of Physiology, University of Oslo, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway
| | - O J Kaasbøll
- Centre for Heart Failure Research, University of Oslo, Oslo, Norway; Institute for Surgical Research, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - K Alfsnes
- Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Centre for Heart Failure Research, University of Oslo, Oslo, Norway; K.G.Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
| | - Ståle H Nymo
- Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Centre for Heart Failure Research, University of Oslo, Oslo, Norway; K.G.Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
| | - A Rashidi
- Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G.Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
| | - I K Ohm
- Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Centre for Heart Failure Research, University of Oslo, Oslo, Norway
| | | | - P Aukrust
- Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G.Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - L E Vinge
- Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Centre for Heart Failure Research, University of Oslo, Oslo, Norway
| | - A Yndestad
- Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Centre for Heart Failure Research, University of Oslo, Oslo, Norway; K.G.Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway
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18
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Vicencio JM, Yellon DM, Sivaraman V, Das D, Boi-Doku C, Arjun S, Zheng Y, Riquelme JA, Kearney J, Sharma V, Multhoff G, Hall AR, Davidson SM. Plasma exosomes protect the myocardium from ischemia-reperfusion injury. J Am Coll Cardiol 2015; 65:1525-36. [PMID: 25881934 DOI: 10.1016/j.jacc.2015.02.026] [Citation(s) in RCA: 433] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 02/02/2015] [Accepted: 02/03/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND Exosomes are nanometer-sized vesicles released from cells into the blood, where they can transmit signals throughout the body. Shown to act on the heart, exosomes' composition and the signaling pathways they activate have not been explored. We hypothesized that endogenous plasma exosomes can communicate signals to the heart and provide protection against ischemia and reperfusion injury. OBJECTIVES This study sought to isolate and characterize exosomes from rats and healthy volunteers, evaluate their cardioprotective actions, and identify the molecular mechanisms involved. METHODS The exosome-rich fraction was isolated from the blood of adult rats and human volunteers and was analyzed by protein marker expression, transmission electron microscopy, and nanoparticle tracking analysis. This was then used in ex vivo, in vivo, and in vitro settings of ischemia-reperfusion, with the protective signaling pathways activated on cardiomyocytes identified using Western blot analyses and chemical inhibitors. RESULTS Exosomes exhibited the expected size and expressed marker proteins CD63, CD81, and heat shock protein (HSP) 70. The exosome-rich fraction was powerfully cardioprotective in all tested models of cardiac ischemia-reperfusion injury. We identified a pro-survival signaling pathway activated in cardiomyocytes involving toll-like receptor (TLR) 4 and various kinases, leading to activation of the cardioprotective HSP27. Cardioprotection was prevented by a neutralizing antibody against a conserved HSP70 epitope expressed on the exosome surface and by blocking TLR4 in cardiomyocytes, identifying the HSP70/TLR4 communication axis as a critical component in exosome-mediated cardioprotection. CONCLUSIONS Exosomes deliver endogenous protective signals to the myocardium by a pathway involving TLR4 and classic cardioprotective HSPs.
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Affiliation(s)
- Jose M Vicencio
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Derek M Yellon
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
| | - Vivek Sivaraman
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Debashish Das
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Claire Boi-Doku
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Sapna Arjun
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Ying Zheng
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Jaime A Riquelme
- Advanced Center for Chronic Diseases and Centro Estudios Moleculares de la Célula, Facultad de Ciencias Químicas y Farmacéuticas and Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Jessica Kearney
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Vikram Sharma
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Gabriele Multhoff
- Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | - Andrew R Hall
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Sean M Davidson
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
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19
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Zhang XJ, Zhang P, Li H. Interferon regulatory factor signalings in cardiometabolic diseases. Hypertension 2015; 66:222-47. [PMID: 26077571 DOI: 10.1161/hypertensionaha.115.04898] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 05/14/2015] [Indexed: 12/24/2022]
Affiliation(s)
- Xiao-Jing Zhang
- From the Department of Cardiology, Renmin Hospital (X.-J.Z., P.Z., H.L.) and Cardiovascular Research Institute (X.-J.Z., P.Z., H.L.), Wuhan University, Wuhan, China; and State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, PR China (X.-J.Z.)
| | - Peng Zhang
- From the Department of Cardiology, Renmin Hospital (X.-J.Z., P.Z., H.L.) and Cardiovascular Research Institute (X.-J.Z., P.Z., H.L.), Wuhan University, Wuhan, China; and State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, PR China (X.-J.Z.)
| | - Hongliang Li
- From the Department of Cardiology, Renmin Hospital (X.-J.Z., P.Z., H.L.) and Cardiovascular Research Institute (X.-J.Z., P.Z., H.L.), Wuhan University, Wuhan, China; and State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, PR China (X.-J.Z.).
