Failing heart loses its metabolic flexibility, relying increasingly on glucose as its preferential substrate and decreasing fatty acid oxidation (FAO). Peroxisome proliferator-activated receptor α (PPARα) is a key regulator 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 MHC-PPARαmice in a manner similar to that of diabetic cardiomyopathy, whereas cardiac dysfunction is enhanced in PPARα 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 PPARα during heart failure using an inducible transgenic model. After eight weeks of TAC, left ventricular (LV) function had decreased with the reduction of PPARα expression in wild-type mice. We examined the effect of PPARα induction during heart failure using the Tet-Off system. Eight weeks after the TAC operation, LV construction was preserved significantly by PPARα induction with an increase in PPARα targeted genes related to fatty acid metabolism. The increase of expression of fibrosis-related genes was significantly attenuated by PPARα induction. Metabolic rates measured 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 PPARα. Myocardial high-energy phosphates were significantly preserved by PPARα induction. These results suggest that PPARα activation during pressure-overloaded heart failure improved myocardial function and energetics. Thus, activating PPARα and modulation of FAO could be a promising therapeutic strategy for heart failure.
- heart failure
- energy metabolism
- fatty acid oxidation
- PPAR alfa
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology