Key result
Extracellular S100A1 is significantly elevated in the serum of patients with acute myocardial infarction and acts as a beneficial alarmin by inducing an immunomodulatory and anti-fibrotic phenotype in cardiac fibroblasts via TLR4.
Why the study?
Does extracellular S100A1 modulate myocardial inflammation, infarct size, and left ventricular function following myocardial infarction?
Does extracellular S100A1 modulate myocardial inflammation, infarct size, and left ventricular function following myocardial infarction?
p-value: p=0.004
S100A1 acts as a novel cardiac alarmin released from necrotic cardiomyocytes that promotes an immunomodulatory and anti-fibrotic phenotype in cardiac fibroblasts, exerting a beneficial net effect on post-MI healing.
May support S100A1 modulation as post-MI therapy axis; leaves open effects on inflammation, infarct size, and LV function in humans.
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-κB. 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.
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Rohde et al. (2014) studied Acute ST-segment elevation myocardial infarction (STEMI) (n=24). S100A1 release vs. Controls without acute cardiac events was evaluated on S100A1 serum peak concentrations (p=0.004). Extracellular S100A1 is significantly elevated in the serum of patients with acute myocardial infarction and acts as a beneficial alarmin by inducing an immunomodulatory and anti-fibrotic phenotype in cardiac fibroblasts via TLR4.
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