Effect of pioglitazone on expression of hypoxia-inducible factor 1α and vascular endothelial growth factor in ischemic hindlimb of diabetic rats

M. Zhang, X. Gao, S.-j. Bai, X.-m. Ye, J. Zhang

Department of Endocrinology, Qingpu Branch, Zhongshan Hospital, Fudan University, China. zhangjianmin0608@163.com

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• Metabolism

OBJECTIVE: 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.

MATERIALS AND METHODS: 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.

RESULTS: 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).

CONCLUSIONS: 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.

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