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1 University College London, The Hatter Institute and Centre for Cardiology, London, United Kingdom
* To whom correspondence should be addressed. E-mail: hatter-institute{at}ucl.ac.uk.
Pharmacological activation of the pro-survival kinases Akt and Erk1/2, at the time of reperfusion, following a lethal ischemic period, protects the heart against ischemia-reperfusion injury. We hypothesized that ischemic preconditioning (IPC) protects the heart by phosphorylating the pro-survival kinases Akt and Erk1/2, at the time of reperfusion. In isolated perfused Sprague-Dawley rat hearts subjected to 35 minutes of lethal ischemia, the phosphorylation states of Akt, Erk1/2, p70S6K were determined after 15 minutes of reperfusion, and infarct size was measured after 120 minutes of reperfusion. IPC induced a biphasic response in both Akt and Erk1/2 phosphorylation, the first occurring during the preconditioning phase and a second phase occurring during the reperfusion phase, following the lethal ischemic period. IPC induced a four-fold increase in Akt, Erk1/2 and p70S6K phosphorylation, at the time of reperfusion, and reduced the infarct-risk volume ratio (56.9±5.7% in control vs 20.9±3.6% for IPC; P<0.01). Inhibiting the IPC-induced phosphorylation of Akt, Erk1/2 and p70S6K at the time of reperfusion, with the PI3K inhibitor, LY294002, or the MEK1/2 inhibitor, PD98059, respectively, abrogated IPC-induced protection (46.3±5.8% for IPC+LY, 49.2±4.0% for IPC+PD vs 20.9±3.6% for IPC; P<0.01), demonstrating that the phosphorylation of these kinases, at the time of reperfusion, is required for IPC-induced protection. In conclusion, we demonstrate that the reperfusion phase following sustained ischemia plays an essential role in mediating IPC-induced protection. Specifically, we demonstrate that IPC protects the heart by phosphorylating the pro-survival kinases, Akt and Erk1/2, at the time of reperfusion.
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