Increase of intracellular Ca(2+) during ischemia/reperfusion injury of heart is mediated by cyclic ADP-ribose.

Abstract

While the molecular mechanisms by which oxidants cause cytotoxicity are still poorly understood, disruption of Ca(2+) homeostasis appears to be one of the critical alterations during the oxidant-induced cytotoxic process. Here, we examined the possibility that oxidative stress may alter the metabolism of cyclic ADP-ribose (cADPR), a potent Ca(2+)-mobilizing second messenger in the heart. Isolated heart perfused by Langendorff technique was subjected to ischemia/reperfusion injury and endogenous cADPR level was determined using a specific radioimmunoassay. Following ischemia/reperfusion injury, a significant increase in intracellular cADPR level was observed. The elevation of cADPR content was closely correlated with the increase in ADP-ribosyl cyclase activity. Inclusion of oxygen free radical scavengers, 2,2,6,6-tetramethyl-1-piperidinyloxy and mannitol, in the reperfusate prevented the ischemia/reperfusion-induced increases in cADPR level and the ADP-ribosyl cyclase activity. Exposure of isolated cardiomyocytes to t-butyl hydroperoxide increased the ADP-ribosyl cyclase activity, cADPR level, and intracellular Ca(2+) concentration ([Ca(2+)](i)) and consequently resulting in cell lethal damage. The oxidant-induced elevation of [Ca(2+)](i) as well as cell lethal damage was blocked by a cADPR antagonist, 8-bromo-cADPR. These results provide evidence for involvement of cADPR and its producing enzyme in alteration of Ca(2+) homeostasis during the ischemia/reperfusion injury of the heart.

• Authors: Guang-Hua Xie, So-Young Rah, Kye Sook Yi, Myung Kwan Han, Soo Wan Chae, Mie-Jae Im, Uh-Hyun Kim
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 307 Issue 3 Pg. 713-8 (Aug 01 2003) ISSN: 0006-291X [Print] United States
• PMID: 12893282 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Free Radical Scavengers
• Reactive Oxygen Species
• Cyclic ADP-Ribose
• ADP-ribosyl Cyclase
• Calcium

Topics

• ADP-ribosyl Cyclase (metabolism)
• Animals
• Calcium (metabolism)
• Cell Survival
• Cells, Cultured
• Cyclic ADP-Ribose (metabolism)
• Free Radical Scavengers (pharmacology)
• Heart (drug effects)
• Myocardial Reperfusion Injury (metabolism)
• Myocardium (metabolism)
• Myocytes, Cardiac (cytology, metabolism)
• Organ Culture Techniques
• Oxidative Stress
• Rabbits
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Second Messenger Systems