ONOO−‐mediated oxidative modification of extracellular matrix aggravates atherosclerosis by affecting biological behaviors of vascular smooth muscle cells

Abstract Atherosclerosis (AS) is a principal contributor to stroke and coronary heart disease in humans characterized by chronic low‐grade inflammation. The extracellular matrix (ECM) plays critical roles in regulating the function of arteries. However, the effect of changes in ECM on AS development is rarely studied. In this context, we intend to study the effect of oxidizing agent peroxynitrite (ONOO − )‐mediated oxidization of ECM proteins on the biological behaviors of vascular smooth muscle cells (SMCs) and the development of AS. AS mouse models were established, and mouse coronary artery smooth muscle cells (MCASMCs) were cultured in vitro to derive ECM (SMC‐ECM), which was obtained by deoxycholate (DOC)‐based decellularization. Further, MCASMCs were subjected to the determination of ECM oxidative damage and ECM protein structure. Finally, roles of ONOO − ‐mediated oxidization of ECM in SMC adhesion and migration and in AS development were explored through Transwell assay, transcriptome sequencing, and gene enrichment analysis. High concentration of ONOO − was found in the serum of AS mice, and ONOO − could stimulate the development of AS. SMC‐ECM with intact structure can be obtained in vitro by DOC treatment. Functionally, ONOO − ‐mediated oxidization destroyed the three‐dimensional structure of SMC‐ECM proteins, affected SMC adhesion and migration and promoted the absorption efficiency of lipids while reducing the efflux of cholesterol. In addition, the expression of inflammation‐ and oxidative stress‐related genes was significantly increased in ECM subjected to ONOO − ‐mediated oxidization, thereby contributing to AS progression. ONOO − ‐mediated oxidative modification of ECM aggravates AS by affecting the biological behavior of SMCs.