Department of Molecular Research for Vascular Diseases, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Hypertens Res. 2010 Jan;33(1):22-8. doi: 10.1038/hr.2009.187. Epub 2009 Nov 13.
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.
最近人们认识到脂联素通过 AMP 激活的蛋白激酶（AMPK）的激活来保护血管并防止动脉粥样硬化变化，并且已经阐明了其一些分子机制。AMPK 可能是代谢异常的治疗靶点，是一种丝氨酸/苏氨酸激酶，由三个亚基（α、β和γ）组成的异三聚体蛋白。它由上游激酶 LKB1 和 AMP/ATP 比值的增加激活。一些合成代谢酶被直接磷酸化和抑制，表明 AMPK 通过负调控合成途径来抑制 ATP 的消耗。LKB1-AMPK 途径对于控制细胞极性和有丝分裂至关重要。此外，AMPK 与细胞自噬有关。AMPK 的激活可以诱导自噬并延长导致细胞凋亡的时间。在血管内皮细胞中过表达新构建的、组成型激活的 AMPK-α突变体时，缺氧条件下的细胞凋亡减少。AMPK 可以通过抑制 MEK-ERK 通路来抑制血管平滑肌的生长。在缺血再灌注后，心肌细胞中显性负性 AMPK 的过表达通过抑制葡萄糖摄取和脂肪酸β氧化来抑制心脏功能。由于与 Wolff-Parkinson-White 综合征相关的γ2 基因突变导致心肌中糖原颗粒积累的心脏肥厚被认为在大多数情况下是激活型。有必要阐明 AMPK 的组织特异性和应激特异性激活机制。
