Objectives: 
Diabetic cardiomyopathy is associated with suppression of cardiac autophagy, the underlying mechanisms of autophagy in diabetic cardiomyopathy have been poorly understood. Peroxisome proliferator-activated receptor α (PPAR-α) activation mediates autophagy to inhibit inflammation and protect against acute heart failure. Cytochrome P450 epoxygenase 2J (CYP2J) and its metabolites are ligands for the PPAR-α, however, the role of CYP2J2 in autophagy is not known in diabetic cardiomyopathy. Thus, this study was designed to investigate decreased CYP2J expression and its metabolite are associated with diminished autophagy in diabetic ob-/ob- rats with diabetic cardiomyopathy. 

Methods: 
Otsuka Long Evans Tokushima Fatty (OLETF) and its counterpart Long Evans Tokushima Otsuka (LETO) as controls rat were used of type II diabetes animal model with obesity. OLEFT and LETO were started to intake high glucose diet (20% sucrose) at age 12 weeks and fenofibrate were administered to LETO (n=7) and OLETF (n=7) for 2 weeks. Expression of CYP2J3, PPAR-, and autophagy marker LC-II, Beclin-1 was detected by western blot and RT-PCR in control and fenofibrate treated ob-/ob- rats. Following parameters were measured at 30 weeks: blood pressure, heart rate, LVDP and LVEDP.

Results: 
The expression of CYP2J3 and PPAR- protein and mRNA were markedly decreased and the expression of LC-II, Beclin-1 were also decreased in ob-/ob- rats. Administration of PPAR- agonist fenofibrate restored the expression of PPAR- and CYP2J3, and subsequently induced the expression of LC-II and Beclin-1. Blood pressure, heart rate, LVDP and LVEDP were improved corresponding to protein expression. The treatment of CYP2J3 siRNA abolished LC-II, Beclin-1 expression, in addition , administration of fenofibrate and 11,12-EET significantly induced LC-II and Beclin-1 expression in H2O2 treated H9C2 cells.

Conclusions: 
Decreased CYP2J3 and PPAR- expression induce the reduction of cardiac autophagy in ob-/ob- rats. Thus, the enhancement of PPAR- and CYP2J and its metabolite 11,12-EET may represent a novel approach to prevent diabetic cardiomyopathy via the activation of autophagy.

04 - CYTOCHROME EPOXYGENASE P450 2J PROMOTE PPAR Α -MEDIATED AUTOPHAGY IN OB-/OB- RATS