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1 Merck Sharp & Dohme Cardiovascular Research Center, 2 Institute for Surgical Research, 3 Department of Cardiology, and 4 Institute of Pathology, National Hospital, University of Oslo, N-0027 Oslo, Norway
Calcineurin
has recently been implicated as a mediator in the signaling
pathways that transform intracellular calcium signals to the phenotype
of myocardial hypertrophy. The present study was conducted to examine
the effects of cyclosporin A (CsA), an inhibitor of calcineurin, on
myocardial hypertrophy and remodeling during congestive heart failure
(CHF) in rats. After ligation of the left coronary artery, rats were
randomized to treatment with CsA or vehicle for 14 days. Compared with
vehicle, CsA substantially attenuated myocardial hypertrophy in the CHF
rats as assessed by alterations in ventricular weight-to-tibial length
ratios (P < 0.05). Myocardial gene expression of
skeletal 
-actin was also reduced in the failing left ventricle (LV)
after treatment with CsA (P < 0.05), although the mRNA
levels were still substantially elevated relative to those of sham
rats. CsA-induced inhibition of compensatory myocardial hypertrophy in
the CHF rats led to increased dilatation of the LV cavity and reduced
fractional shortening and peak positive and negative first derivatives
of LV pressure (P < 0.05). Plasma renin and
endothelin-1 levels were increased in the CHF-CsA rats, providing
humoral cues of aggravated cardiac function. Thus this study supports a
crucial role of calcineurin-dependent pathways in the mechanisms of
compensatory myocardial hypertrophy during CHF. In addition, our data
indicate that inhibition of compensatory myocardial hypertrophy exerts
detrimental effects on cardiac remodeling and function after myocardial infarction.
calcineurin; myocardium; heart failure
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