Glutaredoxin-1 overexpression enhances neovascularization and diminishes ventricular remodeling in chronic myocardial infarction.
Glutaredoxin-1 overexpression enhances neovascularization and diminishes ventricular remodeling in chronic myocardial infarction.
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DOI：
10.1371/journal.pone.0034790
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Maulik N
中科院分区：
文献类型：
--
作者：
Adluri RS;Thirunavukkarasu M;Zhan L;Dunna NR;Akita Y;Selvaraju V;Otani H;Sanchez JA;Ho YS;Maulik N
氧化应激在心力衰竭的病理生理过程中起着关键作用，包括对心肌梗死后新生血管的调节。氧化还原分子硫氧还蛋白(TRX)和谷氧还蛋白(GRX)超家族通过清除活性氧来主动维持细胞内硫醇-氧化还原动态平衡。在这两个超家族中，TRX-1的促血管生成功能在慢性心肌梗死模型中已有报道，而GRX-1的类似作用尚不清楚。本研究试图确定GRX-1在心肌梗死后新生血管和心室重塑中的作用。将野生型(WT)和GRX-1转基因(GRX-1TG/+)小鼠随机分为野生型假手术组(WTS)、GRX-1TG/+Sham(GRX-1TG/+S)、WTMI、GRX-1TG/+MI。永久性结扎左前降支诱发心肌梗死。假手术组在不结扎左前降支的情况下进行相同的时间匹配手术。与WTMI组相比，GRX-1TG/+MI组的小动脉密度在手术干预后7天(D)显著增加。此外，与WTMI组相比，GRX-1TG/+MI组在MI后30d观察到心肌功能参数的改善，包括降低LVIDs、LVIDd、增加射血分数和缩短分数。此外，与WTMI组相比，GRX-1TG/+MI组的氧化应激和心肌细胞凋亡明显减轻。Western印迹分析和凝胶位移分析显示，GRX-1TG/+MI组p-Akt、血管内皮生长因子、Ang-1、Bcl2、Survivin的表达和NF-κB的DNA结合活性分别高于WTMI组。这些结果首次证明GRX-1通过AKT、VEGFAng-1和NF-κB介导的血管新生以及Bcl2和Survivin介导的抗细胞凋亡途径，明显诱导心肌梗死后血管生成，减轻心肌重塑。
Oxidative stress plays a critical role in the pathophysiology of cardiac failure, including the modulation of neovascularization following myocardial infarction (MI). Redox molecules thioredoxin (Trx) and glutaredoxin (Grx) superfamilies actively maintain intracellular thiol-redox homeostasis by scavenging reactive oxygen species. Among these two superfamilies, the pro-angiogenic function of Trx-1 has been reported in chronic MI model whereas similar role of Grx-1 remains uncertain. The present study attempts to establish the role of Grx-1 in neovascularization and ventricular remodeling following MI. Wild-type (WT) and Grx-1 transgenic (Grx-1Tg/+) mice were randomized into wild-type sham (WTS), Grx-1Tg/+ Sham (Grx-1Tg/+S), WTMI, Grx-1Tg/+MI. MI was induced by permanent occlusion of the LAD coronary artery. Sham groups underwent identical time-matched surgical procedures without LAD ligation. Significant increase in arteriolar density was observed 7 days (d) after surgical intervention in the Grx-1Tg/+MI group as compared to the WTMI animals. Further, improvement in myocardial functional parameters 30 d after MI was observed including decreased LVIDs, LVIDd, increased ejection fraction and, fractional shortening was also observed in the Grx-1Tg/+MI group as compared to the WTMI animals. Moreover, attenuation of oxidative stress and apoptotic cardiomyocytes was observed in the Grx-1Tg/+MI group as compared to the WTMI animals. Increased expression of p-Akt, VEGF, Ang-1, Bcl-2, survivin and DNA binding activity of NF-κB were observed in the Grx-1Tg/+MI group when compared to WTMI animals as revealed by Western blot analysis and Gel-shift analysis, respectively. These results are the first to demonstrate that Grx-1 induces angiogenesis and diminishes ventricular remodeling apparently through neovascularization mediated by Akt, VEGF, Ang-1 and NF-κB as well as Bcl-2 and survivin-mediated anti-apoptotic pathway in the infarcted myocardium.
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影响因子：
37.8
作者：
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通讯作者：
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15.9
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Boekstegers, Peter
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