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Cross talk of the first-line defense TLRs with PI3K/Akt pathway, in preconditioning therapeutic approach. MOLECULAR AND CELLULAR THERAPIES 2015; 3:4. [PMID: 26056605 PMCID: PMC4456045 DOI: 10.1186/s40591-015-0041-7] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Accepted: 05/19/2015] [Indexed: 01/04/2023]
Abstract
Toll-like receptor family (TLRs), pattern recognition receptors, is expressed not only on immune cells but also on non-immune cells, including cardiomyocytes, fibroblasts, and vascular endothelial cells. One main function of TLRs in the non-immune system is to regulate apoptosis. TLRs are the central mediators in hepatic, pulmonary, brain, and renal ischemic/reperfusion (I/R) injury. Up-regulation of TLRs and their ligation by either exogenous or endogenous danger signals plays critical roles in ischemia/reperfusion-induced tissue damage. Conventional TLR-NF-κB pathways are markedly activated in failing and ischemic myocardium. Recent studies have identified a cross talk between TLR activation and the PI3K/Akt pathway. The activation of TLRs is proposed to be the most potent preconditioning method after ischemia, to improve the cell survival via the mechanism involved the PI3K/Akt signaling pathway and to attenuate the subsequent TLR-NF-κB pathway stimulation. Thus, TLRs could be a great target in the new treatment approaches for myocardial I/R injury.
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Pourrajab F, Yazdi MB, Zarch MB, Zarch MB, Hekmatimoghaddam S. Cross talk of the first-line defense TLRs with PI3K/Akt pathway, in preconditioning therapeutic approach. MOLECULAR AND CELLULAR THERAPIES 2015; 3:4. [PMID: 26056605 PMCID: PMC4456045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Accepted: 05/19/2015] [Indexed: 11/21/2023]
Abstract
Toll-like receptor family (TLRs), pattern recognition receptors, is expressed not only on immune cells but also on non-immune cells, including cardiomyocytes, fibroblasts, and vascular endothelial cells. One main function of TLRs in the non-immune system is to regulate apoptosis. TLRs are the central mediators in hepatic, pulmonary, brain, and renal ischemic/reperfusion (I/R) injury. Up-regulation of TLRs and their ligation by either exogenous or endogenous danger signals plays critical roles in ischemia/reperfusion-induced tissue damage. Conventional TLR-NF-κB pathways are markedly activated in failing and ischemic myocardium. Recent studies have identified a cross talk between TLR activation and the PI3K/Akt pathway. The activation of TLRs is proposed to be the most potent preconditioning method after ischemia, to improve the cell survival via the mechanism involved the PI3K/Akt signaling pathway and to attenuate the subsequent TLR-NF-κB pathway stimulation. Thus, TLRs could be a great target in the new treatment approaches for myocardial I/R injury.
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Affiliation(s)
- Fatemeh Pourrajab
- />School of Medicine, Shahid Sadoughi University of Medical Sciences, Professor Hessabi 11 BLV, Shohadaye Gomnam BLV, Yazd, Iran P.O. 8915173149
- />Department of Clinical Biochemistry and Molecular Biology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mohammad Baghi Yazdi
- />School of Medicine, Shahid Sadoughi University of Medical Sciences, Professor Hessabi 11 BLV, Shohadaye Gomnam BLV, Yazd, Iran P.O. 8915173149
| | - Mojtaba Babaei Zarch
- />School of Medicine, Shahid Sadoughi University of Medical Sciences, Professor Hessabi 11 BLV, Shohadaye Gomnam BLV, Yazd, Iran P.O. 8915173149
| | - Mohammadali Babaei Zarch
- />School of Medicine, Shahid Sadoughi University of Medical Sciences, Professor Hessabi 11 BLV, Shohadaye Gomnam BLV, Yazd, Iran P.O. 8915173149
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Vilahur G, Badimon L. Ischemia/reperfusion activates myocardial innate immune response: the key role of the toll-like receptor. Front Physiol 2014; 5:496. [PMID: 25566092 PMCID: PMC4270170 DOI: 10.3389/fphys.2014.00496] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 12/02/2014] [Indexed: 01/04/2023] Open
Abstract
Recent data have indicated that the myocardium may act as an immune organ initiating cardiac innate immune response and inflammation. It has been suggested that activation of the immune system occurs upon the interaction of damage-associated molecular patterns (DAMPs) generated and released during ischemic damage with pattern recognition receptors (Toll like receptors; TLR) present in cardiac cells. Among TLRs, TLR4, and TLR2 are the ones mostly expressed in cardiac tissue. Whereas TLR4 has shown to play a detrimental role in myocardial ischemia/reperfusion (I/R) injury, the effect elicited by TLR2 activation remains controversial. Once activated, TLR signaling may occur via the Myd88- and Trif- dependent pathways leading to NFκB and IFN-3 activation, respectively, and subsequent stimulation of pro-inflammatory and immunomodulatory cytokine gene expression. Cytokine release contributes to neutrophils activation, recruitment, adhesion and infiltration to the site of cardiac injury further perpetuating the inflammatory process. This mini-review will focus on the current knowledge regarding the role of the heart in inducing and coordinating the innate inflammatory response via the TLR signaling pathway in myocardial I/R injury.
