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Aspirin Protects Heart Against Ischemia-reperfusion Injury Via LKB1-Sestrn2-AMPK Signaling Cascade
Yanping Bi MD, Shaoxin Lu MS3, Chelsea Luckett, Ji Li PhD, UNIV OF MISSISSIPPI MED CENTER, Jackson, MS
AMP-activated protein kinase (AMPK) is a stress signaling enzyme that orchestrates the regulation of energy pathways. Intrinsic AMPK activation protects the heart against ischemic injury, but whether the pharmacologic AMPK stimulation by aspirin mitigates ischemia-reperfusion (I/R) damage is unknown.
Aspirin as an emerging AMPK agonist could stimulate the cardiac AMPK signaling pathway that attenuates myocardial ischemia-reperfusion injury.
The cardioprotective activity of aspirin was evaluated in an in vivo regional I/R (45 min/24 hours) injury model in which the left anterior descending coronary artery (LAD) was occluded and released. The Langendroff perfused heart system was used to approach an ex vivo global ischemia and reperfusion model.
Isolated mouse hearts ex vivo pre-treated with aspirin had better recovery of left ventricular contractile function (55% vs. 29% of baseline heart rate-pressure product; p<0.05) and less myocardial necrosis (56% reduction in infarct size; p<0.01) during post-ischemic reperfusion. Pre-treatment with aspirin in vivo attenuated myocardial infarction in C57BL/6J mice undergoing left coronary artery occlusion and reperfusion compared to vehicle (36% vs. 18%, p<0.05). Mouse hearts with genetically inactivated AMPK catalytic subunit were not protected by aspirin treatment, indicating the critical role of cardiac AMPK activation by aspirin in cardioprotection against ischemic injury. Moreover, pre-treatment with aspirin in vivo increased the AMPK downstream phosphorylation and inactivation of eukaryotic elongation factor 2 (eEF2), preserved energy charge during ischemia and delayed the development of ischemic contracture. Aspirin treatment augmented the interaction between AMPK upstream LKB1 and Sestrin2-AMPK complex, also enhanced activation of AMPK downstream endothelial nitric oxide synthase (eNOS) during ischemia, which partially attenuated myocardial stunning.
AMPK is a therapeutic target that can be stimulated by a direct-acting small molecule in order to prevent injury during I/R. The use of aspirin may represent a novel strategy to protect the heart and other solid organs against ischemia.