Feng Yue, Zhu Zixiong, He Yubin, Li Xuewen
Department of Cardiovascular Medicine, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, 030032 Taiyuan, Shanxi, China.
Rev Cardiovasc Med. 2025 Aug 30;26(8):36391. doi: 10.31083/RCM36391. eCollection 2025 Aug.
The AMP-activated protein kinase (AMPK) alpha (AMPK) subunit is the catalytic subunit in the AMPK complex and includes both 1 and 2 isoforms. Phosphorylation of upstream kinases at the Thr172 site in the -subunit is critical for AMPK activation. The kinases upstream of AMPK include liver kinase B1 (LKB1), calcium/calmodulin-dependent protein kinase kinase (CaMKK), and transforming growth factor -activated kinase 1 (TAK1). LKB1 predominantly regulates the AMPK2 isoforms, whereas the phosphorylating roles of CaMKK and TAK1 in different isoforms of AMPK have yet to be properly defined. Moreover, the understanding of the roles of AMPK1 and 2 remains limited. Significant differences exist between the AMPK1 and AMPK2 isoforms regarding tissue distribution, cellular localization, and cardiac-unique roles, with AMPK2 being the predominant catalytic isoform in the heart. During heart failure (HF), activated AMPK isoforms, particularly AMPK2, 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 2 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.
AMP激活的蛋白激酶（AMPK）α亚基是AMPK复合物中的催化亚基，包括1和2两种亚型。α亚基中Thr172位点上游激酶的磷酸化对于AMPK激活至关重要。AMPK的上游激酶包括肝激酶B1（LKB1）、钙/钙调蛋白依赖性蛋白激酶激酶β（CaMKKβ）和转化生长因子β激活激酶1（TAK1）。LKB1主要调节AMPK2亚型，而CaMKKβ和TAK1在AMPK不同亚型中的磷酸化作用尚未明确界定。此外，对AMPK1和2作用的了解仍然有限。AMPK1和AMPK2亚型在组织分布、细胞定位和心脏独特作用方面存在显著差异，其中AMPK2是心脏中主要的催化亚型。在心力衰竭（HF）期间，激活的AMPK亚型，特别是AMPK2，可促进能量代谢重塑，改善线粒体功能障碍，激活线粒体自噬，减轻氧化应激，并减少心肌细胞死亡，从而保护心脏功能并延缓HF进展。因此，选择性激活含有特定2亚型的AMPK复合物的药物可能有助于治疗HF。然而，目前AMPK激活剂的亚型选择性不强，直接激动剂仍在临床试验中，间接激动剂虽然在临床上广泛使用，但有一些非AMPK依赖性作用。因此，迫切需要开发具有更高特异性、疗效和更少副作用的亚型选择性激活剂药物。