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Affiliation(s)
- Gemma Vilahur
- Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau Barcelona, Spain
| | - Lina Badimon
- Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau Barcelona, Spain ; Cardiovascular Research Chair, Universitat Autònoma de Barcelona Barcelona, Spain
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Wagner KB, Felix SB, Riad A. Innate immune receptors in heart failure: Side effect or potential therapeutic target? World J Cardiol 2014; 6:791-801. [PMID: 25228958 PMCID: PMC4163708 DOI: 10.4330/wjc.v6.i8.791] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Revised: 04/18/2014] [Accepted: 06/11/2014] [Indexed: 02/06/2023] Open
Abstract
Heart failure (HF) is a leading cause of mortality and morbidity in western countries and occasions major expenses for public health systems. Although optimal medical treatment is widely available according to current guidelines, the prognosis of patients with HF is still poor. Despite the etiology of the disease, increased systemic or cardiac activation of the innate immune system is well documented in several types of HF. In some cases there is evidence of an association between innate immune activation and clinical outcome of patients with this disease. However, the few large trials conducted with the use of anti-inflammatory medication in HF have not revealed its benefits. Thus, greater understanding of the relationship between alteration in the immune system and development and progression of HF is urgently necessary: prior to designing therapeutic interventions that target pathological inflammatory processes in preventing harmful cardiac effects of immune modulatory therapy. In this regard, relatively recently discovered receptors of the innate immune system, i.e., namely toll-like receptors (TLRs) and nod-like receptors (NLRs)-are the focus of intense cardiovascular research. These receptors are main up-stream regulators of cytokine activation. This review will focus on current knowledge of the role of TLRs and NLRs, as well as on downstream cytokine activation, and will discuss potential therapeutic implications.
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Krenz M, Baines C, Kalogeris T, Korthuis R. Cell Survival Programs and Ischemia/Reperfusion: Hormesis, Preconditioning, and Cardioprotection. ACTA ACUST UNITED AC 2013. [DOI: 10.4199/c00090ed1v01y201309isp044] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Moghimpour Bijani F, Vallejo JG, Rezaei N. Toll-like receptor signaling pathways in cardiovascular diseases: challenges and opportunities. Int Rev Immunol 2013; 31:379-95. [PMID: 23083347 DOI: 10.3109/08830185.2012.706761] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Toll-like receptors (TLRs), a family of surface molecules, are involved in innate immune responses. Recent studies indicated that TLRs play a critical role in inflammatory responses to exogenous and endogenous triggers. This article focuses on probable effects of TLRs in the morbidity of cardiovascular events, e.g., ischemic reperfusion (I/R) injury and atherosclerosis. TLR2 and TLR4 have been shown to have the most fundamental role in promoting cytokine production and subsequent inflammatory damages in these states. Blockade of these receptors may be beneficial in both preventing the occurrence and decreasing the complications in cardiovascular events. However, controversies exist on the certainty of this beneficial effect; therefore, additional studies are needed.
