OBJECTIVE Heme oxygenase-1 (HO-1), an inducible isoform of heme oxygenase, can exert vaso-protective effects.However, such vascular benefit in diabetic vasculopathy remains largely unclear.The present study aims at investigating the impact of HO-1 induction on endothelial function in diabetic db/db mice.METHODS Diabetic db/db and non-diabetic db/m + mice were treated intraperitoneally with hemin (a potent inducer of HO-1) or vehicle for two weeks.The aortae were isolated and suspended in myograph for isometric force measurement; levels of marker proteins were determined by the Western blotting method; nitric oxide (NO) production in cultured human umbilical vein endothelial cells (HUVEC) was estimated using NO-sensitive DAF-DA fluorescence dye.RESULTS Two-week hemin administration augmented endothelium-dependent relaxations in response to acetylcholine in db/db mouse aortae which was antagonized by the co-treatment with the HO-1 inhibitor Sn(Ⅳ) mesoporphyrin Ⅸ dichloride (SnMP) and largely inhibited by the PI3K inhibitor wortmannin and Akt inhibitorV.Overnight treatment with hemin and bilirubin (a metabolic product of HO-1 activity) in organ culture improved endothelial function in db/db mouse aortae and SnMP inhibited the effect of hemin but not that of bilirubin while Akt inhibitor V inhibited the effect of both hemin and bilirubin.Meanwhile hemin treatment increased the phosphorylation level of eNOS and Akt in diabetic mouse aortae.Furthermore, hemin and bilirubin restored the lost NO production and increased eNOS and Akt phosphorylation in HUVECs exposed to high glucose and this effect was inhibited by Akt inhibitor V and dominant-negative Akt transfection which suppresses Akt expression.In addition, hemin treatment also improved the acetylcholine-induced relaxation in renal arteries from diabetic patients.CONCLUSION The present study demonstrates that the PDK/Akt signaling pathway is likelyto mediate the vascular benefit of HO-1 induction in restoring the impaired endothelial function in diabetic mice.The novel findings suggest that HO-1 induction could be a useful strategy for alleviation of diabetes-associated vascular dysfunction.