Morphine may induce cardioprotection by targeting mitochondria, but little is known about the exact mitochondrial events that mediate
morphine's protection. We aimed to address the role of the mitochondrial
Src tyrosine kinase in
morphine's protection. Isolated rat hearts were subjected to 30 min
ischemia and 2h of reperfusion.
Morphine was given before the onset of
ischemia.
Infarct size and
troponin I release were measured to evaluate cardiac injury. Oxidative stress was evaluated by measuring
mitochondrial protein carbonylation and mitochondrial ROS generation. HL-1 cells were subjected to simulated
ischemia/reperfusion and LDH release and mitochondrial membrane potential (ΔΨm) were measured.
Morphine reduced
infarct size as well as cardiac
troponin I release which were aborted by the selective
Src tyrosine kinase inhibitors PP2 and Src-I1.
Morphine also attenuated LDH release and prevented a loss of ΔΨm at reperfusion in a
Src tyrosine kinase dependent manner in HL-1 cells. However,
morphine failed to reduce LDH release in HL-1 cells transfected with Src
siRNA.
Morphine increased mitochondrial Src phosphorylation at reperfusion and this was abrogated by PP2.
Morphine attenuated
mitochondrial protein carbonylation and mitochondrial
superoxide generation at reperfusion through
Src tyrosine kinase. The inhibitory effect of
morphine on the mitochondrial complex I activity was reversed by PP2. These data suggest that
morphine induces cardioprotection by preventing mitochondrial oxidative stress through mitochondrial
Src tyrosine kinase. Inhibition of mitochondrial complex I at reperfusion by
Src tyrosine kinase may account for the prevention of mitochondrial oxidative stress by
morphine.