Zhang M, Gao X, Bai S-j, Ye X-m, Zhang J
Department of Endocrinology, Qingpu Branch, Zhongshan Hospital, Fudan University, China.
Eur Rev Med Pharmacol Sci. 2014;18(9):1307-14.
To observe effects of the drug pioglitazone on expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in diabetic rats with hindlimb ischemia, and explore the role of pioglitazone in angiogenesis after ischemia and its possible mechanism.
The diabetic rat model was established by high-fat and high-sugar diet and intraperitoneal injection of streptozotocin. The diabetic rats with the unilateral hindlimb ischemia were randomly divided into diabetic model group and pioglitazone treated group, and the normal rats with unilateral hindlimb ischemia were selected as the control group. RT-PCR and Western blotting techniques were employed for analysis and detection of HIF-1α and VEGF expression, as well as detection of capillary density by immunohistochemical staining and ischemic hindlimb perfusion by Doppler ultrasonography were measured.
Compared with the control group, the fasting glucose, fasting insulin, insulin resistance index, total cholesterol, triglycerides and low-density lipoprotein cholesterol in diabetic rats were significantly increased. This was accompanied by increased mRNA and protein expression of HIF-1α and VEGF, and decreased microvessel density (MVD) of the ischemic limb (p < 0.05). The above indicators in pioglitazone-treated diabetic rats were significantly decreased (p < 0.01) with decreased expression of HIF-1α and VEGF (p < 0.01), while the microvessel density (MVD) of the ischemic limb was increased (p < 0.01) and blood perfusion was also increased (p < 0.01). The expression of HIF-1α and VEGF were positively correlated (p < 0.05) in diabetic rats with hind limb angiopathy, while HIF-1α and VEGF were all negatively correlated with the microvessel density (MVD).
HIF-1α and VEGF expression in diabetic rats with hind limb angiopathy were increased. Pioglitazone has a promoting effect on ischemic limb angiogenesis in diabetic rats. It suggested that pioglitazone may improve ischemic limb angiogenesis mechanisms correlated with regulating the HIF-1α/VEGF hypoxia response pathway.
观察吡格列酮对糖尿病后肢缺血大鼠缺氧诱导因子-1α（HIF-1α）和血管内皮生长因子（VEGF）表达的影响，探讨吡格列酮在缺血后血管生成中的作用及其可能机制。
采用高脂高糖饮食联合腹腔注射链脲佐菌素建立糖尿病大鼠模型。将单侧后肢缺血的糖尿病大鼠随机分为糖尿病模型组和吡格列酮治疗组，选取单侧后肢缺血的正常大鼠作为对照组。采用RT-PCR和Western印迹技术分析检测HIF-1α和VEGF表达，通过免疫组织化学染色检测毛细血管密度，并用多普勒超声测量缺血后肢灌注情况。
与对照组相比，糖尿病大鼠空腹血糖、空腹胰岛素、胰岛素抵抗指数、总胆固醇、甘油三酯和低密度脂蛋白胆固醇显著升高。同时伴有缺血肢体HIF-1α和VEGF的mRNA及蛋白表达增加，微血管密度（MVD）降低（p<0.05）。吡格列酮治疗的糖尿病大鼠上述指标显著降低（p<0.01），HIF-1α和VEGF表达降低（p<0.01），而缺血肢体的微血管密度（MVD）增加（p<0.01），血流灌注也增加（p<0.01）。糖尿病后肢血管病变大鼠中HIF-1α和VEGF表达呈正相关（p<0.05），而HIF-1α和VEGF均与微血管密度（MVD）呈负相关。
糖尿病后肢血管病变大鼠HIF-1α和VEGF表达增加。吡格列酮对糖尿病大鼠缺血肢体血管生成有促进作用。提示吡格列酮可能通过调节HIF-1α/VEGF缺氧反应途径改善缺血肢体血管生成机制。
