Most Patrick, Seifert Hanna, Gao Erhe, Funakoshi Hajime, Völkers Mirko, Heierhorst Jörg, Remppis Andrew, Pleger Sven T, DeGeorge Brent R, Eckhart Andrea D, Feldman Arthur M, Koch Walter J
Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Circulation. 2006 Sep 19;114(12):1258-68. doi: 10.1161/CIRCULATIONAHA.106.622415. Epub 2006 Sep 4.
Diminished cardiac S100A1 protein levels are characteristic of ischemic and dilated human cardiomyopathy. Because S100A1 has recently been identified as a Ca2+-dependent inotropic factor in the heart, this study sought to explore the pathophysiological relevance of S100A1 levels in development and progression of postischemic heart failure (HF).
S100A1-transgenic (STG) and S100A1-knockout (SKO) mice were subjected to myocardial infarction (MI) by surgical left anterior descending coronary artery ligation, and survival, cardiac function, and remodeling were compared with nontransgenic littermate control (NLC) and wild-type (WT) animals up to 4 weeks. Although MI size was similar in all groups, infarcted S100A1-deficient hearts (SKO-MI) responded with acute contractile decompensation and accelerated transition to HF, rapid onset of cardiac remodeling with augmented apoptosis, and excessive mortality. NLC/WT-MI mice, displaying a progressive decrease in cardiac S100A1 expression, showed a later onset of cardiac remodeling and progression to HF. Infarcted S100A1-overexpressing hearts (STG-MI), however, showed preserved global contractile performance, abrogated apoptosis, and prevention from cardiac hypertrophy and HF with superior survival compared with NLC/WT-MI and SKO-MI. Both Gq-protein-dependent signaling and protein kinase C activation resulted in decreased cardiac S100A1 mRNA and protein levels, whereas Gs-protein-related signaling exerted opposite effects on cardiac S100A1 abundance. Mechanistically, sarcoplasmic reticulum Ca2+ cycling and beta-adrenergic signaling were severely impaired in SKO-MI myocardium but preserved in STG-MI.
Our novel proof-of-concept study provides evidence that downregulation of S100A1 protein critically contributes to contractile dysfunction of the diseased heart, which is potentially responsible for driving the progressive downhill clinical course of patients with HF.
心脏S100A1蛋白水平降低是人类缺血性和扩张型心肌病的特征。由于S100A1最近被确定为心脏中一种依赖钙的变力因子，本研究旨在探讨S100A1水平在缺血性心力衰竭（HF）发生发展中的病理生理相关性。
通过手术结扎左前降支冠状动脉使S100A1转基因（STG）和S100A1基因敲除（SKO）小鼠发生心肌梗死（MI），并与非转基因同窝对照（NLC）和野生型（WT）动物比较长达4周的生存率、心脏功能和重塑情况。尽管所有组的MI大小相似，但梗死的S100A1缺陷心脏（SKO-MI）出现急性收缩功能失代偿，并加速向HF转变，心脏重塑迅速开始，伴有凋亡增加和死亡率过高。NLC/WT-MI小鼠心脏S100A1表达逐渐降低，心脏重塑出现较晚且进展为HF。然而，梗死的S100A1过表达心脏（STG-MI）与NLC/WT-MI和SKO-MI相比，整体收缩功能得以保留，凋亡被消除，预防了心脏肥大和HF，生存率更高。Gq蛋白依赖性信号传导和蛋白激酶C激活均导致心脏S100A1 mRNA和蛋白水平降低，而Gs蛋白相关信号传导对心脏S100A1丰度产生相反影响。机制上，SKO-MI心肌中的肌浆网钙循环和β-肾上腺素能信号传导严重受损，但在STG-MI中得以保留。
我们这项新颖的概念验证研究提供了证据，表明S100A1蛋白的下调对患病心脏的收缩功能障碍起关键作用，这可能是导致HF患者临床病情逐渐恶化的原因。
