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 variety of Ca2+-dependent signaling pathways culminating in left ventricular hypertrophy (LVH). Most of the recent experimental support for this hypothesis is derived from in vitro studies or in vivo studies in transgenic mice expressing activated calcineurin or mutant sarcomeric proteins. The aim of the present study was to test whether calcineurin inhibitors, cyclosporin A (CsA) and FK 506, prevent pressure-overload LVH using 2 standard rat models: (1) the spontaneously hypertensive rat (SHR) and (2) aortic banding. The major new findings are 2-fold. First, in SHR, LVH (left ventricular weight 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 calcineurin-mediated transcriptional activation in skeletal muscle. Second, in rats with 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 sufficient to inhibit 90% of total calcineurin phosphatase activity in the hypertrophied myocardium. In the latter experiments, CsA blocked neither the elevated left ventricular end-diastolic pressures, a measure of diastolic function, nor the induction in atrial natriuretic peptide mRNA in the hypertrophic ventricles. Thus, in numerous experiments, systemic administration of potent calcineurin inhibitors did not prevent the development of LVH in 2 classic models of pressure-overload hypertrophy. These results demonstrate that pressure-overload hypertrophy can arise through calcineurin-independent pathways.
Zhang
W
W
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Tex. 75235-8586, USA.
Kowal
R C
RC
Rusnak
F
F
Sikkink
R A
RA
Olson
E N
EN
Victor
R G
RG
D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology; D019703:Calcineurin / Q000502:physiology; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D008026:Ligation; D008297:Male; D011183:Postoperative Complications / Q000401:mortality; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000494:pharmacology
D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D019703:Calcineurin; D016559:Tacrolimus