Activation of PPAR-α in the early stage of heart failure maintained myocardial function and energetics in pressure-overload heart failure

Failing heart loses its metabolic flexibility, relying increasingly on glucose as its preferential substrate and decreasing fatty acid oxidation (FAO). Peroxisome proliferator-activated receptor alpha (PPAR-alpha) is a key reg- ulator of this substrate shift. However, its role during heart failure is complex and remains unclear. Recent studies reported that heart failure develops in the heart of myosin heavy chain-PPAR-alpha transgenic mice in a manner similar to that of diabetic cardiomyopathy, whereas cardiac dysfunction is enhanced in PPAR-alpha knockout mice in response to chronic pressure overload. We created a pressure-overload heart failure model in mice through transverse aortic constriction (TAC) and activated PPAR-alpha during heart failure using an inducible transgenic model. alphafter 8 wk of TAC, left ventricular (LV) function had decreased with the reduction of PPAR-alpha expression in wild-type mice. We examined the effect of PPAR-alpha induction during heart failure using the Tet-Off system. Eight weeks after the TAC opera- tion, LV construction was preserved significantly by PPAR-alpha induction with an increase in PPAR-alpha-targeted genes related to fatty acid metabolism. The increase of expression of fibrosis-related genes was significantly attenuated by PPAR-alpha induction. Metabolic rates mea- sured by isolated heart perfusions showed a reduction in FAO and glucose oxidation in TAC hearts, but the rate of FAO preserved significantly owing to the induction of PPAR-alpha. Myocardial high- energy phosphates were significantly preserved by PPAR-alpha induction. These results suggest that PPAR-alpha activation during pressure-over- loaded heart failure improved myocardial function and energetics. Thus activating PPAR-alpha and modulation of FAO could be a promis- ing therapeutic strategy for heart failure.