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Am J Physiol Heart Circ Physiol 293: H3122-H3129, 2007. First published September 7, 2007; doi:10.1152/ajpheart.00687.2007
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Calcineurin inhibition normalizes beta-adrenergic responsiveness in the spontaneously hypertensive rat

Scott M. MacDonnell,1 Hajime Kubo,1 David M. Harris,5 Xiongwen Chen,1 Remus Berretta,1 Mary F. Barbe,3 Stephen Kolwicz,2 Patricia O. Reger,2 Andrea Eckhart,5 Brian F. Renna,2 Walter J. Koch,5 Steven R. Houser,1,4 and Joseph R. Libonati1,2,4

1Cardiovascular Research Center and the Departments of 2Kinesiology, 3Physical Therapy, and 4Physiology, Temple University, Philadelphia; and 5Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania

Submitted 13 June 2007 ; accepted in final form 6 September 2007

Calcineurin, a Ca2+-regulated protein phosphatase, links myocardial Ca2+ signaling with hypertrophic gene transcription. Calcineurin abundance increases in pressure-overload hypertrophy and may reduce agonist-mediated phospholamban (PLB) phosphorylation to underlie blunted beta-adrenergic receptor (beta-AR) responsiveness in hypertension. This hypothesis was tested by measuring the effects of calcineurin inhibition on changes in cardiac contractility caused by beta-adrenergic stimulation in spontaneously hypertensive rats (SHR). Female SHR (age: 7 mo) and age-matched female Wistar-Kyoto rats (WKY) were studied. Heart weight-to-body weight ratio (P < 0.01) and systolic blood pressure (P < 0.01) were greater in SHR compared with WKY and were associated with increased myocardial calcineurin mRNA (CnAbeta) and activity (P < 0.05). beta-AR stimulation with isoproterenol (Iso) increased calcineurin activity (P < 0.05) in both WKY and SHR hearts, and this activity was suppressed with cyclosporin A (CsA) treatment. In SHR, CsA improved left ventricular whole heart and isolated myocyte beta-AR responsiveness by normalizing PLB phosphorylation at Ser16 and Thr17 (P < 0.05). These CsA-induced, PLB-mediated effects were associated with an augmentation in cardiomyocyte peak Ca2+ and a reduced rate (time constant of isovolumic pressure relaxation, tau) and magnitude of diastolic Ca2+ during beta-AR stimulation. In conclusion, CsA normalized the blunted beta-AR responsiveness associated with hypertension, in part, by mitigating calcineurin activity while improving PLB phosphorylation and subsequent sarcoplasmic reticulum Ca2+ regulation.

myocardium; hypertrophy; phosphatase; protein kinase A; calcium calmodulin kinase II


Address for reprint requests and other correspondence: J. R. Libonati, Temple Univ., 122 Pearson Hall, 1800 N. Broad St., Philadelphia, PA 19122 (e-mail: jlibonat{at}temple.edu)




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