Prevention of Fibrosis and Pathological Cardiac Remodeling by Salinomycin.
Prevention of Fibrosis and Pathological Cardiac Remodeling by Salinomycin.
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DOI：
10.1161/circresaha.120.317791
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发表时间：
2021-05-28
影响因子：
20.1
通讯作者：
Small EM
中科院分区：
文献类型：
--
作者：
Burke RM;Dirkx RA Jr;Quijada P;Lighthouse JK;Mohan A;O'Brien M;Wojciechowski W;Woeller CF;Phipps RP;Alexis JD;Ashton JM;Small EM
心肌病的特征是激活的驻留心脏成纤维细胞沉积细胞外基质，称为肌成纤维细胞。目前还没有治疗方法来钝化最终导致心力衰竭的病理性纤维化和脑室僵硬的发展。我们进行了一项高通量筛选，以确定可能限制心力衰竭进展的肌成纤维细胞激活的小分子抑制物。我们评估了多醚离子载体盐霉素在患者来源的心脏成纤维细胞和临床前小鼠缺血性和非缺血性心力衰竭模型中的治疗效果。在这里，我们证明了盐霉素在心力衰竭患者的心脏成纤维细胞中显示出强大的抗纤维化活性。在临床前研究中，盐霉素可预防缺血性和非缺血性心脏病小鼠模型的心脏纤维化和功能衰退。值得注意的是，盐霉素介入治疗可以减轻高血压继发的病理性心脏重构，并限制严重心肌梗死后的瘢痕扩张。从机制上讲，盐霉素通过抑制p38/MAPK(丝裂原活化蛋白激酶)和Rho信号通路来抑制心脏成纤维细胞的激活。盐霉素还可促进心肌细胞存活和增加冠脉血管密度，提示盐霉素的心肌保护作用是通过整合多种相关心肌细胞类型中的多种机制来实现的。这些数据证实盐霉素是一种针对多种心脏保护途径的抗纤维化药物，因此有望用于心力衰竭患者的治疗。本文提供了一个图形摘要。
Cardiomyopathy is characterized by the deposition of extracellular matrix by activated resident cardiac fibroblasts called myofibroblasts. There are currently no therapeutic approaches to blunt the development of pathological fibrosis and ventricle chamber stiffening that ultimately leads to heart failure. We undertook a high-throughput screen to identify small molecule inhibitors of myofibroblast activation that might limit the progression of heart failure. We evaluated the therapeutic efficacy of the polyether ionophore salinomycin in patient-derived cardiac fibroblasts and preclinical mouse models of ischemic and nonischemic heart failure. Here, we demonstrate that salinomycin displays potent anti-fibrotic activity in cardiac fibroblasts obtained from heart failure patients. In preclinical studies, salinomycin prevents cardiac fibrosis and functional decline in mouse models of ischemic and nonischemic heart disease. Remarkably, interventional treatment with salinomycin attenuates preestablished pathological cardiac remodeling secondary to hypertension and limits scar expansion when administered after a severe myocardial infarction. Mechanistically, salinomycin inhibits cardiac fibroblast activation by preventing p38/MAPK (mitogen activated protein kinase) and Rho signaling. Salinomycin also promotes cardiomyocyte survival and improves coronary vessel density, suggesting that cardioprotection conferred by salinomycin occurs via the integration of multiple mechanisms in multiple relevant cardiac cell types. These data establish salinomycin as an antifibrotic agent that targets multiple cardioprotection pathways, thereby holding promise for the treatment of heart failure patients. A graphic abstract is available for this article.