Cyclosporin A inhibits cardiac hypertrophy and enhances cardiac dysfunction during postinfarction failure in rats

Calcineurin has recently been implicated as a mediator in the signaling pat hways that transform intracellular calcium signals to the phenotype of myoc ardial hypertrophy. The present study was conducted to examine the effects of cyclosporin A (CsA), an inhibitor of calcineurin, on myocardial hypertro phy and remodeling during congestive heart failure (CHF) in rats. After lig ation of the left coronary artery, rats were randomized to treatment with C sA or vehicle for 14 days. Compared with vehicle, CsA substantially attenua ted myocardial hypertrophy in the CHF rats as assessed by alterations in ve ntricular weight-to-tibial length ratios (P< 0.05). Myocardial gene express ion of skeletal alpha-actin was also reduced in the failing left ventricle (LV) after treatment with CsA (P< 0.05), although the mRNA levels were stil l substantially elevated relative to those of sham rats. CsA-induced inhibi tion of compensatory myocardial hypertrophy in the CHF rats led to increase d dilatation of the LV cavity and reduced fractional shortening and peak po sitive and negative first derivatives of LV pressure (P< 0.05). Plasma reni n and endothelin-1 levels were increased in the CHF-CsA rats, providing hum oral cues of aggravated cardiac function. Thus this study supports a crucia l role of calcineurin-dependent pathways in the mechanisms of compensatory myocardial hypertrophy during CHF. In addition, our data indicate that inhi bition of compensatory myocardial hypertrophy exerts detrimental effects on cardiac remodeling and function after myocardial infarction.