Reactivation of peroxisome proliferator-activated receptor α is associated with contractile dysfunction in hypertrophied rat heart

In pressure overload-induced hypertrophy, the heart increases its reliance on glucose as a fuel while decreasing fatty acid oxidation. A key regulator of this substrate switching in the hypertrophied heart is peroxisome proliferator-activated receptor alpha (PPAR alpha). We tested the hypothesis that down-regulation of PPAR alpha is an essential component of cardiac hypertrophy at the levels of increased mass, gene expression, and metabolism by pharmacologically reactivating PPA alpha. Pressure overload (induced by constriction of the ascending aorta for 7 days in rats) resulted in cardiac hypertrophy, increased expression of fetal genes (atrial natriuretic factor and skeletal alpha -actin), decreased expression of PPAR alpha and PPAR alpha -regulated genes (medium chain acyl-CoA dehydrogenase and pyruvate dehydrogenase kinase 4), and caused substrate switching (measured ex vivo in the isolated working heart preparation). Treatment of rats with the specific PPAR alpha agonist WY-14,643 (8 days) did not affect the trophic response or atrial natriuretic factor induction to pressure overload. However, PPAR alpha activation blocked skeletal alpha -actin induction, reversed the down-regulation of measured PPAR alpha -regulated genes in the hypertrophied heart, and prevented substrate switching. This PPAR alpha reactivation concomitantly resulted in severe depression of cardiac power and efficiency in the hypertrophied heart (measured ex vivo). Thus, PPAR alpha down-regulation is essential for the maintenance of contractile function of the hypertrophied heart.