Induction of heme oxygenase-1 ameliorates vascular dysfunction in streptozotocin-induced type 2 diabetic rats

摘要

Aims: To explore the effects of heme oxygenase-1 (HO-1) on vascular dysfunction in high fat diet streptozotocin-induced type 2 diabetic (T2D) rats. Methods: Rats received a high-fat diet followed by a low dose of streptozotocin (30. mg/kg) to induce T2D. T2D rats were treated with hemin (1, 5, or 25. mg/kg) or carbon monoxide-releasing molecule-2 (CORM-2, 5. mg/kg) for 4. weeks. Isometric contractions of aortic rings were measured. The expression of cyclooxygenase-2 (COX-2) and activities of HO, SOD, and MDA were evaluated. Results: The fasting blood glucose, blood insulin levels, and IR index in T2D rats were higher than those in the control group, which were ameliorated by HO-1 inducer hemin. The antidiabetic effect was accompanied by enhanced HO activity. The vascular relaxation response to ACh was decreased in T2D rats, while treatment with hemin could prevent such decrease in vasorelaxation. An increase in COX-2 expression was found in the aortas of T2D rats. Treatment of T2D rats with COX-2 inhibitor NS398 restored ACh-induced vasodilation. COX-2 overexpression in T2D rats was inhibited by hemin. Hemin treatment also inhibited the decline of SOD activity and the increase of MDA content in the aorta of T2D rats. CORM-2, an agent which releases the HO-1 product CO, could mimic the beneficial effect of hemin. Conclusion: Induction of HO-1 with hemin ameliorates the abnormality of endothelium-dependent vascular relaxation in T2D rats. A possible mechanism involves suppression of reactive oxygen species production and inhibition of COX-2 up-regulation induced by diabetes mellitus.