The Role of AMPKα in the Mechanism of Development and Treatment of Heart Failure

The AMP-activated protein kinase (AMPK) alpha (AMPKα) subunit is the catalytic subunit in the AMPK complex and includes both α1 and α2 isoforms. Phosphorylation of upstream kinases at the Thr172 site in the α-subunit is critical for AMPK activation. The kinases upstream of AMPK include liver kinase B1 (LKB1), calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ), and transforming growth factor β-activated kinase 1 (TAK1). LKB1 predominantly regulates the AMPKα2 isoforms, whereas the phosphorylating roles of CaMKK and TAK1 in different isoforms of AMPKα have yet to be properly defined. Moreover, the understanding of the roles of AMPKα1 and α2 remains limited. Significant differences exist between the AMPKα1 and AMPKα2 isoforms regarding tissue distribution, cellular localization, and cardiac-unique roles, with AMPKα2 being the predominant catalytic isoform in the heart. During heart failure (HF), activated AMPKα isoforms, particularly AMPKα2, promote the remodeling of energy metabolism, ameliorate mitochondrial dysfunction, activate mitophagy, attenuate oxidative stress, and reduce cardiomyocyte death, thereby protecting cardiac function and delaying HF progression. Thus, drugs that selectively activate AMPK complexes containing specific α2 isoforms may help treat HF. However, AMPK activators are not currently very subtype-selective, direct agonists remain in clinical trials, and indirect agonists, although widely used in the clinic, have some non-AMPK-dependent effects. Therefore, a compelling need exists to develop subtype-selective activator drugs with greater specificity and efficacy and fewer side effects.