Type V Collagen in Scar Tissue Regulates the Size of Scar after Heart Injury
Type V Collagen in Scar Tissue Regulates the Size of Scar after Heart Injury
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DOI：
10.1016/j.cell.2020.06.030
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发表时间：
2020-08-06
期刊：
影响因子：
64.5
通讯作者：
Deb, Arjun
中科院分区：
文献类型：
--
作者：
Yokota, Tomohiro;McCourt, Jackie;Deb, Arjun
心肌梗塞后的疤痕组织大小是心血管结局的独立预测因素，但人们对调节疤痕大小的因素知之甚少。我们证明，V 型胶原蛋白（心脏疤痕的氨基成分）可调节缺血性损伤后心脏疤痕的大小。 V 型胶原蛋白的消耗导致梗塞后疤痕尺寸反常增大，同时心脏功能恶化。对 100 只近交系小鼠进行的系统遗传学方法表明，V 型胶原蛋白是损伤后心脏功能的关键驱动因素。我们发现，V 型胶原蛋白缺乏会改变疤痕组织的机械特性，并且基质和细胞之间的相互反馈改变会诱导机械敏感性整合素的表达，从而驱动成纤维细胞活化并增加疤痕尺寸。西仑吉肽是一种特定整合素抑制剂，可挽救 V 型胶原蛋白缺陷小鼠损伤后疤痕增加的表型。这些观察结果表明，V 型胶原蛋白以整合素依赖性方式调节疤痕大小。
Scar tissue size following myocardial infarction is an independent predictor of cardiovascular outcomes, yet little is known about factors regulating scar size. We demonstrate that collagen V, aminor constituent of heart scars, regulates the size of heart scars after ischemic injury. Depletion of collagen V led to a paradoxical increase in post-infarction scar size with worsening of heart function. A systems genetics approach across 100 in-bred strains of mice demonstrated that collagen V is a critical driver of postinjury heart function. We show that collagen V deficiency alters the mechanical properties of scar tissue, and altered reciprocal feedback between matrix and cells induces expression of mechanosensitive integrins that drive fibroblast activation and increase scar size. Cilengitide, an inhibitor of specific integrins, rescues the phenotype of increased post-injury scarring in collagen-V-deficient mice. These observations demonstrate that collagen V regulates scar size in an integrin-dependent manner.