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(Circulation Research. 1997;80:76-81.)
© 1997 American Heart Association, Inc.

Articles

Hydroxyl Radical Inhibits Sarcoplasmic Reticulum Ca²⁺-ATPase Function by Direct Attack on the ATP Binding Site

Kai Y. Xu, Jay L. Zweier, Lewis C. Becker

the Department of Medicine, Division of Cardiology, The Johns Hopkins Medical Institutions, Baltimore, Md.

Correspondence to Dr Kai Y. Xu, The Johns Hopkins Medical Institutions, Department of Medicine, Cardiology Division, 5501 Hopkins Bayview Circle, Room 3A-29, Baltimore, MD 21224.

Oxygen-derived free radicals have been reported to damage the sarcoplasmic reticulum (SR) Ca²⁺-ATPase, potentially contributing to cellular Ca²⁺ overload and myocardial damage after ischemia and reperfusion. To determine whether the ATP binding site on Ca²⁺-ATPase is involved in oxygen radical injury, SR vesicles containing bound Ca²⁺-ATPase were isolated from rabbit cardiac and skeletal muscle and exposed to a hydroxyl radical (·OH)–generating system consisting of H₂O₂ and Fe³⁺-nitrilotriacetic acid in amounts that generate a magnitude of ·OH similar to that which occurs in the reperfused heart. ·OH exposure completely inhibited Ca²⁺-ATPase activity and SR ⁴⁵Ca uptake for both cardiac and skeletal muscle. In contrast, when the purified vesicles were premixed with l mmol/L ATP before exposure to ·OH, complete protection was observed: there was no loss of ATPase activity or ⁴⁵Ca transport. No significant protection occurred with adenosine, sucrose, AMP, or ADP (l mmol/L each). SDS–gel electrophoresis indicated that ·OH did not damage the primary structure of the enzyme. Electron paramagnetic resonance spin-trapping experiments demonstrated that ATP did not scavenge ·OH. These results suggest that ·OH denatures the SR Ca²⁺-ATPase by directly attacking the ATP binding site, and occupation of the active site by ATP protects against ·OH-induced loss of enzymatic activity and SR Ca²⁺ transport. The depletion of ATP that occurs during ischemia may enhance the toxic effect of ·OH at the time of reperfusion.

Key Words: sarcoplasmic reticulum • Ca²⁺-ATPase • ATP • hydroxyl radical • ischemia/reperfusion

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