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Affiliation(s)
- Faezeh Moghimpour Bijani
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
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Kokkinopoulos I. 670 nm LED ameliorates inflammation in the CFH(-/-) mouse neural retina. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2013; 122:24-31. [PMID: 23584451 DOI: 10.1016/j.jphotobiol.2013.03.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Revised: 03/12/2013] [Accepted: 03/17/2013] [Indexed: 12/27/2022]
Abstract
Para-inflammation in the neural retina is thought to contribute to the onset of some age-related retinal diseases. Continuous innate immune system activation, manifests in progressive chronic inflammation, macrophage invasion and cell loss, resulting in visual loss. We have previously shown that mitochondrial function is augmented following 670 nm LED exposure, leading to reduced retinal inflammation. Here, it was asked whether 670 nm LED regulates para-inflammation in an aged-related macular degeneration mouse model. Mutant CFH(-/-) mice were exposed to four 90 s exposures over 2 days for 1 week and 8 weeks. These regimes significantly reduced activated macrophage number, TNF-alpha and MIF protein expression levels. Immuno-reactivity to C3, C3b and calcitonin, all markers of inflammatory status were also altered. Finally, innate immune proteins, TLR 2 and 4, showed a marked decrease in protein expression. These findings support the notion that 670 nm LED regulates innate immunity, alleviating inflammation in the neural retina of an age-related macular degeneration mouse model.
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Affiliation(s)
- Ioannis Kokkinopoulos
- School of Biomedical and Health Sciences, Wolfson Centre for Age-Related Diseases, King's College London, UK.
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Hermansson C, Lundqvist A, Wasslavik C, Palmqvist L, Jeppsson A, Hultén LM. Reduced expression of NLRP3 and MEFV in human ischemic heart tissue. Biochem Biophys Res Commun 2013. [DOI: 10.1016/j.bbrc.2012.11.070] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Bustamante J, Tamayo E, Herreros J. Genomics in cardiovascular diseases: analysis of the importance of the toll-like receptor signaling pathway. Int J Gen Med 2012. [PMID: 23204853 PMCID: PMC3508562 DOI: 10.2147/ijgm.s33416] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
The development of techniques for genomics study makes it possible for us to further our knowledge about the physiopathology of various immunological or infectious diseases. These techniques improve our understanding of the development and evolution of such diseases, including those of cardiovascular origin, whilst they help to bring about the design of new therapeutic strategies. We are reviewing the genetic alterations of immunity in said field, and focusing on the signaling pathway of toll-like receptors because not only does this play a decisive role in response to microorganisms, it is also heavily involved in modulating the inflammatory response to tissue damage, a side effect of numerous cardiovascular diseases. These alterations in tissue homeostasis are present under a wide range of circumstances, such as reperfusion ischemia (myocardial infarction) phenomena, arteriosclerosis, or valvulopathy.
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Affiliation(s)
- J Bustamante
- Department of Cardiovascular Surgery, Hospital Universitario La Princesa, Madrid
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Cao Z, Ren D, Ha T, Liu L, Wang X, Kalbfleisch J, Gao X, Kao R, Williams D, Li C. CpG-ODN, the TLR9 agonist, attenuates myocardial ischemia/reperfusion injury: involving activation of PI3K/Akt signaling. Biochim Biophys Acta Mol Basis Dis 2012; 1832:96-104. [PMID: 22917564 DOI: 10.1016/j.bbadis.2012.08.008] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Revised: 07/31/2012] [Accepted: 08/08/2012] [Indexed: 01/04/2023]
Abstract
BACKGROUND Toll-like receptors (TLRs) have been implicated in myocardial ischemia/reperfusion (I/R) injury. The TLR9 ligand, CpG-ODN has been reported to improve cell survival. We examined effect of CpG-ODN on myocardial I/R injury. METHODS Male C57BL/6 mice were treated with either CpG-ODN, control-ODN, or inhibitory CpG-ODN (iCpG-ODN) 1h prior to myocardial ischemia (60min) followed by reperfusion. Untreated mice served as I/R control (n=10/each group). Infarct size was determined by TTC straining. Cardiac function was examined by echocardiography before and after myocardial I/R up to 14days. RESULTS CpG-ODN administration significantly decreased infarct size by 31.4% and improved cardiac function after myocardial I/R up to 14days. Neither control-ODN nor iCpG-ODN altered I/R-induced myocardial infarction and cardiac dysfunction. CpG-ODN attenuated I/R-induced myocardial apoptosis and prevented I/R-induced decrease in Bcl2 and increase in Bax levels in the myocardium. CpG-ODN increased Akt and GSK-3β phosphorylation in the myocardium. In vitro data suggested that CpG-ODN treatment induced TLR9 tyrosine phosphorylation and promoted an association between TLR9 and the p85 subunit of PI3K. Importantly, PI3K/Akt inhibition and Akt kinase deficiency abolished CpG-ODN-induced cardioprotection. CONCLUSION CpG-ODN, the TLR9 ligand, induces protection against myocardial I/R injury. The mechanisms involve activation of the PI3K/Akt signaling pathway.
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Affiliation(s)
- Zhijuan Cao
- Department of Surgery, East Tennessee State University, Johnson City, TN 37614, USA
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Zuurbier CJ, Jong WMC, Eerbeek O, Koeman A, Pulskens WP, Butter LM, Leemans JC, Hollmann MW. Deletion of the innate immune NLRP3 receptor abolishes cardiac ischemic preconditioning and is associated with decreased Il-6/STAT3 signaling. PLoS One 2012; 7:e40643. [PMID: 22848390 PMCID: PMC3407219 DOI: 10.1371/journal.pone.0040643] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Accepted: 06/13/2012] [Indexed: 01/04/2023] Open
Abstract
Objective Recent studies indicate that the innate immune system is not only triggered by exogenous pathogens and pollutants, but also by endogenous danger signals released during ischemia and necrosis. As triggers for the innate immune NLRP3 inflammasome protein complex appear to overlap with those for cardiac ischemia-reperfusion (I/R) and ischemic preconditioning (IPC), we explored the possibility that the NLRP3 inflammasome is involved in IPC and acute I/R injury of the heart. Principal Findings Baseline cardiac performance and acute I/R injury were investigated in isolated, Langendorff-perfused hearts from wild-type (WT), ASC−/− and NLRP3−/− mice. Deletion of NLRP3 inflammasome components ASC−/− or NLRP3−/− did not affect baseline performance. The deletions exacerbated I/R-induced mechanical dysfunction, but were without effect on I/R-induced cell death. When subjected to IPC, WT and ASC−/− hearts were protected against I/R injury (improved function and less cell death). However, IPC did not protect NLRP3−/− hearts against I/R injury. NLRP3−/− hearts had significantly decreased cardiac IL-6 levels with a trend towards lower IL-1β levels at end reperfusion, suggesting abrogation of IPC through diminished IL-6 and/or IL-1β signaling. Subsequent experiments showed that neutralising IL-6 using an antibody against IL-6 abrogated IPC in WT hearts. However, inhibition of the IL-1r receptor with the IL-1 receptor inhibitor Anakinra (100 mg/L) did not abrogate IPC in WT hearts. Analysis of survival kinases after IPC demonstrated decreased STAT3 expression in NLRP3−/− hearts when compared to WT hearts. Conclusions The data suggest that the innate immune NLRP3 protein, in an NLRP3-inflammasome-independent fashion, is an integral component of IPC in the isolated heart, possibly through an IL-6/STAT3 dependent mechanism.
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Affiliation(s)
- Coert J Zuurbier
- Laboratory of Experimental Intensive Care and Anesthesiology, Department of Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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Timmers L, Pasterkamp G, de Hoog VC, Arslan F, Appelman Y, de Kleijn DPV. The innate immune response in reperfused myocardium. Cardiovasc Res 2012; 94:276-83. [DOI: 10.1093/cvr/cvs018] [Citation(s) in RCA: 186] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
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Ha T, Liu L, Kelley J, Kao R, Williams D, Li C. Toll-like receptors: new players in myocardial ischemia/reperfusion injury. Antioxid Redox Signal 2011; 15:1875-93. [PMID: 21091074 PMCID: PMC3159106 DOI: 10.1089/ars.2010.3723] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Innate immune and inflammatory responses have been implicated in myocardial ischemia/reperfusion (I/R) injury. However, the mechanisms by which innate immunity and inflammatory response are involved in myocardial I/R have not been elucidated completely. Recent studies highlight the role of Toll-like receptors (TLRs) in the induction of innate immune and inflammatory responses. Growing evidence has demonstrated that TLRs play a critical role in myocardial I/R injury. Specifically, deficiency of TLR4 protects the myocardium from ischemic injury, whereas modulation of TLR2 induces cardioprotection against ischemic insult. Importantly, cardioprotection induced by modulation of TLRs involves activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, suggesting that there is a crosstalk between TLRs and PI3K/Akt signaling pathways. In addition, TLRs also associate with other coreceptors, such as macrophage scavenger receptors in the recognition of their ligands. TLRs are also involved in the induction of angiogenesis, modulation of stem cell function, and expression of microRNA, which are currently important topic areas in myocardial I/R. Understanding how TLRs contribute to myocardial I/R injury could provide basic scientific knowledge for the development of new therapeutic approaches for the treatment and management of patients with heart attack.
