Calcineurin inhibition normalizes beta-adrenergic responsiveness in the spontaneously hypertensive rat.

Abstract

Calcineurin, a Ca(2+)-regulated protein phosphatase, links myocardial Ca(2+) 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 Ser(16) and Thr(17) (P < 0.05). These CsA-induced, PLB-mediated effects were associated with an augmentation in cardiomyocyte peak Ca(2+) and a reduced rate (time constant of isovolumic pressure relaxation, tau) and magnitude of diastolic Ca(2+) 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 Ca(2+) regulation.

• Authors: Scott M MacDonnell, Hajime Kubo, David M Harris, Xiongwen Chen, Remus Berretta, Mary F Barbe, Stephen Kolwicz, Patricia O Reger, Andrea Eckhart, Brian F Renna, Walter J Koch, Steven R Houser, Joseph R Libonati
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 293 Issue 5 Pg. H3122-9 (Nov 2007) ISSN: 0363-6135 [Print] United States
• PMID: 17827263 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Adrenergic, beta
• Calcineurin
• Calcium

Topics

• Animals
• Calcineurin (metabolism)
• Calcium (metabolism)
• Calcium Signaling
• Cells, Cultured
• Female
• Hypertension (metabolism)
• Myocytes, Cardiac (metabolism)
• Phosphorylation
• Rats
• Rats, Inbred SHR
• Rats, Inbred WKY
• Receptors, Adrenergic, beta (metabolism)