A small molecule AMPK activator protects the heart against ischemia–reperfusion injury

Abstract

AMP-activated protein kinase (AMPK) is a stress signaling enzyme that orchestrates the regulation of energy-generating and -consuming pathways. Intrinsic AMPK activation protects the heart against ischemic injury and apoptosis, but whether pharmacologic AMPK stimulation mitigates ischemia-reperfusion damage is unknown. The aims of this study were to determine whether direct stimulation of AMPK using a small molecule activator, A-769662, attenuates myocardial ischemia-reperfusion injury, and to examine its cardioprotective mechanisms. Isolated mouse hearts pre-treated with A-769662 had better recovery of left ventricular contractile function (55% vs. 29% of baseline rate-pressure product; p=0.03) and less myocardial necrosis (56% reduction in infarct size; p<0.01) during post-ischemic reperfusion compared to control hearts. Pre-treatment with A-769662 in vivo attenuated infarct size in C57Bl/6 mice undergoing left coronary artery occlusion and reperfusion compared to vehicle (36% vs. 18%, p=0.025). Mouse hearts with genetically inactivated AMPK were not protected by A-769662, indicating the specificity of this compound. Pre-treatment with A-769662 increased the phosphorylation and inactivation of eukaryotic elongation factor 2 (eEF2), preserved energy charge during ischemia, delayed the development of ischemic contracture, and reduced myocardial apoptosis and necrosis. A-769662 also augmented endothelial nitric oxide synthase (eNOS) activation during ischemia, which partially attenuated myocardial stunning, but did not prevent necrosis. AMPK is a therapeutic target that can be stimulated by a direct-acting small molecule in order to prevent injury during ischemia-reperfusion. The use of AMPK activators may represent a novel strategy to protect the heart and other solid organs against ischemia.

Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart

“…Interestingly, AMPK is also activated during ischemic preconditioning (40,41), the physiologic phenomenon by which preceding short durations of ischemia decrease the susceptibility to necrosis during more prolonged and potentially injurious ischemia. AMPK is also activated by other treatment regimens that prevent ischemic injury, such as heat shock (10), adrenergic stimulation (42), and nitric oxide (43).…”

“…AMPK is also activated by other treatment regimens that prevent ischemic injury, such as heat shock (10), adrenergic stimulation (42), and nitric oxide (43). AMPK activation is sufficient to precondition the heart, based the results of recent pharmacologic studies with a direct AMPK activator (41). PKCe activation is also involved in ischemic preconditioning, and previous studies have linked PKCe to the activation of mitochondrial ATP-sensitive potassium channels (44,45).…”

AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases

“…One of the primary functions of AMPK activation is to induce glucose uptake, which has been observed in hypertrophied hearts of animal models ( 165 ) and humans ( 166 ), suggesting a functional role of AMPK in cardiac hypertrophy ( 162,167 ) and ischemia ( 168,169 ). Further evidence of AMPK in cardiac function comes from AMPK mutation that leads to myocardial metabolic storage disease with coexistence of hypertrophy and defects in conduction system ( 167 ).…”

An investigation on cardioprotective potential of Marrubium vulgare aqueous fraction against ischaemia-reperfusion injury in isolated rat heart

“…The lactate levels of these samples (the marker of the anaerobic glycolysis) were measured with lab assays [15,20].…”