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.

中文翻译：

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ONOO介导的细胞外基质氧化修饰通过影响血管平滑肌细胞的生物学行为加重动脉粥样硬化

动脉粥样硬化 (AS) 是人类中风和冠心病的主要原因，其特征是慢性低度炎症。细胞外基质 (ECM) 在调节动脉功能中起关键作用。然而，很少研究 ECM 变化对 AS 发展的影响。在这种情况下，我们打算研究氧化剂过氧亚硝酸盐（ONOO ^-) 介导的 ECM 蛋白氧化对血管平滑肌细胞 (SMC) 的生物学行为和 AS 的发展。建立AS小鼠模型，体外培养小鼠冠状动脉平滑肌细胞（MCASMCs），通过脱氧胆酸盐（DOC）脱细胞获得ECM（SMC-ECM）。此外，对 MCASMCs 进行了 ECM 氧化损伤和 ECM 蛋白结构的测定。最后，通过 Transwell 分析、转录组测序和基因富集分析探索了 ONOO ^{-介导的 ECM 氧化在 SMC 粘附和迁移以及 AS 发育中的作用。}在 AS 小鼠血清中发现高浓度 ONOO ^{-和 ONOO -}可以促进 AS 的发展。通过 DOC 处理可以在体外获得结构完整的 SMC-ECM。在功能上，ONOO ^-介导的氧化破坏了 SMC-ECM 蛋白的三维结构，影响了 SMC 的粘附和迁移，提高了脂质的吸收效率，同时减少了胆固醇的流出。此外，在经受 ONOO ^-介导的氧化作用的 ECM 中，炎症和氧化应激相关基因的表达显着增加，从而促进了 AS 的进展。ONOO ^-介导的 ECM 氧化修饰通过影响 SMC 的生物学行为加重 AS。