RESEARCH ARTICLE Energetics and Metabolism: Activation of PPAR-alpha in the early stage of heart failure maintained myocardial function and energetics in pressure-overload heart failure

摘要

Kaimoto S, Hoshino A, Ariyoshi M, Okawa Y, Tateishi S, Ono K, Uchihashi M, Fukai K, Iwai-Kanai E, Matoba S. Activation of PPAR-a in the early stage of heart failure maintained myocardial function and energetics in pressure-overload heart failure. Am J Physiol Heart Circ Physiol 312: H305-H313, 2017. First published December 23, 2016; doi:10.1152/ajpheart.00553.2016.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 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 myosin heavy chain-PPAR-alpha trans-genic 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. After 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 operation, 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 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 PPAR-alpha. Myocardial high-energy phosphates were significantly preserved by PPAR-alpha induction. These results suggest that PPAR-alpha activation during pressure-overloaded heart failure improved myocardial function and energetics. Thus activating PPAR-alpha and modulation of FAO could be a promising therapeutic strategy for heart failure. NEW & NOTEWORTHY The present study demonstrates the role of PPAR-alpha activation in the early stage of heart failure using an inducible transgenic mouse model. Induction of PPAR-alpha preserved heart function, and myocardial energetics. Activating PPAR-alpha and modulation of fatty acid oxidation could be a promising therapeutic strategy for heart failure.