Myocardial Ischemia Activates an Injurious Innate Immune Signaling via Cardiac Heat Shock Protein 60 and Toll-like Receptor 4

Li, Yan; Si, Rui; Feng, Yan; Chen, Howard H.; Zou, Lin; Wang, E.; Zhang, Ming; Warren, H. Shaw; Sosnovik, David E.; Chao, Wei

doi:10.1074/jbc.m111.246124

Cited by 130 publications

(112 citation statements)

References 64 publications

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“…The HSP60 is a DAMP molecule that can be actively secreted from ischaemic cardiomyocytes through specific pathways dependent on both lipid rafts and exosomes 31. Studies from other labs and ours have showed that ischaemia, either alone or followed by reperfusion, induces marked release of HSP60 from cardiomyocytes, which can activate TLR4 and induce cytokine expression in cardiomyocytes 15, 18, 31, 32. Furthermore, we found HSP60 in the circulation of post‐infarct CHF rats 16.…”

Section: Discussionsupporting

confidence: 54%

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Liu

Yin

Cao

et al. 2015

J Cellular Molecular Medi

140

108

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It remains unclear whether and how cardiomyocytes contribute to the inflammation in chronic heart failure (CHF). We recently reviewed the capacity of cardiomyocytes to initiate inflammation, by means of expressing certain immune receptors such as toll‐like receptors (TLRs) that respond to pathogen‐ and damage‐associated molecular patterns (PAMP and DAMP). Previous studies observed TLR4‐mediated inflammation within days of myocardial infarction (MI). This study examined TLR4 expression and function in cardiomyocytes of failing hearts after 4 weeks of MI in rats. The increases of TLR4 mRNA and proteins, as well as inflammatory cytokine production, were observed in both the infarct and remote myocardium. Enhanced immunostaining for TLR4 was observed in cardiomyocytes but not infiltrating leucocytes. The injection of lentivirus shRNA against TLR4 into the infarcted heart decreased inflammatory cytokine production and improved heart function in vivo. Accordingly, in cardiomyocytes isolated from CHF hearts, increases of TLR4 mRNA and proteins were detected. More robust binding of TLR4 with lipopolysaccharide (LPS), a PAMP ligand for TLR4, and heat shock protein 60 (HSP60), a DAMP ligand for TLR4, was observed in CHF cardiomyocytes under a confocal microscope. The maximum binding capacity (Bmax) of TLR4 was increased for LPS and HSP60, whereas the binding affinity (Kd) was not significantly changed. Furthermore, both LPS and HSP60 induced more robust production of inflammatory cytokines in CHF cardiomyocytes, which was reduced by TLR4‐blocking antibodies. We conclude that the expression, ligand‐binding capacity and pro‐inflammatory function of cardiomyocyte TLR4 are up‐regulated after long‐term MI, which promote inflammation and exacerbate heart failure.

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Section: Discussionsupporting

confidence: 54%

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Liu

Yin

Cao

et al. 2015

J Cellular Molecular Medi

140

108

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“…The discrepant results may be attributed to the use of neonatal rather than embryonic CMC. Finally, a very recent study on transgenic mice showed that myocardial ischemia activates an innate immune signaling via HSP60 and toll-like receptor (TLR)4 that in turn plays an important role in mediating apoptosis and inflammation during I/R [28]. All together, these data show that the involvement of HSP60 in CMC apoptosis is a controversial topic that we will address in the following paragraph.…”

Section: Hsp60 Can Protect Cardiomyocytes From Ischaemia/reperfusion mentioning

confidence: 97%

Heat Shock Protein-60 and Risk for Cardiovascular Disease

Rizzo¹,

Macario²,

Macario³

et al. 2011

CPD

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Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide. There is growing evidence that molecular chaperones, many of which are heat shock proteins HSPs, are involved in CVD pathogenesis. In this review we focus on HSP60, the human mitochondrial chaperone that also displays extramitochondrial and extracellular functions. HSP60 is typically cytoprotective but a number of stress conditions determine its conversion to a potentially toxic molecule for cells and tissues. We present illustrative examples of specific subtypes of CVD where HSP60 is implicated in the initiation and/or progression of disease. The data not only indicate a pathogenic role for HSP60 but also its potential as a biomarker with applications for diagnosis, assessing prognosis and response to treatment, as well as for preventing and treating CVD.

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“…Knockout mouse studies have proven useful for identifying specific roles for DAMP receptors in modulating cardiac remodelling after injury or stress (summarised in Table 1). Global knockout or deficiency of TLR2 [34][35][36][37][38][39], TLR3 [40,41] and TLR4 [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56] generally confers improvement of cardiac function and less adverse remodelling after injury, although detrimental effects have also been reported in TLR2 knockout mice [57]. In contrast to the perceived detrimental roles of TLRs 2, 3 and 4 in post-MI remodelling, a recent study suggested that TLR5 may play a beneficial role in protecting the heart from ischaemia/reperfusion injury [58].…”

Section: Damp Receptors and Cardiac Remodellingmentioning

confidence: 99%

“…A number of HSPs are also known to act as DAMPs when released from necrotic cells including HSP60, HSP70 and HSP27. The inflammatory response to myocardial ischaemia/reperfusion is mediated in part via cellular release of cardiac HSP60 acting via TLR4 to induce cardiomyocyte apoptosis and cytokine release [51,109], although it is not clear whether CF play a role in this. HSP70 is also released into the circulation early after MI, and extracellular HSP70 stimulated inflammatory cytokine release from monocytes via TLR4 [110].…”

Section: Heat Shock Proteinsmentioning

confidence: 99%

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

Turner

2016

Journal of Molecular and Cellular Cardiology

169

124

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Cardiac fibroblasts (CF) are well-established as key regulators of extracellular matrix (ECM) turnover in the context of myocardial remodelling and fibrosis. Recently, this cell type has also been shown to act as a sensor of myocardial damage by detecting and responding to damage-associated molecular patterns (DAMPs) upregulated with cardiac injury. CF express a range of innate immunity pattern recognition receptors (TLRs, NLRs, IL-1R1, RAGE) that are stimulated by a host of different DAMPs that are evident in the injured or remodelling myocardium. These include intracellular molecules released by necrotic cells (heat shock proteins, high mobility group box 1 protein, S100 proteins), proinflammatory cytokines (interleukin-1), specific ECM molecules up-regulated in response to tissue injury (fibronectin-EDA, tenascin-C) or molecules modified by a pathological environment (advanced glycation end product-modified proteins observed with diabetes). DAMP receptor activation on fibroblasts is coupled to altered cellular function including changes in proliferation, migration, myofibroblast transdifferentiation, ECM turnover and production of fibrotic and inflammatory paracrine factors, which directly impact on the heart's ability to respond to injury. This review gives an overview of the important role played by CF in responding to myocardial DAMPs and how the DAMP/CF axis could be exploited experimentally and therapeutically.3

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Myocardial Ischemia Activates an Injurious Innate Immune Signaling via Cardiac Heat Shock Protein 60 and Toll-like Receptor 4

Cited by 130 publications

References 64 publications

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Heat Shock Protein-60 and Risk for Cardiovascular Disease

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

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