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 α (PPARα). We tested the hypothesis that down-regulation of PPARα is an essential component of cardiac hypertrophy at the levels of increased mass, gene expression, and metabolism by pharmacologically reactivating PPARα. 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 α-actin), decreased expression of PPARα and PPARα-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 PPARα agonist WY-14,643 (8 days) did not affect the trophic response or atrial natriuretic factor induction to pressure overload. However, PPARα activation blocked skeletal α-actin induction, reversed the down-regulation of measured PPARα-regulated genes in the hypertrophied heart, and prevented substrate switching. This PPARα reactivation concomitantly resulted in severe depression of cardiac power and efficiency in the hypertrophied heart (measured ex vivo ). Thus, PPARα down-regulation is essential for the maintenance of contractile function of the hypertrophied heart.