Abstract 12476: Increased Cytochrome P4502E1 Expression and Altered Hydroxyeicosatetraenoic Acid Formation Mediate Diabetic Vascular Dysfunction: Rescue by Guanylyl-Cyclase Activation
Background: We investigated the mechanisms underlying vascular endothelial and contractile dysfunction in diabetes as well as the effect of HMR1766, a novel nitric oxide (NO)-independent activator of soluble guanylyl cyclase (sGC).
Methods: Diabetes was induced by single intravenous injection of streptozotocin (50 mg/ml) in male Wistar rats. Two weeks after induction of diabetes rats were treated with either placebo or HMR1766 (10 mg/kg twice daily) for another 2 weeks. After a total 4 weeks of hyperglycaemia, vascular function was assessed by organ bath studies and vascular protein expression was studied by RNA microarrays and Western Blot.
Results: Endothelial function and contractile vasomotor responses were significantly impaired, while vascular superoxide formation was increased in the aorta from diabetic versus healthy control rats. Cytochrome P4502E1 (CYP2E1) was identified as the highest upregulated gene in diabetic aorta using RNA microarrays. CYP2E1 protein was significantly increased (16-fold) in diabetic aorta. CYP2E1 is the source of the vasomodulators 18- and 19-HETE, which were both significantly increased in diabetes and are known to reduce 20-hydroxy-eicosatetraenoic acid (20-HETE), a potent vasoconstrictor. Induction of CYP2E1 expression by isoniazide in healthy rats mimicked the diabetic non-contractile vascular response. Pre-incubation of aortae from STZ-diabetic rats in vitro with 20-HETE rescued contractile function. cGMP is an endogenous inhibitor of CYP2E1. Since cGMP levels/signalling are dramatically reduced during diabetic endothelial dysfunction, chronic sGC acticvation was performed in vivo for the last 2 weeks using the novel sGC activator HMR1766. Chronic treatment with HMR1766 improved NO sensitivity and endothelial function, reduced CYP2E1 expression and superoxide formation, lowered 19-HETE and enhanced 20-HETE levels, and reversed the contractile deficit observed in placebo-treated diabetic rats.
Conclusions: Upregulation of CYP2E1 is essentially involved in diabetic vascular dysfunction. Chronic treatment with the sGC activator HMR1766 reduced oxidative stress, decreased CYP2E1 levels, and normalized vasomotor function in diabetic rats.
- © 2010 by American Heart Association, Inc.