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Cardiovascular Research 1997 36(1):67-77; doi:10.1016/S0008-6363(97)00183-1
© 1997 by European Society of Cardiology
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Copyright © 1997, European Society of Cardiology

Membrane phosphorylation protects the cardiac sarcoplasmic reticulum Ca2+-ATPase against chlorinated oxidants in vitro

Alexander Y Antipenko and Madeleine A Kirchberger*

Department of Physiology and Biophysics, Box 1218, The Mount Sinai School of Medicine of the City University of New York, 1 Gustave L. Levy Place, New York, NY 10029, USA

* Corresponding author. Tel. (+1-212) 241-6543; fax (+1-212) 860-3369.

Objective: The calcium (Ca) pump of cardiac sarcoplasmic reticulum (SR) membranes is vulnerable to oxidation and hence likely to be damaged by chlorinated compounds, specifically hypochlorite (NaOCl) and monochloramine (NH2Cl), the most potent oxidants produced upon neutrophil activation. This could occur during prolonged ischemia or myocardial infarction when tissue levels of catecholamines are high. Phospholamban (PLN), the phosphorylatable regulator of the Ca pump, plays a central role in the effects of β-adrenergic agonists on the heart. The purpose of this study was to investigate a possible role of PLN in determining the pump's sensitivity to NaOCl and NH2Cl. Methods: Ca-uptake and Ca2+-ATPase activities in purified phosphorylated and control canine cardiac microsomes, incubated at increasing concentrations of NaOCl or NH2Cl, were related to the extent of PLN phosphorylation by protein kinase A, which was quantitated by PhosphorImager analysis. Results and Conclusions: Our data indicate that microsomal phosphorylation protects the Ca pump fully against 10 µM NaOCl or NH2Cl, which inhibit Ca-uptake by 21–41% when assayed at 25 or 37°C and saturating Ca2+ in unphosphorylated microsomes, and protects partially at higher oxidant concentrations. The protective effect of protein kinase A on Ca-uptake is proportional to the amount of phosphorylated PLN. No comparable protection against similar oxidative damage of the Ca pump is observed when light fast skeletal muscle microsomes, which lack PLN, are incubated under conditions favorable for phosphorylation nor when PLN's inhibition of the cardiac Ca pump is relieved by proteolytic cleavage of its cytoplasmic domain. Our findings contribute toward an understanding of possible endogenous protective mechanisms that may promote calcium homeostasis in myocardial cells in inflammatory states associated with neutrophil activation and may suggest an approach toward development of protective strategies against oxidative damage in the heart.

KEYWORDS Sarcoplasmic reticulum; Ca2+-ATPase; Phospholamban; Beta-adrenergic agonists; Myocardial ischemia; Myocardial infarction; Dog, skeletal muscle microsomes


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