Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, Farmington Avenue, Farmington, CT, USA.
J Mol Cell Cardiol. 2011 Jan;50(1):239-47. doi: 10.1016/j.yjmcc.2010.11.002. Epub 2010 Nov 11.
Oxidative stress plays a crucial role in disruption of neovascularization by alterations in thioredoxin 1 (Trx1) expression and its interaction with other proteins after myocardial infarction (MI). We previously showed that Trx1 has angiogenic properties, but the possible therapeutic significance of overexpressing Trx1 in chronic MI has not been elucidated. Therefore, we explored the angiogenic and cardioprotective potential of Trx1 in an in vivo MI model using transgenic mice overexpressing Trx1. Wild-type (W) and Trx1 transgenic (Trx1(Tg/+)) mice were randomized into W sham (WS), Trx1(Tg/+) sham (TS), WMI, and TMI. MI was induced by permanent occlusion of LAD coronary artery. Hearts from mice overexpressing Trx1 exhibited reduced fibrosis and oxidative stress and attenuated cardiomyocyte apoptosis along with increased vessel formation compared to WMI. We found significant inhibition of Trx1 regulating proteins, TXNIP and AKAP 12, and increased p-Akt, p-eNOS, p-GSK-3β, HIF-1α, β-catenin, VEGF, Bcl-2, and survivin expression in TMI compared to WMI. Echocardiography performed 30days after MI revealed significant improvement in myocardial functions in TMI compared to WMI. Our study identifies a potential role for Trx1 overexpression and its association with its regulatory proteins TXNIP, AKAP12, and subsequent activation of Akt/GSK-3β/β-catenin/HIF-1α-mediated VEGF and eNOS expression in inducing angiogenesis and reduced ventricular remodeling. Hence, Trx1 and other proteins identified in our study may prove to be potential therapeutic targets in the treatment of ischemic heart disease.
氧化应激在心肌梗死（MI）后通过硫氧还蛋白 1（Trx1）表达的改变及其与其他蛋白质的相互作用导致新生血管形成受损中起关键作用。我们之前表明 Trx1 具有血管生成特性，但过表达 Trx1 在慢性 MI 中的可能治疗意义尚未阐明。因此，我们使用过表达 Trx1 的转基因小鼠在体内 MI 模型中探索了 Trx1 的血管生成和心脏保护潜力。野生型（W）和 Trx1 转基因（Trx1（Tg / +））小鼠被随机分为 W 假手术（WS）、Trx1（Tg / +）假手术（TS）、WMI 和 TMI。通过永久闭塞 LAD 冠状动脉诱导 MI。与 WMI 相比，过表达 Trx1 的心脏表现出减少的纤维化和氧化应激，减弱的心肌细胞凋亡以及增加的血管形成。我们发现 Trx1 调节蛋白 TXNIP 和 AKAP 12 的显著抑制，以及 p-Akt、p-eNOS、p-GSK-3β、HIF-1α、β-catenin、VEGF、Bcl-2 和 survivin 在 TMI 中的表达增加，与 WMI 相比。MI 后 30 天进行的超声心动图显示 TMI 中心肌功能的显著改善与 WMI 相比。我们的研究确定了过表达 Trx1 及其与调节蛋白 TXNIP、AKAP12 的关联以及随后激活 Akt/GSK-3β/β-catenin/HIF-1α 介导的 VEGF 和 eNOS 表达在诱导血管生成和减少心室重构中的潜在作用。因此，我们研究中鉴定的 Trx1 和其他蛋白质可能被证明是治疗缺血性心脏病的潜在治疗靶点。
