Innate immunity and cardiomyocytes in ischemic heart disease

Lin, Li; Knowlton, Anne A

doi:10.1016/j.lfs.2014.01.062

Cited by 73 publications

(86 citation statements)

References 92 publications

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“…Most of the studies addressing cardiomyocyte TLR4 were performed in models of acute ischaemia/reperfusion. While multiple studies show that systemic deficiency of TLR4 alleviates myocardial inflammation and injury following acute ischaemia/reperfusion 7, 11, 33, controversies exist as to the causal role of cardiomyocyte TLR4 ( versus leucocyte TLR4). In isolated perfused mouse heart subjected to global ischaemia and reperfusion, Ao et al .…”

Section: Discussionmentioning

confidence: 99%

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

Liu

Yin

Cao

et al. 2015

J Cellular Molecular Medi

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139

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: Discussionmentioning

confidence: 99%

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

Liu

Yin

Cao

et al. 2015

J Cellular Molecular Medi

Self Cite

139

108

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“…Immediately after an ischemic insult, cardiac remodeling is initiated by a transient inflammatory response triggered through danger‐associated molecular (DAMP) patterns and cytokines released from injured cardiomyocytes, attracting immune cells into the infarcted area 5, 6. Once the wound is “cleared” and the inflammatory phase is repressed, fibroblasts are activated and recruited, followed by their proliferation and differentiation into myofibroblasts 7, 8.…”

Section: Introductionmentioning

confidence: 99%

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soppert

Kraemer

Beckers

et al. 2018

JAHA

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BackgroundAlthough macrophage migration inhibitory factor (MIF) has been demonstrated to mediate cardioprotection in ischemia/reperfusion injury and antagonize fibrotic effects through its receptor, CD74, the function of the soluble CD74 receptor ectodomain (sCD74) and its interaction with circulating MIF have not been explored in cardiac disease.Methods and ResultsCardiac fibroblasts were isolated from hearts of neonatal mice and differentiated into myofibroblasts. Co‐treatment with recombinant MIF and sCD74 induced cell death (P<0.001), which was mediated by receptor‐interacting serine/threonine‐protein kinase (RIP)1/RIP3‐dependent necroptosis (P=0.0376). This effect was specific for cardiac fibroblasts and did not affect cardiomyocytes. Gene expression analyses using microarray and RT‐qPCR technology revealed a 4‐fold upregulation of several interferon‐induced genes upon co‐treatment of myofibroblasts with sCD74 and MIF (Ifi44: P=0.011; Irg1: P=0.022; Clec4e: P=0.011). Furthermore, Western blot analysis confirmed the role of sCD74 as a modulator of MIF signaling by diminishing MIF‐mediated protein kinase B (AKT) activation (P=0.0197) and triggering p38 activation (P=0.0641). We obtained evidence that sCD74 inhibits MIF‐mediated survival pathway through the C‐X‐C chemokine receptor 4/AKT axis, enabling the induction of CD74‐dependent necroptotic processes in cardiac myofibroblasts. Preliminary clinical data revealed a lowered sCD74/MIF ratio in heart failure patients (17.47±10.09 versus 1.413±0.6244).ConclusionsThese findings suggest that treatment of cardiac myofibroblasts with sCD74 and MIF induces necroptosis, offering new insights into the mechanism of myofibroblast depletion during scar maturation. Preliminary clinical data provided first evidence about a clinical relevance of the sCD74/MIF axis in heart failure, suggesting that these proteins may be a promising target to modulate cardiac remodeling and disease progression in heart failure.

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“…Extensive experimental evidence suggests persistent activation of the innate immune system is considered to be deleterious to the heart, although the initial immune response provides a short-term adaptive response to limit the cardiac injury [1,14,18,28,30]. In the infarcted heart, an excessive inflammatory activation is sufficient to cause maladaptive remodeling, by inducing death of surviving cardiomyocytes and enhancing ischemic myocardial injury [3,9,14,22,37].…”

Section: Introductionmentioning

confidence: 99%

MCP-1-induced protein attenuates post-infarct cardiac remodeling and dysfunction through mitigating NF-κB activation and suppressing inflammation-associated microRNA expression

et al. 2015

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MCP-1-induced protein (MCPIP, also known as ZC3H12A) has recently been uncovered to act as a negative regulator of inflammation. Expression of MCPIP was elevated in the ventricular myocardium of patients with ischemic heart failure. However, the role of MCPIP in the development of post-infarct cardiac inflammation and remodeling is unknown. The objective of the present study was to investigate whether MCPIP exerts an inhibitory effect on the cardiac inflammatory response and adverse remodeling after myocardial infarction (MI). Mice with cardiomyocyte-specific expression of MCPIP and their wild-type littermates (FVB/N) were subjected to permanent ligation of left coronary artery. The levels of MCPIP were significantly increased in the ischemic myocardium and sustained for 4 weeks after MI. Acute infarct size was comparable between groups. However, constitutive overexpression of MCPIP in the murine heart resulted in improved survival rate, decreased cardiac hypertrophy, less of fibrosis and scar formation, and better cardiac performance at 28 days after MI, along with a markedly reduced monocytic cell infiltration, less cytokine expression, decreased caspase-3/7 activities and apoptotic cell death compared to the wild-type hearts. Cardiomyocyte-specific expression of MCPIP also attenuated activation of cardiac NF-κB signaling and expression of inflammation-associated microRNAs (miR-126, -146a, -155, and -199a) when compared with the post-infarct wild-type hearts. In vitro, MCPIP expression suppressed hypoxia-induced NF-κB-luciferase activity in cardiomyocytes. In conclusion, MCPIP expression in the ischemic myocardium protects against adverse cardiac remodeling and dysfunction following MI by modulation of local myocardial inflammation, possibly through mitigating NF-κB signaling and suppressing inflammation-associated microRNA expression.

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Innate immunity and cardiomyocytes in ischemic heart disease

Cited by 73 publications

References 92 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

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

MCP-1-induced protein attenuates post-infarct cardiac remodeling and dysfunction through mitigating NF-κB activation and suppressing inflammation-associated microRNA expression

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