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S100A1 is released from ischemic cardiomyocytes and signals myocardial damage via Toll-like receptor 4.

ABSTRACT: Members of the S100 protein family have been reported to function as endogenous danger signals (alarmins) playing an active role in tissue inflammation and repair when released from necrotic cells. Here, we investigated the role of S100A1, the S100 isoform with highest abundance in cardiomyocytes, when released from damaged cardiomyocytes during myocardial infarction (MI). Patients with acute MI showed significantly increased S100A1 serum levels. Experimental MI in mice induced comparable S100A1 release. S100A1 internalization was observed in cardiac fibroblasts (CFs) adjacent to damaged cardiomyocytes. In vitro analyses revealed exclusive S100A1 endocytosis by CFs, followed by Toll-like receptor 4 (TLR4)-dependent activation of MAP kinases and NF-?B. CFs exposed to S100A1 assumed an immunomodulatory and anti-fibrotic phenotype characterized i.e. by enhanced intercellular adhesion molecule-1 (ICAM1) and decreased collagen levels. In mice, intracardiac S100A1 injection recapitulated these transcriptional changes. Moreover, antibody-mediated neutralization of S100A1 enlarged infarct size and worsened left ventricular functional performance post-MI. Our study demonstrates alarmin properties for S100A1 from necrotic cardiomyocytes. However, the potentially beneficial role of extracellular S100A1 in MI-related inflammation and repair warrants further investigation.

SUBMITTER: Rohde D

PROVIDER: S-EPMC4203355 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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S100A1 is released from ischemic cardiomyocytes and signals myocardial damage via Toll-like receptor 4.

Rohde David D Schön Christoph C Boerries Melanie M Didrihsone Ieva I Ritterhoff Julia J Kubatzky Katharina F KF Völkers Mirko M Herzog Nicole N Mähler Mona M Tsoporis James N JN Parker Thomas G TG Linke Björn B Giannitsis Evangelos E Gao Erhe E Peppel Karsten K Katus Hugo A HA Most Patrick P

EMBO molecular medicine 20140406 6

Members of the S100 protein family have been reported to function as endogenous danger signals (alarmins) playing an active role in tissue inflammation and repair when released from necrotic cells. Here, we investigated the role of S100A1, the S100 isoform with highest abundance in cardiomyocytes, when released from damaged cardiomyocytes during myocardial infarction (MI). Patients with acute MI showed significantly increased S100A1 serum levels. Experimental MI in mice induced comparable S100A1 ...[more]

PMID: 24833748

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Project description:This study investigated the hypothesis whether S100A1 gene therapy can improve pathological key features in human failing ventricular cardiomyocytes (HFCMs).Depletion of the Ca²?-sensor protein S100A1 drives deterioration of cardiac performance toward heart failure (HF) in experimental animal models. Targeted repair of this molecular defect by cardiac-specific S100A1 gene therapy rescued cardiac performance, raising the immanent question of its effects in human failing myocardium.Enzymatically isolated HFCMs from hearts with severe systolic HF were subjected to S100A1 and control adenoviral gene transfer and contractile performance, calcium handling, signaling, and energy homeostasis were analyzed by video-edge-detection, FURA2-based epifluorescent microscopy, phosphorylation site-specific antibodies, and mitochondrial assays, respectively.Genetically targeted therapy employing the human S100A1 cDNA normalized decreased S100A1 protein levels in HFCMs, reversed both contractile dysfunction and negative force-frequency relationship, and improved contractile reserve under beta-adrenergic receptor (?-AR) stimulation independent of cAMP-dependent (PKA) and calmodulin-dependent (CaMKII) kinase activity. S100A1 reversed underlying Ca²? handling abnormalities basally and under ?-AR stimulation shown by improved SR Ca²? handling, intracellular Ca²? transients, diastolic Ca²? overload, and diminished susceptibility to arrhythmogenic SR Ca²? leak, respectively. Moreover, S100A1 ameliorated compromised mitochondrial function and restored the phosphocreatine/adenosine-triphosphate ratio.Our results demonstrate for the first time the therapeutic efficacy of genetically reconstituted S100A1 protein levels in HFCMs by reversing pathophysiological features that characterize human failing myocardium. Our findings close a gap in our understanding of S100A1's effects in human cardiomyocytes and strengthen the rationale for future molecular-guided therapy of human HF.

Project description:BackgroundCellular senescence is a stable cell-cycle arrest induced by telomere shortening and various types of cellular stress including oxidative stress, oncogene activation, DNA damage etc. Heme oxygenase-1 (HO-1) is an inducible stress-response protein that plays antioxidant and anti-apoptotic effects. However, the role and underlying mechanisms of HO-1 in cellular senescence in heart are largely unknown.MethodsEchocardiography was employed to detect the effect of HO-1 on heart function in adult mice with myocardial infarction (MI) and aged mice. The senescence markers, p53, p16 and LaminB, were analyzed by western blot. The immunofluorescence and immunohistochemical staining were applied to analyze the expression level of p16. SA-?-Gal staining showed the level of cardiomyocyte senescence.FindingsWe found that hemin significantly induced the expression of HO-1, which notably suppressed cardiomyocyte senescence containing the secretion of senescence-associated secretory phenotype. Further studies showed that systemic HO-1 transgenic overexpression improved heart function by inhibiting aging-induced extracellular matrix deposition and fibrogenesis. More importantly, treatment of hemin improved heart function in MI mice. Furthermore, forced expression of HO-1 blunted cardiomyocyte senescence in natural aged mice and in primary cultured neonatal mouse cardiomyocytes.InterpretationOur study revealed that HO-1 improved heart function and attenuated cardiomyocyte senescence triggered by ischemic injury and aging. In addition, HO-1 induction alleviated H2O2-induced cardiomyocyte senescence. Finally, our study suggested a novel mechanism of HO-1 to play cardioprotective effect. FUND: This study was supported by the National Natural Science Foundation of China (81770284 to Hongli Shan); and the National Natural Science Foundation of China (81673425, 81872863 to Yuhong Zhou). The National Natural Science Foundation of China (81473213 to Chaoqian Xu). National Key R&D Program of China (2017YFC1307403 to Baofeng Yang), National Natural Science Foundation of China (81730012 to Baofeng Yang).

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S100A1 is released from ischemic cardiomyocytes and signals myocardial damage via Toll-like receptor 4.

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S100A1 is released from ischemic cardiomyocytes and signals myocardial damage via Toll-like receptor 4.

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