Functional, cellular, and molecular characterization of the angiogenic response to chronic myocardial ischemia in diabetes
Functional, cellular, and molecular characterization of the angiogenic response to chronic myocardial ischemia in diabetes
复制标题
DOI：
10.1161/circulationaha.106.680157
复制
发表时间：
2007-09-11
期刊：
影响因子：
37.8
通讯作者：
Sellke, Frank W.
中科院分区：
文献类型：
--
作者：
Boodhwani, Munir;Sodha, Neel R.;Sellke, Frank W.
背景-缺血性心脏病是糖尿病患者最常见的死亡原因。虽然治疗性血管生成对这些患者来说是一个有吸引力的选择，但他们似乎减少了心肌缺血时的侧支形成。本研究旨在建立糖尿病和慢性心肌缺血的大型动物模型，评估糖尿病对血管生成反应的影响，并阐明其中的分子通路。方法和结果-使用胰腺β细胞特异性毒素四氧嘧啶（150 mg/kg; n = 8）诱导雄性尤卡坦迷你酒患糖尿病。对照组为8头年龄匹配的猪。诱导8周后，在旋转冠状动脉周围放置ameroid缩窄器诱导慢性缺血。在ameroid放置后3周和7周使用同位素标记微球评估心肌灌注和功能。观察内皮细胞密度和血管生成介质的心肌表达。糖尿病动物表现出明显的内皮功能障碍。糖尿病动物侧支依赖性灌注和左室功能明显受损。糖尿病动物内皮细胞密度也降低（173 +/- 14 vs 234 +/- 23细胞/hpf， P = 0.03）。VEGF、Ang-1、Tie-2表达降低，抗血管生成蛋白、血管抑制素（angiostatin，升高4.4 +/- 0.9倍，P < 0.001）、内皮抑制素（endostatin，升高2.9 +/- 0.4倍，P = 0.03）显著升高。结论：糖尿病会严重损害心肌对慢性缺血的血管生成反应。本研究中发现的促血管生成和抗血管生成介质为糖尿病血管生成反应的调节提供了新的靶点。
Background - Ischemic heart disease is the most common cause of mortality in diabetic patients. Although therapeutic angiogenesis is an attractive option for these patients, they appear to have reduced collateral formation in response to myocardial ischemia. The aims of this study were to establish a large animal model of diabetes and chronic myocardial ischemia, evaluate the effects of diabetes on the angiogenic response, and elucidate the molecular pathways involved.Methods and Results - Diabetes was induced in male Yucatan miniswine using a pancreatic beta-cell specific toxin, alloxan (150 mg/kg; n = 8). Age-matched swine served as controls (n = 8). Eight weeks after induction, chronic ischemia was induced by ameroid constrictor placement around the circumflex coronary artery. Myocardial perfusion and function were assessed at 3 and 7 weeks after ameroid placement using isotope-labeled microspheres. Endothelial cell density and myocardial expression of angiogenic mediators was evaluated. Diabetic animals exhibited significant endothelial dysfunction. Collateral dependent perfusion and LV function were significantly impaired in diabetic animals. Diabetic animals also demonstrated reduced endothelial cell density (173 +/- 14 versus 234 +/- 23 cells/hpf, P = 0.03). Expression of VEGF, Ang-1, and Tie-2 was reduced, whereas antiangiogenic proteins, angiostatin (4.4 +/- 0.9-fold increase, P < 0.001), and endostatin (2.9 +/- 0.4-fold increase, P = 0.03) were significantly elevated in the diabetic myocardium.Conclusions - Diabetes results in a profound impairment in the myocardial angiogenic response to chronic ischemia. Pro- and antiangiogenic mediators identified in this study offer novel targets for the modulation of the angiogenic response in diabetes.