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Affiliation(s)
- Tuanzhu Ha
- Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
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Topkara VK, Evans S, Zhang W, Epelman S, Staloch L, Barger PM, Mann DL. Therapeutic targeting of innate immunity in the failing heart. J Mol Cell Cardiol 2011; 51:594-9. [PMID: 21074541 PMCID: PMC3053440 DOI: 10.1016/j.yjmcc.2010.11.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2010] [Revised: 10/22/2010] [Accepted: 11/02/2010] [Indexed: 12/22/2022]
Abstract
Recent studies suggest that the heart possesses an intrinsic system that is intended to delimit tissue injury, as well as orchestrate homoeostatic responses within the heart. The extant literature suggests that this intrinsic stress response is mediated, at least in part, by a family of pattern recognition receptors that belong to the innate immune system, including CD14, the soluble pattern recognition receptor for lipopolysaccharide, and Toll-like receptors 2, 3, 4, 5, 6, 7, and 9. Although this intrinsic stress response system provides a short-term adaptive response to tissue injury, the beneficial effects of this phylogenetically ancient system may be lost if myocardial expression of these molecules either becomes sustained and/or excessive, in which case the salutary effects of activation of these pathways are contravened by the known deleterious effects of inflammatory signaling. Herein we present new information with regard to activation of innate immune gene expression in the failing human heart, as well as review the novel TLR antagonists that are being developed for other indications outside of heart failure. This review will discuss the interesting possibility that the TLR pathway may represent a new target for the development of novel heart failure therapeutics. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."
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Affiliation(s)
- Veli K Topkara
- Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8086, St. Louis, MO 63110, USA
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Abstract
The discovery and characterization of the TLR (Toll-like receptor) family has led to a better understanding of the innate immune system. The strategy of innate immune recognition is based on the detection of constitutive and conserved products of micro-organisms. However, host molecules that are released during injury can also activate TLRs. Engagement of TLRs by microbial or host-derived molecules induces the expression of pro-inflammatory cytokines, which may have both beneficial and detrimental effects on the host. In addition to being expressed in immune cells, TLRs are expressed in other tissues such as those of the cardiovascular system. In the present review, the role of TLRs in septic cardiomyopathy, viral myocarditis, atherosclerosis, ischaemia/reperfusion injury and cardiac remodelling after myocardial infarction are outlined, with attention paid to genetically modified murine models. Although much has been learned about stress-induced TLR activation in the tissues of the cardiovascular system, the role of individual TLRs in initiating and integrating homoeostatic responses within the heart remains to be defined. Accumulating evidence indicates that TLRs may play an important role in the pathogenesis of atherosclerosis, viral myocarditis, dilated cardiomyopathy, cardiac allograft rejection and sepsis-induced left ventricular dysfunction. Moreover, heart failure of diverse aetiology is also now recognized to have an important immune component, with TLR signalling influencing the process of cardiac remodelling and prognosis. In the present review, we outline the biology of TLRs as well as the current experimental and clinical evidence for the role of TLRs in cardiovascular diseases.
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Mann DL. The emerging role of innate immunity in the heart and vascular system: for whom the cell tolls. Circ Res 2011; 108:1133-45. [PMID: 21527743 PMCID: PMC3084988 DOI: 10.1161/circresaha.110.226936] [Citation(s) in RCA: 300] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2010] [Accepted: 02/24/2011] [Indexed: 12/15/2022]
Abstract
Recent studies suggest that the heart possesses an innate immune system that is intended to delimit tissue injury, as well as orchestrate homoeostatic responses, within the heart. The extant literature suggests that this intrinsic stress response system is mediated, at least in part, by a family of pattern recognition receptors, most notably the Toll-like receptors. Although the innate immune system provides a short-term adaptive response to tissue injury, the beneficial effects of this phylogenetically ancient system may be lost if innate immune signaling becomes sustained and/or excessive; in which case, the salutary effects of activation of these pathways are contravened by the known deleterious effects of inflammatory signaling. Herein, the biology of innate immune signaling in the heart is reviewed, as well as the literature suggesting that the innate immune system is involved in the pathogenesis of atherosclerosis, acute coronary syndromes, stroke, viral myocarditis, sepsis, ischemia/reperfusion injury, and heart failure. The review concludes by discussing new therapies that are being developed to modulate the innate immune system.
