Abstract
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.
Highlights
Pressure overload of the heart activates a complex series of interconnected signaling cascades resulting in adaptive responses for the maintenance of a normal cardiac output [1, 2]
Trophic and Gene Expression Markers of Hypertrophy—One week after the initial ascending aortic constriction, the heart weight and the heart weight/body weight ratio both increased, with no effect on body weight (Table I). This trophic response was observed when pressure overload was induced in animals that were treated with the PPAR␣ agonist (Table I)
Chronic reactivation of PPAR␣ in the hypertrophied heart had no effect on the trophic response or the induction of ANF mRNA in response to pressure overload
Summary
Pressure overload of the heart activates a complex series of interconnected signaling cascades resulting in adaptive responses for the maintenance of a normal cardiac output [1, 2]. 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 ␣-actin), decreased expression of PPAR␣ and PPAR␣-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).
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