Background: Endothelial dysfunction is closely associated with the pathogenesis of cardiovascular diseases. Cardiovascular systems have different isoforms of cytochrome P450 (CYPs) which generate epoxyeicosatrienoic acids (EETs) considered as EDHFs and implicated in cardiovascular pathophysiology by regulating several signaling cascades affecting inflammation, proliferation and apoptosis. Studies have shown that CYP2J2 expression is regulated by PPAR慣 and activation of CYP epoxygenases lead to an antiinflammatory effect, and which is potential therapeutic target for vascular disease in DM. Here, we examine the relation between CYP2J3 (homologous to human CYP2J2) and PPAR慣 in DM induced rat hearts. Methods: PPAR慣 agonist fenofibrate and antagonist GW6471 were administrated for 2 weeks to ob-/ob- rats. Acetylcholine (ACh)-induced vasodilation was measured in thoracic aortic ring. PPAR慣 and CYP2J3 protein and mRNA expression were determined by Western blot and RT-PCR. 11,12-EET was measured by LC/MS. TNF慣 induced NF-kB expression was examined in CYP2J2 overexpressed BAECs. Results: Expression of CYP2J3 and 11,12-EET were significantly reduced by PPAR慣 dependent manner in ob-/ob- rat hearts. Concurrently, ACh-induced vasodilation in aortic ring was decreased. Fenofibrate recovered CYP2J3 expression, 11,12-EET activity and improves ACh-induced vasodilation. Administration of GW6471 decreased CYP2J3 expression and 11,12-EET level in ob-/ob- rats. TNF慣 induced NF-kB activation was reduced by fenofibrate, whereas, GW6471 and PPAR慣 siRNA reduced the CYP2J2 expression and did not inhibit NF-kB expression in CYP2J2 overexpressed BAECs. Conclusions: Suppressed activity of CYP2J3 and 11,12-EET may contribute to endothelial dysfunction in ob-/ob- rat hearts. NF-kB expression is reduced by CYP2J2 and PPAR慣 dependent manner. These results suggest that PPAR慣 may be involved in the regulation of CYP2J3 expression and 11,12-EET synthesis, which represent a endogenous pathway to maintain endothelial function in DM.