Serine protease inhibitor, SerpinA3n, regulates cardiac remodelling after myocardial infarction

• DOI: 10.1093/cvr/cvae075
• Publication Date: 2024-04-26T09:32:39Z
• Authors: Qihao Sun; Wei Chen; Rimao Wu; Bo Tao; Ping Wang; Baiming Sun; Juan F Alvarez; Feiyang Ma; David Ceja Galindo; Sean P Maroney; Anthony J Saviola; Kirk C Hansen; Shen Li; Arjun Deb
• Keywords: Mice, Knockout; Male; 0303 health sciences; Ventricular Remodeling; Myocardium; Myocardial Infarction; Fibrosis; Ventricular Function, Left; Extracellular Matrix; Mice, Inbred C57BL; Disease Models, Animal; 03 medical and health sciences; Animals; Myocytes, Cardiac; Serpins; Acute-Phase Proteins

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