Reduced endoglin activity limits cardiac fibrosis and improves survival in heart failure.
Reduced endoglin activity limits cardiac fibrosis and improves survival in heart failure.
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DOI：
10.1161/circulationaha.111.080002
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发表时间：
2012-06-05
期刊：
影响因子：
37.8
通讯作者：
Karas RH
中科院分区：
文献类型：
--
作者：
Kapur NK;Wilson S;Yunis AA;Qiao X;Mackey E;Paruchuri V;Baker C;Aronovitz MJ;Karumanchi SA;Letarte M;Kass DA;Mendelsohn ME;Karas RH
心力衰竭是世界范围内发病率和死亡率的主要原因。转化生长因子β1(β1)是一种普遍表达的细胞因子，可促进心脏纤维化，而心肌纤维化是进展性心力衰竭的重要组成部分。膜相关的endoglin是转化生长因子β-1信号的共同受体，已被研究在血管重塑和子痫前期中。我们推测，内皮源性蛋白表达减少可能会限制心力衰竭患者的心脏纤维化。我们首次报道了心力衰竭受试者左心室(LV)中Endoglin的表达增加，并利用中和抗体和小干扰RNA方法确定了转化生长因子β1在人心脏成纤维细胞中的信号转导需要Enoglin。我们进一步证实，在压力超负荷所致心力衰竭的小鼠模型中，减少endoglin的表达可以减轻心脏纤维化，保护左心功能，并提高存活率。先前的研究表明，Endoglin的胞外区可以被切割并以可溶性Enoglin(Seng)的形式释放到循环中，从而扰乱内皮细胞内转化生长因子β1的信号转导。我们现在证明了Seng限制了转化生长因子β1信号转导和心脏成纤维细胞I型胶原的合成，并进一步证明了Seng治疗可以减轻在体心衰模型中的心脏纤维化。我们的研究结果表明，Endoglin是心脏成纤维细胞中转化生长因子β1信号的关键成分，靶向Endoglin可以减轻心脏纤维化，从而为心力衰竭患者提供一种潜在的新的治疗方法。
Heart failure is a major cause of morbidity and mortality worldwide. The ubiquitously expressed cytokine, transforming growth factor beta-1 (TGFβ1), promotes cardiac fibrosis, an important component of progressive heart failure. Membrane-associated endoglin is a co-receptor for TGFβ1 signaling and has been studied in vascular remodeling and preeclampsia. We hypothesized that reduced endoglin expression may limit cardiac fibrosis in heart failure. We first report that endoglin expression is increased in the left ventricle (LV) of human subjects with heart failure and determined that endoglin is required for TGFβ1 signaling in human cardiac fibroblasts using neutralizing antibodies and a siRNA approach. We further identified that reduced endoglin expression attenuates cardiac fibrosis, preserves LV function, and improves survival in a mouse model of pressure-overload induced heart failure. Prior studies have shown that the extracellular domain of endoglin can be cleaved and released into the circulation as soluble endoglin (sEng), which disrupts TGFβ1 signaling in endothelium. We now demonstrate that sEng limits TGFβ1 signaling and Type I collagen synthesis in cardiac fibroblasts and further show that sEng treatment attenuates cardiac fibrosis in an in vivo model of heart failure. Our results identify endoglin as a critical component of TGFβ1 signaling in the cardiac fibroblast and that targeting endoglin attenuates cardiac fibrosis, thereby providing a potentially novel therapeutic approach for individuals with heart failure.