The role of AMP-activated protein kinase in the cardiovascular system.
It has recently been recognized that adiponectin protects the vasculature and prevents atherosclerotic change through AMP-activated protein kinase (AMPK) activation, and some of its molecular mechanisms have been clarified. AMPK, which might be a therapeutic target of metabolic abnormality, is a serine-threonine kinase, heterotrimer protein composed of three subunits of alpha, beta and gamma. It is activated by an upper kinase LKB1 and an increase in the AMP/ATP ratio. Some anabolic enzymes are directly phosphorylated and inhibited, suggesting that AMPK suppresses ATP consumption by negatively regulating the synthetic pathway. The LKB1-AMPK pathway is pivotal for controlling cellular polarity and mitosis. Furthermore, AMPK has been associated with cellular autophagy. AMPK activation could induce autophagy and prolong a period leading to cell apoptosis. Apoptosis under anoxic conditions was decreased when newly constructed, constitutively active mutants of AMPK-alpha were overexpressed in vascular endothelial cells. AMPK could inhibit the growth of vascular smooth muscle through MEK-ERK pathway inhibition. After ischemia reperfusion, dominant-negative AMPK overexpression inhibits cardiac function through the suppression of glucose uptake and fatty acid beta-oxidation in cardiac myocytes. Cardiac hypertrophy with accumulation of glycogen granules because of gene mutation of gamma2 associated with the Wolff-Parkinson-White syndrome has been considered an activated type in most cases. It is necessary to clarify the tissue-specific and stress-specific activation mechanism of AMPK.
Nagata
Daisuke
D
Department of Molecular Research for Vascular Diseases, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan. dskngtendo0504-tky@umin.ac.jp
Hirata
Yasunobu
Y
D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002320:Cardiovascular Physiological Phenomena; D002319:Cardiovascular System / Q000201:enzymology*; D006801:Humans
D055372:AMP-Activated Protein Kinases