AMP-activated protein kinase (AMPK) is a critical regulator of cellular metabolism and plays an important role in diabetes, cancer, and vascular disease. In the heart, AMPK activation is an essential component of the adaptive response to cardiomyocyte stress that occurs during myocardial ischemia. During ischemia-reperfusion, AMPK activation modulates glucose and fatty acid metabolism, mitochondrial function, endoplasmic reticulum (ER) stress, autophagy, and apoptosis. Pharmacological activation of AMPK prevents myocardial necrosis and contractile dysfunction during ischemia-reperfusion and potentially represents a cardioprotective strategy for the treatment of myocardial infarction. This review discusses novel mechanisms of AMPK activation in the ischemic heart, the role of endogenous AMPK activation during ischemia, and the potential therapeutic applications for AMPK-directed therapy.

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AMPK: energy sensor and survival mechanism in the ischemic heart

Molecular machinery and interplay of apoptosis and autophagy in coronary heart disease

Activated protein C: biased for translation

Background AMP-activated Protein Kinase (AMPK) is a stress-activated kinase that protects against cardiomyocyte injury during ischemia and reperfusion. c-Jun N-terminal kinase (JNK), a mitogen activated protein kinase, is activated by ischemia and reperfusion. NF-κB is an important transcription factor involved in ischemia and reperfusion injury. Methods and Results The intrinsic activation of AMPK attenuates the inflammation which occurred during ischemia/reperfusion through the modulation of the JNK mediated NF-κB signaling pathway. Rat cardiac myoblast H9c2 cells were subjected to hypoxia and/or reoxygenation to investigate the signal transduction that occurred during myocardial ischemia/reperfusion. Mitochondrial function was measured by the Seahorse XF24 V7 PS system. Hypoxia treatment triggered AMPK activation in H9c2 cells in a time dependent manner. The inhibition of hypoxic AMPK activation through a pharmacological approach (Compound C) or siRNA knockdown of AMPK α catalytic subunits caused dramatic augmentation in JNK activation, inflammatory NF-κB phosphorylation, and apoptosis during hypoxia and reoxygenation. Inhibition of AMPK activation significantly impaired mitochondrial function and increased the generation of reactive oxygen species (ROS) during hypoxia and reoxygenation. In contrast, pharmacological activation of AMPK by metformin significantly inhibited mitochondrial permeability transition pore (mPTP) opening and ROS generation. Moreover, AMPK activation significantly attenuated the JNK-NF-κB signaling cascade and inhibited mRNA and protein levels of pro-inflammatory cytokines, such as TNF-α and IL-6, during hyopoxia/reoxygenation in H9c2 cells. Intriguingly, both pharmacologic inhibition of JNK by JNK-IN-8 and siRNA knockdown of JNK signaling pathway attenuated NF-κB phosphorylation and apoptosis but did not affect AMPK activation in response to hypoxia and reoxygenation. Conclusions AMPK activation modulates JNK-NF-κB signaling cascade during hypoxia and reoxygenation stress conditions. Cardiac AMPK activation plays a critical role in maintaining mitochondrial function and inhibiting the inflammatory response caused by ischemic insults.

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Activation of AMPK inhibits inflammatory response during hypoxia and reoxygenation through modulating JNK-mediated NF-κB pathway.

The regulation of AMPK in the ischemic heart remains incompletely understood. Recent evidence implicates the role of Sestrin2 in the AMPK signaling pathway, and it is hypothesized that Sestrin2 plays an influential role during myocardial ischemia to promote AMPK activation. Sestrin2 protein was found to be expressed in adult cardiomyocytes and accumulated in the heart during ischemic conditions. Sestrin2 knockout (KO) mice were used to determine the importance of Sestrin2 during ischemia and reperfusion (I/R) injury. When wild-type (WT) and Sestrin2 KO mice were subjected to in vivo I/R, myocardial infarct size was significantly greater in Sestrin2 KO compared with WT hearts. Similarly, Langendorff perfused hearts indicated exacerbated postischemic contractile function in Sestrin2 KO hearts compared with WT. Ischemic AMPK activation was found to be impaired in the Sestrin2 KO hearts. Immunoprecipitation of Sestrin2 demonstrated an association with AMPK. Moreover, liver kinase B1 (LKB1), a major AMPK upstream kinase, was associated with the Sestrin2-AMPK complex in a time-dependent manner during ischemia, whereas this interaction was nearly abolished in Sestrin2 KO hearts. Thus, Sestrin2 plays an important role in cardioprotection against I/R injury, serving as an LKB1-AMPK scaffold to initiate AMPK activation during ischemic insults.

Sestrin2 promotes LKB1-mediated AMPK activation in the ischemic heart

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1538-7836.2011.04331.x

Ji Li

Papers

Activated protein C protects against myocardial ischemic/reperfusion injury through AMP-activated protein kinase signaling