Abstract 15336: Morphine Attenuates Mitochondria Oxidative Stress by Modulating Complex I Activity Upon Reperfusion Via Mitochondrial Src Tyrosine Kinase and Reduces Infarct Size in Rat Hearts
Although morphine has been demonstrated to protect the heart from ischemia/reperfusion injury through various signaling mechanisms, the signaling events occurring within mitochondria that mediate morphine's protection remain unclear. This study was aimed to test the hypothesis that morphine protects the heart from ischemia/reperfusion injury by inhibiting mitochondrial complex I at reperfusion through activation of Src tyrosine kinase. Isolated rat hearts were subjected to 30 min ischemia followed by 2 h of reperfusion. Morphine (1 µM) was given 5 min before the onset of ischemia for 10 min. Morphine reduced mitochondrial protein carbonylation (65.7 ± 5.9 % of control, n = 5), a surrogate marker of mitochondrial oxidative stress, 30 min after the onset of reperfusion and this was reversed by the selective Src tyrosine kinase inhibitor PP2 (113.8 ± 11.9 % of control, n = =5). Morphine was also able to inhibit mitochondrial complex I activity at 10 min of reperfusion (81.6 ± 4.6 % of control, n = 7), an effect that was prevented by PP2 (109.3 ± 6.8 %, n = 6), implying that Src tyrosine kinase may regulate complex I activity. In support, immunoprecipitation study showed that Src and phospho-Src were located in complex I. Experiments further revealed that morphine increased mitochondrial Src phosphorylation (175.6 ± 26.8 % of control, n = 6) and this was again abolished by PP2 (91.1 ± 15.1 %, n = 6). Infarct study showed that morphine reduces infarct size (25.2 ± 4.8 % of risk zone, n = 6) compared to control (50.2 + 2.9 %), and this was inhibited by PP2 (44.2 ± 5.4 %). In conclusion, morphine reduces mitochondrial oxidative stress upon reperfusion by modulating complex I activity via mitochondrial Src tyrosine kinases, which may underlie the cardioprotective effect of morphine.
- © 2011 by American Heart Association, Inc.