© 2000 American Heart Association, Inc.
Integrative Physiology |
Sarcoplasmic Reticulum Ca2+/Calmodulin-Dependent Protein Kinase Is Altered in Heart Failure
From the Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre and Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Correspondence to Naranjan S. Dhalla, Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, 351 Taché Ave, Winnipeg, Manitoba R2H 2A6, Canada. E-mail cvso{at}sbrc.umanitoba.ca
Abstract—Although Ca2+/calmodulin-dependent protein kinase-II (CaMK) is known to phosphorylate different Ca2+ cycling proteins in the cardiac sarcoplasmic reticulum (SR) and regulate its function, the status of CaMK in heart failure has not been investigated previously. In this study, we examined the hypothesis that changes in the CaMK-mediated phosphorylation of the SR Ca2+ cycling proteins are associated with heart failure. For this purpose, heart failure in rats was induced by occluding the coronary artery for 8 weeks, and animals with >30% infarct of the left ventricle wall plus septum mass were used. Noninfarcted left ventricle was used for biochemical assessment; sham-operated animals served as control. A significant depression in SR Ca2+ uptake and release activities was associated with a decrease in SR CaMK phosphorylation of the SR proteins, ryanodine receptor (RyR), Ca2+ pump ATPase (SR/endoplasmic reticulum Ca2+ ATPase [SERCA2a]), and phospholamban (PLB) in the failing heart. The SR protein contents for RyR, SERCA2a, and PLB were decreased in the failing hearts. Although the SR Ca2+/calmodulin-dependent CaMK activity, CaMK content, and CaMK autophosphorylation were depressed, the SR phosphatase activity was enhanced in the failing heart. On the other hand, the cAMP-dependent protein kinase–mediated phosphorylation of RyR and PLB was not affected in the failing heart. On the basis of these results, we conclude that alterations in SR CaMK-mediated phosphorylation may be partly responsible for impaired SR function in heart failure.
Key Words: Ca2+/calmodulin-dependent protein kinase • cAMP-dependent protein kinase • sarcoplasmic reticulum • myocardial infarction • congestive heart failure
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