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Gender Influences on Sarcoplasmic Reticulum Ca2+-handling in Failing Human Myocardium

https://doi.org/10.1006/jmcc.2001.1394Get rights and content

Abstract

Gender has recently been implicated as an important modulator of cardiovascular disease. However, it is not known how gender may specifically influence the Ca2+-handling deficits that characterize the depressed cardiac contractility of human heart failure. To elucidate the contributory role of gender to sarcoplasmic reticulum (SR) Ca2+cycling alterations, the protein levels of SR Ca2+-ATPase (SERCA), phospholamban, and calsequestrin, as well as the site-specific phospholamban phosphorylation status, were quantified in a mixed gender population of failing (n=14) and donor (n=15) myocardia. The apparent affinity (EC50) and the maximal velocity (Vmax) of SR Ca2+-uptake were also determined to lend functional significance to any observed protein alterations. Phospholamban and calsequestrin levels were not altered; however, SERCA protein levels were significantly reduced in failing hearts. Additionally, phospholamban phosphorylation (serine-16 and threonine-17 sites) and myocardial cAMP content were both attenuated. The alterations in SR protein levels were also accompanied by a decreased Vmaxand an increased EC50(diminished apparent affinity) of SR Ca2+-uptake for Ca2+in failing myocardia. Myocardial protein levels and Ca2+uptake parameters were then analyzed with respect to gender, which revealed that the decreases in phosphorylated serine-16 were specific to male failing hearts, reflecting increases in the EC50values of SR Ca2+-uptake for Ca2+, compared to donor males. These findings suggest that although decreased SERCA protein and phospholamban phosphorylation levels contribute to depressed SR Ca2+-uptake and left ventricular function in heart failure, the specific subcellular alterations which underlie these effects may not be uniform with respect to gender.

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    Both authors contributed equally to this work. Please address all correspondence to: E. G. Kranias, Department of Pharmacology & Cell Biophysics, University of Cincinnati, 231 Albert B. Sabin Way, Cincinnati OH 45267-0575, USA. Fax: 513-558-2269.E-mail: [email protected] paper was guest edited by Gerd P. Hasenfuss, M.D.

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