Calmodulin participation in oxygen radical-induced cardiac sarcoplasmic reticulum calcium uptake reduction |
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| Authors: | E Okabe Y Kato H Sasaki G Saito M L Hess H Ito |
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| Affiliation: | 1. Center for Plastic & Reconstructive Surgery, Department of Hand & Reconstructive Surgery, Zhejiang Provincial People''s Hospital, Affiliated People''s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China;2. Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA;3. Department of Orthopaedics, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China;1. National Heart Research Institute Singapore, National Heart Centre, Singapore;2. Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore;3. Institute of Biochemistry, Medical School, Justus-Liebig University, 35392 Giessen, Germany;4. Department of Biochemistry, Medical Faculty, Justus Liebig-University, Giessen, Germany;5. Yong Loo Lin School of Medicine, National University Singapore, Singapore;6. The Hatter Cardiovascular Institute, University College London, London, UK;7. Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan |
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| Abstract: | The effect of scavengers of oxygen radicals on canine cardiac sarcoplasmic reticulum (SR) Ca2+ uptake velocity was investigated at pH 6.4, the intracellular pH of the ischemic myocardium. With the generation of oxygen radicals from a xanthine-xanthine oxidase reaction, there was a significant depression of SR Ca2+ uptake velocity. Xanthine alone or xanthine plus denatured xanthine oxidase had no effect on this system. Superoxide dismutase (SOD), a scavenger of .O2-, or denatured SOD had no effect on the depression of Ca2+ uptake velocity induced by the xanthine-xanthine oxidase reaction. However, catalase, which can impair hydroxyl radical (.OH) formation by destroying the precursor H2O2, significantly inhibited the effect of the xanthine-xanthine oxidase reaction. This effect of catalase was enhanced by SOD, but not by denatured SOD. Dimethyl sulfoxide (Me2SO), a known .OH scavenger, completely inhibited the effect of the xanthine-xanthine oxidase reaction. The observed effect of oxygen radicals and radical scavengers was not seen in the calmodulin-depleted SR vesicles. Addition of exogenous calmodulin, however, reproduced the effect of oxygen radicals and the scavengers. The effect of oxygen radicals was enhanced by the calmodulin antagonists (compounds 48/80 and W-7) at concentrations which showed no effect alone on Ca2+ uptake velocity. Taken together, these findings strongly suggest that .OH, but not .O2-, is involved in a mechanism that may cause SR dysfunction, and that the effect of oxygen radicals is calmodulin dependent. |
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