Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut Health Center, Farmington, Connecticut, USA.
Diabetes. 2010 Jan;59(1):51-60. doi: 10.2337/db09-0336. Epub 2009 Sep 30.
Hyperglycemia impairs angiogenesis in response to ischemia, leading to ventricular remodeling. Although the effects of overexpressing angiogenic growth factors have been studied in inducing angiogenesis, the formation of functional vessels remains a challenge. The present study evaluates the reversal of diabetes-mediated impairment of angiogenesis in the infarcted diabetic rat myocardium by proangiogenic gene therapy.
AdVEGF and AdAng1 were intramyocardially administered in combination immediately after myocardial infarction to nondiabetic and diabetic rats. Ad*LacZ was similarly administered to the respective control groups. The hearts were excised for molecular and immunohistochemical analysis at predetermined time points. The myocardial function was measured by echocardiography 30 days after the intervention.
We observed reduced fibrosis and increased capillary/arteriolar density along with reduced ventricular remodeling, as assessed by echocardiography in the treated diabetic animals compared with the nontreated diabetic controls. We also observed increased phosphorylated mitogen-activated protein kinase-activated protein kinase-2, 2 days after the treatment and increased expression of vascular endothelial growth factor (VEGF), Flk-1, angiopoietin-1 (Ang-1), Tie-2, and survivin, 4 days after treatment in the diabetic animals. Gel shift analysis revealed that the combination gene therapy stimulated the DNA binding activity of nuclear factor-kappaB in the diabetic animals.
Our preclinical data demonstrate the efficacy of coadministration of adenoviral VEGF and Ang-1 in increasing angiogenesis and reducing ventricular remodeling in the infarcted diabetic myocardium. These unique results call for the initiation of a clinical trial to assess the efficacy of this therapeutic strategy in the treatment of diabetes-related human heart failure.
高血糖会损害缺血后的血管生成，导致心室重构。虽然过表达血管生成生长因子已被用于诱导血管生成，但功能性血管的形成仍然是一个挑战。本研究评估了促血管生成基因治疗逆转糖尿病大鼠心肌梗死后血管生成受损的作用。
在心肌梗死后立即将 AdVEGF 和 AdAng1 经心肌内给药联合用于非糖尿病和糖尿病大鼠。Ad*LacZ 也被类似地用于各自的对照组。在预定的时间点取出心脏进行分子和免疫组织化学分析。干预 30 天后通过超声心动图测量心肌功能。
与未治疗的糖尿病对照组相比，我们观察到治疗的糖尿病动物的纤维化减少，毛细血管/小动脉密度增加，心室重构减少，这通过超声心动图评估。我们还观察到治疗后 2 天糖尿病动物中磷酸化丝裂原活化蛋白激酶激活的蛋白激酶-2 增加，治疗后 4 天血管内皮生长因子（VEGF）、Flk-1、血管生成素-1（Ang-1）、Tie-2 和存活素表达增加。凝胶移位分析显示，联合基因治疗刺激了糖尿病动物核因子-κB 的 DNA 结合活性。
我们的临床前数据表明，共施用腺病毒 VEGF 和 Ang-1 可增加糖尿病大鼠梗死心肌的血管生成并减少心室重构。这些独特的结果呼吁启动一项临床试验，以评估这种治疗策略在治疗与糖尿病相关的人类心力衰竭中的疗效。
