Reactivation of PPARalpha with WY-14,643 in hypertrophied rat hearts prevented substrate switching but resulted in severe depression of cardiac power and efficiency.
Does pharmacological reactivation of PPARalpha with WY-14,643 affect cardiac hypertrophy, gene expression, metabolism, and contractile function in rats with pressure overload-induced hypertrophy?
PPARalpha down-regulation is an essential adaptive mechanism for maintaining contractile function in the hypertrophied heart, as its pharmacological reactivation severely depresses cardiac power.
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 (PPARalpha). We tested the hypothesis that down-regulation of PPARalpha is an essential component of cardiac hypertrophy at the levels of increased mass, gene expression, and metabolism by pharmacologically reactivating PPARalpha. 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 PPARalpha and PPARalpha-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 PPARalpha agonist WY-14,643 (8 days) did not affect the trophic response or atrial natriuretic factor induction to pressure overload. However, PPARalpha activation blocked skeletal alpha-actin induction, reversed the down-regulation of measured PPARalpha-regulated genes in the hypertrophied heart, and prevented substrate switching. This PPARalpha reactivation concomitantly resulted in severe depression of cardiac power and efficiency in the hypertrophied heart (measured ex vivo). Thus, PPARalpha down-regulation is essential for the maintenance of contractile function of the hypertrophied heart.
Young et al. (2001) studied Pressure overload-induced cardiac hypertrophy. PPARalpha agonist WY-14,643 was evaluated on Cardiac mass, gene expression, metabolism, and contractile function. Reactivation of PPARalpha with WY-14,643 in hypertrophied rat hearts prevented substrate switching but resulted in severe depression of cardiac power and efficiency.