Coadministration of adenoviral vascular endothelial growth factor and angiopoietin-1 enhances vascularization and reduces ventricular remodeling in the infarcted myocardium of type 1 diabetic rats.
Coadministration of adenoviral vascular endothelial growth factor and angiopoietin-1 enhances vascularization and reduces ventricular remodeling in the infarcted myocardium of type 1 diabetic rats.
复制标题
作者：
Samuel SM;Akita Y;Paul D;Thirunavukkarasu M;Zhan L;Sudhakaran PR;Li C;Maulik N
高血糖损害血管生成，以应对缺血，导致心室重构。虽然过度表达血管生成生长因子在诱导血管生成中的作用已被研究，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对糖尿病梗死大鼠心肌血管生成损伤的逆转作用。广告。VEGF和Ad。非糖尿病大鼠和糖尿病大鼠在心肌梗死后立即联合给予Ang1。广告。LacZ同样适用于各自的对照组。在预定的时间点切除心脏进行分子和免疫组织化学分析。干预30天后用超声心动图测定心肌功能。我们观察到，与未治疗的糖尿病对照组相比，接受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。我们还观察到，在治疗后2天，有丝分裂原活化蛋白激酶-活化蛋白激酶-2的磷酸化水平升高；在治疗后4天，糖尿病动物血管内皮生长因子（VEGF）、Flk-1、血管生成素-1 （Ang-1）、Tie-2和survivin的表达升高。凝胶位移分析显示，联合基因治疗可刺激糖尿病动物核因子-κB的DNA结合活性。我们的临床前数据证明了腺病毒VEGF和Ang-1在增加梗死糖尿病心肌血管生成和减少心室重构中的作用。这些独特的结果要求启动临床试验，以评估这种治疗策略在治疗糖尿病相关人类心力衰竭中的疗效。
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. Ad.VEGF and Ad.Ang1 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-κB 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.
登录
查看更多内容
影响因子：
37.8
作者：
Boodhwani, Munir;Sodha, Neel R.;Sellke, Frank W.
通讯作者：
Sellke, Frank W.
影响因子：
64.8
作者：
Risau, W
通讯作者：
Risau, W
影响因子：
37.8
作者：
Chou, E;Suzuma, I;King, GL
通讯作者：
King, GL
影响因子：
10.8
作者：
BANAI, S;SHWEIKI, D;KESHET, E
通讯作者：
KESHET, E
影响因子：
4.8
作者：
Papapetropoulos, A;Fulton, D;Sessa, WC
通讯作者：
Sessa, WC