Following myocardial infarction, the heart repairs itself via a fibrotic repair response. The degree of fibrosis is determined by the balance between deposition of extracellular matrix by activated fibroblasts and breakdown of nascent scar tissue by proteases that are secreted predominantly by inflammatory cells. Excessive proteolytic activity and matrix turnover has been observed in human heart failure and protease inhibitors in the injured heart regulate matrix breakdown. Serine protease inhibitors (Serpins) represent the largest and the most functionally diverse family of evolutionary conserved protease inhibitors and levels of the specific Serpin, SerpinA3, have been strongly associated with clinical outcomes in human myocardial infarction as well as non-ischemic cardiomyopathies. Yet, the role of Serpins in regulating cardiac remodeling is poorly understood. We observed the robust expression of Serpins in the infarcted murine heart and demonstrate that genetic deletion of SerpinA3n (mouse homolog of SerpinA3) leads to increased activity of substrate proteases, poorly compacted matrix and significantly worse post infarct cardiac function. Single cell transcriptomics complemented with histology in SerpinA3n deficient animals, demonstrated increased inflammation, adverse myocyte hypertrophy and expression of pro-hypertrophic genes. Proteomic analysis of scar tissue demonstrated decreased cross linking of extracellular matrix peptides consistent with increased proteolysis in SerpinA3n deficient animals. Taken together these observations demonstrate a hitherto unappreciated causal role of Serpins in regulating matrix function and post infarct cardiac remodeling.

中文翻译：

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丝氨酸蛋白酶抑制剂 SerpinA3n 调节心肌梗死后的心脏重塑

心肌梗塞后，心脏通过纤维化修复反应进行自我修复。纤维化的程度取决于活化的成纤维细胞沉积细胞外基质和主要由炎症细胞分泌的蛋白酶分解新生疤痕组织之间的平衡。在人类心力衰竭中观察到过度的蛋白水解活性和基质周转，并且受损心脏中的蛋白酶抑制剂调节基质分解。丝氨酸蛋白酶抑制剂 (Serpin) 代表了最大且功能最多样化的进化保守蛋白酶抑制剂家族，并且特定 Serpin (SerpinA3) 的水平与人类心肌梗塞以及非缺血性心肌病的临床结果密切相关。然而，人们对丝氨酸蛋白酶抑制剂在调节心脏重塑中的作用知之甚少。我们观察到梗塞小鼠心脏中 Serpin 的强烈表达，并证明 SerpinA3n（SerpinA3 的小鼠同源物）的基因缺失会导致底物蛋白酶活性增加、基质压实不良以及梗塞后心脏功能显着恶化。单细胞转录组学与 SerpinA3n 缺陷动物的组织学互补，证明炎症增加、不利的肌细胞肥大和促肥大基因的表达。疤痕组织的蛋白质组学分析表明，细胞外基质肽的交联减少，这与 SerpinA3n 缺陷动物中蛋白水解的增加一致。综上所述，这些观察结果证明了丝氨酸蛋白酶抑制剂在调节基质功能和梗塞后心脏重塑中迄今未被认识到的因果作用。