Failure of calcineurin inhibitors to prevent pressure-overload left ventricular hypertrophy in rats

A rapidly emerging body of literature implicates a pivotal role for the Ca2 +-calmodulin-dependent phosphatase calcineurin as a cellular target for a v ariety of Ca2+-dependent signaling pathways culminating in left ventricular hyper-trophy (LVH). Most of the recent experimental support for this hypot hesis is derived from in vitro studies or in vivo studies in transgenic mic e expressing activated calcineurin or mutant sarcomeric proteins. The aim o f the present study was to test whether calcineurin inhibitors, cyclosporin A (CsA) and FK 506, prevent pressure-overload LVH using 2 standard rat mod els: (1) the spontaneously hypertensive rat (SHR) and (2) aortic banding. T he major new findings are 2-fold. First, in SHR, LVH (left ventricular weig ht to body weight ratio) was unaffected by a dose of CsA (5 mg . kg(-1) . d (-1)) that was sufficient to raise blood pressure and to inhibit calcineuri n-mediated transcriptional activation in skeletal muscle. Second, in rats w ith aortic banding, LVH was unaffected by FK 506 (0.3 mg . kg(-1) . d(-1)) or even higher doses of CsA (10 and 20 mg . kg(-1) . d(-1)) that were suffi cient to inhibit 90% of total calcineurin phosphatase activity in the hyper trophied myocardium. In the latter experiments, CsA blocked neither the ele vated left ventricular end-diastolic pressures, a measure of diastolic func tion, nor the induction in atrial natriuretic peptide mRNA in the hypertrop hic ventricles. Thus, in numerous experiments, systemic administration of p otent calcineurin inhibitors did not prevent the development of LVH in 2 cl assic models of pressure-overload hypertrophy. These results demonstrate th at pressure-overload hypertrophy can arise through calcineurin-independent pathways.