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Affiliation(s)
- Douglas L Mann
- Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
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Hofmann U, Ertl G, Frantz S. Toll-like receptors as potential therapeutic targets in cardiac dysfunction. Expert Opin Ther Targets 2011; 15:753-65. [PMID: 21385118 DOI: 10.1517/14728222.2011.566560] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
INTRODUCTION The innate immune system can detect the highly conserved, relatively invariant structural motifs of pathogens. The most important innate immune receptors, Toll-like receptors (TLRs), represent a first line of defense against infectious pathogens, and play a pivotal role in initiating and shaping innate and adaptive immune responses. TLRs are not only expressed in immune cells, but also in cardiovascular cells. In addition to their role in response to microbial infections, evidence suggests that TLRs can also recognize endogenous ligands and may play a role in mediating cardiomyocyte cell death and survival after non-infectious injury. AREAS COVERED TLRs could be a link between cardiovascular diseases and the immune system. Experimentally, there is good evidence that TLR activation contributes to development and progression of both acute cardiac injury and chronic heart failure. The role of TLRs in myocardial ischemia-reperfusion, remodeling, septic cardiomyoparthy, autoimmune- and viral myocarditis, anthracycline-induced cardiomyopathy and cardiac hypertrophy, in basic as well as clinical science are discussed. EXPERT OPINION Evidence, mainly from animal experiments, indicates that TLRs contribute to all of the myocardial disease states reviewed in this paper. However, the relevance of TLRs as therapeutic targets remains to be defined as clinical data is sparse.
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Affiliation(s)
- Ulrich Hofmann
- University Hospital Würzburg, Department of Internal Medicine I, Oberdürrbacherstraße 6, 97080 Würzburg, Germany
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Wang E, Feng Y, Zhang M, Zou L, Li Y, Buys ES, Huang P, Brouckaert P, Chao W. Toll-like receptor 4 signaling confers cardiac protection against ischemic injury via inducible nitric oxide synthase- and soluble guanylate cyclase-dependent mechanisms. Anesthesiology 2011; 114:603-13. [PMID: 21270629 PMCID: PMC3044772 DOI: 10.1097/aln.0b013e31820a4d5b] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Prior administration of a small dose of lipopolysaccharide confers a cardiac protection against ischemia-reperfusion injury. However, the signaling mechanisms that control the protection are incompletely understood. We tested the hypothesis that Toll-like receptor 4 (TLR4) mediates the ability of lipopolysaccharide to protect against cardiac ischemia-reperfusion injury through distinct intracellular pathways involving myeloid differentiation factor 88 (MyD88), TIR-domain-containing adaptor protein-inducing interferon-β-mediated transcription factor (Trif), inducible nitric oxide synthase (iNOS), and soluble guanylate cyclase (sGC). METHODS Wild-type mice and genetically modified mice, that is TLR4-deficient (TLR4(-def)), TLR2 knockout (TLR2(-/-)), MyD88(-/-), Trif(-/-), iNOS(-/-), and sGCα1(-/-), were treated with normal saline or 0.1 mg/kg lipopolysaccharide intraperitoneally. Twenty-four hours later, isolated hearts were perfused in a Langendorff apparatus and subsequently subjected to 30 min global ischemia and reperfusion for as long as 60 min. Left ventricular function and myocardial infarction sizes were examined. RESULTS Compared with saline-treated mice, lipopolysaccharide-treated mice had markedly improved left ventricular developed pressure and dP/dt(max) (P < 0.01) and reduced myocardial infarction sizes (37.2 ± 3.4% vs. 19.8 ± 4.9%, P < 0.01) after ischemia-reperfusion. The cardiac protective effect of lipopolysaccharide was abolished in the TLR4(-def) and MyD88(-/-) mice but remained intact in TLR2(-/-) or Trif(-/-) mice. iNOS(-/-) mice or wild-type mice treated with the iNOS inhibitor 1400W failed to respond to the TLR4-induced nitric oxide production and were not protected by the lipopolysaccharide preconditioning. Although sGCα(1)(-/-) mice had robust nitric oxide production in response to lipopolysaccharide, they were not protected by the TLR4-elicited cardiac protection. CONCLUSIONS TLR4 activation confers a potent cardiac protection against ischemia-reperfusion injury via a MyD88-dependent, but Trif-independent, mechanism. iNOS/sGC are essential for the TLR4-induced cardiac protection.
