Division of Cardiology, Department of Medicine, University of California, 675 Charles E Young Drive South, Los Angeles, California, 90095 CA, USA.
Cardiovascular Theme, David Geffen School of Medicine, University of California, 675 Charles E Young Drive South, Los Angeles, California, 90095 CA, USA.
Cardiovasc Res. 2024 Jul 2;120(8):943-953. doi: 10.1093/cvr/cvae075.
Following myocardial infarction (MI), the heart repairs itself via a fibrotic repair response. The degree of fibrosis is determined by the balance between deposition of extracellular matrix (ECM) 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 MI as well as non-ischaemic cardiomyopathies. Yet, the role of Serpins in regulating cardiac remodelling is poorly understood. The aim of this study was to understand the role of Serpins in regulating scar formation after MI.
Using a SerpinA3n conditional knockout mice model, we observed the robust expression of Serpins in the infarcted murine heart and demonstrate that genetic deletion of SerpinA3n (mouse homologue 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 ECM peptides consistent with increased proteolysis in SerpinA3n-deficient animals.
Our study demonstrates a hitherto unappreciated causal role of Serpins in regulating matrix function and post-infarct cardiac remodelling.
心肌梗死后（MI），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激活的成纤维细胞沉积细胞外基质（ECM）的程度和蛋白酶分解新生瘢痕组织的程度，这些蛋白酶主要由炎症细胞分泌。在人类心力衰竭中观察到过度的蛋白水解活性和基质转化，受伤心脏中的蛋白酶抑制剂可调节基质分解。丝氨酸蛋白酶抑制剂（Serpins）是进化上保守的最大和功能最多样化的蛋白酶抑制剂家族，特定 Serpin，SerpinA3 的水平与人 MI 以及非缺血性心肌病的临床结局密切相关。然而，Serpins 在调节心脏重塑中的作用仍知之甚少。本研究旨在了解 Serpins 在调节 MI 后瘢痕形成中的作用。
使用 SerpinA3n 条件性敲除小鼠模型，我们观察到 Serpins 在梗死的鼠心中强烈表达，并证明 SerpinA3n（SerpinA3 的小鼠同源物）的基因缺失导致底物蛋白酶活性增加、基质疏松、梗死后心脏功能显著恶化。SerpinA3n 缺陷型动物的单细胞转录组学与组织学补充表明炎症增加、心肌不良肥大和促肥大基因表达增加。瘢痕组织的蛋白质组学分析表明 ECM 肽的交联减少，与 SerpinA3n 缺陷型动物中增加的蛋白水解作用一致。
我们的研究表明 Serpins 在调节基质功能和梗死后心脏重塑方面具有以前未被认识到的因果作用。
