硫氧还蛋白-1 基因治疗增强糖尿病大鼠梗死心肌中的血管生成信号转导并减少心室重构。

Thioredoxin-1 gene therapy enhances angiogenic signaling and reduces ventricular remodeling in infarcted myocardium of diabetic rats.

机构信息

Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030-1110, USA.

出版信息

Circulation. 2010 Mar 16;121(10):1244-55. doi: 10.1161/CIRCULATIONAHA.109.872481. Epub 2010 Mar 1.

DOI:10.1161/CIRCULATIONAHA.109.872481

PMID:20194885

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2852871/

Abstract

BACKGROUND

The present study evaluated the reversal of diabetes-mediated impairment of angiogenesis in a myocardial infarction model of type 1 diabetic rats by intramyocardial administration of an adenoviral vector encoding thioredoxin-1 (Ad.Trx1). Various studies have linked diabetes-mediated impairment of angiogenesis to dysfunctional antioxidant systems in which thioredoxin-1 plays a central role.

METHODS AND RESULTS

Ad.Trx1 was administered intramyocardially in nondiabetic and diabetic rats immediately after myocardial infarction. Ad.LacZ was similarly administered to the respective control groups. The hearts were excised for molecular and immunohistochemical analysis at predetermined time points. Myocardial function was measured by echocardiography 30 days after the intervention. The Ad.Trx1-administered group exhibited reduced fibrosis, oxidative stress, and cardiomyocyte and endothelial cell apoptosis compared with the diabetic myocardial infarction group, along with increased capillary and arteriolar density. Western blot and immunohistochemical analysis demonstrated myocardial overexpression of thioredoxin-1, heme oxygenase-1, vascular endothelial growth factor, and p38 mitogen-activated protein kinase-beta, as well as decreased phosphorylated JNK and p38 mitogen-activated protein kinase-alpha, in the Ad.Trx1-treated diabetic group. Conversely, we observed a significant reduction in the expression of vascular endothelial growth factor in nondiabetic and diabetic animals treated with tin protoporphyrin (SnPP, a heme oxygenase-1 enzyme inhibitor), even after Ad.Trx1 therapy. Echocardiographic analysis after 4 weeks of myocardial infarction revealed significant improvement in myocardial functional parameters such as ejection fraction, fractional shortening, and E/A ratio in the Ad.Trx1-administered group compared with the diabetic myocardial infarction group.

CONCLUSIONS

This study demonstrates for the first time that impairment of angiogenesis and myocardial dysfunction can be regulated by Ad.Trx1 gene therapy in streptozotocin-induced diabetic rats subjected to infarction.

摘要

背景

本研究通过心肌内给予转硫蛋白-1（Trx1）腺病毒载体，评估了在 1 型糖尿病大鼠心肌梗死模型中逆转糖尿病引起的血管生成损伤的作用。多项研究表明，糖尿病引起的血管生成损伤与功能失调的抗氧化系统有关，而 Trx1 在其中起着核心作用。

方法和结果

在心肌梗死后立即，将 Ad.Trx1 心肌内给予非糖尿病和糖尿病大鼠。将 Ad.LacZ 类似地给予各自的对照组。在预定时间点切除心脏进行分子和免疫组织化学分析。超声心动图在干预后 30 天测量心肌功能。与糖尿病心肌梗死组相比，Ad.Trx1 给药组的纤维化、氧化应激、心肌细胞和内皮细胞凋亡减少，毛细血管和小动脉密度增加。Western blot 和免疫组织化学分析显示，在 Ad.Trx1 处理的糖尿病组中，心肌过表达 Trx1、血红素加氧酶-1、血管内皮生长因子和 p38 丝裂原活化蛋白激酶-β，同时磷酸化 JNK 和 p38 丝裂原活化蛋白激酶-α减少。相反，我们观察到在非糖尿病和糖尿病动物中，使用锡原卟啉（SnPP，血红素加氧酶-1 酶抑制剂）治疗后，血管内皮生长因子的表达显著减少，即使在给予 Ad.Trx1 治疗后也是如此。心肌梗死后 4 周的超声心动图分析显示，与糖尿病心肌梗死组相比，Ad.Trx1 给药组的射血分数、缩短分数和 E/A 比等心肌功能参数显著改善。