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Affiliation(s)
- E Wang
- Research Fellow, Anesthesia Center for Critical Care Research, Department of Anesthesia & Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Associate Professor, Department of Anesthesiology, Xiangya Hospital, Central South University, China
| | - Yan Feng
- Research Fellow, Anesthesia Center for Critical Care Research, Department of Anesthesia & Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Ming Zhang
- Research Fellow, Anesthesia Center for Critical Care Research, Department of Anesthesia & Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Lin Zou
- Research Fellow, Anesthesia Center for Critical Care Research, Department of Anesthesia & Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Yan Li
- Research Fellow, Anesthesia Center for Critical Care Research, Department of Anesthesia & Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Emmanuel S. Buys
- Instructor, Anesthesia Center for Critical Care Research, Department of Anesthesia & Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Peigen Huang
- Instructor, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Peter Brouckaert
- Professor, Department for Molecular Biomedical Research, Flanders Institute for Biotechnology, and Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Wei Chao
- Associate Professor, Anesthesia Center for Critical Care Research, Department of Anesthesia & Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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Arslan F, Keogh B, McGuirk P, Parker AE. TLR2 and TLR4 in ischemia reperfusion injury. Mediators Inflamm 2010; 2010:704202. [PMID: 20628516 PMCID: PMC2902053 DOI: 10.1155/2010/704202] [Citation(s) in RCA: 137] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2010] [Accepted: 04/07/2010] [Indexed: 12/15/2022] Open
Abstract
Ischemia reperfusion (I/R) injury refers to the tissue damage which occurs when blood supply returns to tissue after a period of ischemia and is associated with trauma, stroke, myocardial infarction, and solid organ transplantation. Although the cause of this injury is multifactorial, increasing experimental evidence suggests an important role for the innate immune system in initiating the inflammatory cascade leading to detrimental/deleterious changes. The Toll-like Receptors (TLRs) play a central role in innate immunity recognising both pathogen- and damage-associated molecular patterns and have been implicated in a range of inflammatory and autoimmune diseases. In this paper, we summarise the current state of knowledge linking TLR2 and TLR4 to I/R injury, including recent studies which demonstrate that therapeutic inhibition of TLR2 has beneficial effects on I/R injury in a murine model of myocardial infarction.
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Affiliation(s)
- F. Arslan
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
| | - B. Keogh
- Opsona Therapeutics Ltd., Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James' Hospital, Dublin 8, Ireland
| | - P. McGuirk
- Opsona Therapeutics Ltd., Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James' Hospital, Dublin 8, Ireland
| | - A. E. Parker
- Opsona Therapeutics Ltd., Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James' Hospital, Dublin 8, Ireland
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Ha T, Hu Y, Liu L, Lu C, McMullen JR, Kelley J, Kao RL, Williams DL, Gao X, Li C. TLR2 ligands induce cardioprotection against ischaemia/reperfusion injury through a PI3K/Akt-dependent mechanism. Cardiovasc Res 2010; 87:694-703. [PMID: 20421349 DOI: 10.1093/cvr/cvq116] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
AIMS Toll-like receptor (TLR)-mediated signalling pathways have been implicated in myocardial ischaemia/reperfusion (I/R) injury. Activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway protects the myocardium from ischaemic injury. We hypothesized that the modulation of TLR2 would induce cardioprotection against I/R injury via activation of the PI3K/Akt signalling. METHODS AND RESULTS Mice were treated with TLR2 ligands, peptidoglycan (PGN) or Pam3CSK4, respectively, 1 h before the hearts were subjected to ischaemia (1 h), followed by reperfusion (4 h). Infarct size was determined by triphenyltetrazolium chloride staining. Cardiac function and haemodynamic performance were evaluated. Infarct size was significantly reduced in PGN- or Pam3CSK4-treated mice compared with untreated I/R mice. Administration of TLR2 ligands improved cardiac function following I/R. PGN treatment increased the levels of phospho-Akt and phospho-GSK-3beta (glycogen synthase kinase-3beta), compared with untreated I/R hearts. PGN stimulation increased TLR2 tyrosine phosphorylation and association of the p85 subunit of PI3K with TLR2. To investigate the role of PI3K/Akt signalling in PGN-induced cardioprotection, we administered the PI3K inhibitor, Wortmannin, to the mice 15 min before PGN treatment. We also administered PGN to kinase-deficient Akt (kdAkt) transgenic mice 1 h before myocardial I/R. Both PI3K inhibition and kdAkt mice abolished the cardioprotection induced by PGN. To examine the role of TLR2 in PGN-induced cardioprotection, we administrated PGN to TLR2 knockout mice 1 h before the hearts were subjected to I/R. PGN-induced cardioprotection was lost in TLR2-deficient mice. CONCLUSION These results demonstrate that TLR2 ligands induced cardioprotection, which is mediated through a TLR2/PI3K/Akt-dependent mechanism.
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Affiliation(s)
- Tuanzhu Ha
- Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, PO Box 70575, Johnson City, TN 37614-0575, USA
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