Yang Libang, Gregorich Zachery R, Cai Wenxuan, Zhang Patrick, Young Bernice, Gu Yiwen, Zhang Jianyi, Ge Ying
Division of Cardiology, Department of Medicine, University of Minnesota Medical School , Minneapolis, Minnesota 55455, United States.
Department of Biomedical Engineering, School of Engineering, School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama 35294, United States.
J Proteome Res. 2017 May 5;16(5):2101-2112. doi: 10.1021/acs.jproteome.7b00107. Epub 2017 Apr 7.
Postinfarction remodeling and expansion of the peri-infarct border zone (BZ) directly correlate with mortality following myocardial infarction (MI); however, the cellular and molecular mechanisms underlying remodeling processes in the BZ remain unclear. Herein, we utilized a label-free quantitative proteomics approach in combination with immunohistochemical analyses to gain a better understanding of processes contributing to postinfarction remodeling of the peri-infarct BZ in a swine model of MI with reperfusion. Our analysis uncovered a significant down-regulation of proteins involved in energy metabolism, indicating impaired myocardial energetics and possibly mitochondrial dysfunction, in the peri-scar BZ. An increase in endothelial and vascular smooth muscles cells, as well as up-regulation of proteins implicated in vascular endothelial growth factor (VEGF) signaling and marked changes in the expression of extracellular matrix and subendothelial basement membrane proteins, is indicative of active angiogenesis in the infarct BZ. A pronounced increase in macrophages in the peri-infarct BZ was also observed, and proteomic analysis uncovered evidence of persistent inflammation in this tissue. Additional evidence suggested an increase in cellular proliferation that, concomitant with increased nestin expression, indicates potential turnover of endogenous stem cells in the BZ. A marked up-regulation of pro-apoptotic proteins, as well as the down-regulation of proteins important for adaptation to mechanical, metabolic, and oxidative stress, likely contributes to increased apoptosis in the peri-infarct BZ. The cellular processes and molecular pathways identified herein may have clinical utility for therapeutic intervention aimed at limiting remodeling and expansion of the BZ myocardium and preventing the development of heart failure post-MI.
心肌梗死后梗死周边边界区（BZ）的重塑和扩张与心肌梗死（MI）后的死亡率直接相关；然而，BZ重塑过程背后的细胞和分子机制仍不清楚。在此，我们采用无标记定量蛋白质组学方法结合免疫组织化学分析，以更好地了解在MI再灌注猪模型中梗死周边BZ心肌梗死后重塑的相关过程。我们的分析发现，梗死周边BZ中参与能量代谢的蛋白质显著下调，这表明心肌能量代谢受损，可能存在线粒体功能障碍。内皮细胞和血管平滑肌细胞增加，以及与血管内皮生长因子（VEGF）信号传导相关的蛋白质上调，细胞外基质和内皮下基底膜蛋白表达发生显著变化，表明梗死BZ中存在活跃的血管生成。梗死周边BZ中的巨噬细胞也明显增加，蛋白质组学分析发现该组织中存在持续炎症的证据。其他证据表明细胞增殖增加，同时巢蛋白表达增加，这表明BZ中内源性干细胞可能发生更新。促凋亡蛋白的显著上调，以及对机械、代谢和氧化应激适应重要的蛋白质的下调，可能导致梗死周边BZ中细胞凋亡增加。本文确定的细胞过程和分子途径可能对旨在限制BZ心肌重塑和扩张以及预防MI后心力衰竭发展的治疗干预具有临床应用价值。
