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Am J Physiol Heart Circ Physiol (September 7, 2007). doi:10.1152/ajpheart.00687.2007
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Submitted on June 13, 2007
Accepted on September 6, 2007

Calcineurin Inhibition Normalizes Beta-Adrenergic Responsiveness in the Spontaneously Hypertensive Rat

Scott M MacDonnell1, Hajime Kubo2, David M Harris3, Xiongwen Chen1, Remus Berretta1, Mary F Barbe4, Stephen Kolwicz5, Patricia O Reger5, Andrea D Eckhart3, Brian F Renna5, Walter J. Koch6, Steven R Houser7, and Joseph R. Libonati5*

1 Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States
2 Physiology, Temple University School of Medicine, Pennsylvania, United States
3 Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
4 Physical Therapy, Temple University School of Medicine, Philadelphia, Pennsylvania, United States
5 Kinesiology, Temple University, Philadelphia, Pennsylvania, United States
6 Translational Medicine, Jefferson Medical College, Philadelphia, Pennsylvania, United States
7 Physiology, Cardiovascular Research Center, Temple University, Philadelphia, Pennsylvania, United States

* To whom correspondence should be addressed. E-mail: joseph.libonati{at}temple.edu.

Objective: 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). Methods and Results: Female SHR (age: 7 months) and age matched female Wistar Kyoto (WKY) rats were studied. Heart weight to body weight ratio (P<0.01) and systolic blood pressure (P<0.01) were greater in SHR compared to WKY and were associated with increased myocardial calcineurin mRNA (CnA{beta} ) 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 cyclosporine 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 (tau) and magnitude of diastolic Ca2+ during {beta}-AR stimulation. Conclusion: CsA normalized the blunted {beta}-AR responsiveness associated with hypertension, in part, by mitigating calcineurin activity while improving PLB phosphorylation and subsequent SR Ca2+ regulation.




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