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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 (
-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 ) and activity (P<0.05). -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 -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 -AR stimulation. Conclusion: CsA normalized the blunted -AR responsiveness associated with hypertension, in part, by mitigating calcineurin activity while improving PLB phosphorylation and subsequent SR Ca2+ regulation.
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