Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA; California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA.
Department of Integrative Biology and Physiology, University of California, CA 90095, USA.
Cell. 2020 Aug 6;182(3):545-562.e23. doi: 10.1016/j.cell.2020.06.030. Epub 2020 Jul 3.
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, a minor 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.
心肌梗死后的疤痕组织大小是心血管结局的独立预测因子，但对于调节疤痕大小的因素知之甚少。我们证明，胶原 V，心脏疤痕的少量成分，调节缺血性损伤后心脏疤痕的大小。胶原 V 的耗竭导致梗塞后疤痕大小的反常增加，心脏功能恶化。对 100 个近交系小鼠进行的系统遗传学方法表明，胶原 V 是损伤后心脏功能的关键驱动因素。我们表明，胶原 V 缺乏会改变疤痕组织的机械性能，基质和细胞之间的相互反馈会改变，从而诱导表达机械敏感性整合素，驱动成纤维细胞激活并增加疤痕大小。西仑吉肽，一种特定整合素的抑制剂，可挽救胶原 V 缺陷型小鼠中损伤后疤痕过度增生的表型。这些观察结果表明，胶原 V 通过整合素依赖性方式调节疤痕大小。
