title: Metformin-induced AMP-activated protein kinase activation regulates phenylephrine-mediated contraction of rat aorta.
abstract: The aim of the present study is to determine the effects and molecular mechanisms by which activation of LKB1-AMP-activated protein kinase (AMPK) by metformin regulates vascular smooth muscle contraction. The essential ability of vascular smooth muscle cells (VSMCs) to contract and relax in response to an elevation and reduction in intravascular pressure is necessary for appropriate blood flow regulation. Thus, vessel contraction is a critical mechanism for systemic blood flow regulation. In cultured rat VSMCs, AMPK activation through LKB1 by metformin-inhibited phenylephrine-mediated myosin light chain kinase (MLCK) and myosin light chain phosphorylation (p-MLC). Conversely, inhibition of AMPK and LKB1 reversed phenylephrine-induced MLCK and p-MLC phosphorylation. Measurement of the tension trace in rat aortic rings also showed that the effect of AMPK activation by metformin decreased phenylephrine-induced contraction. Metformin inhibited PE-induced p-MLC and α-smooth muscle actin co-localization. Our results suggest that activation of AMPK by LKB1 decreases VSMC contraction by inhibiting MLCK and p-MLC, indicating that induction by the AMPK-LKB1 pathway may be a new therapeutic target to lower high blood pressure.
authors.affiliation: Department of Pharmacology, Aging-associated Vascular Disease Research Center, Yeungnam University, Daegu 705-717, Republic of Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Sung
authors.forename: Hyoung Chul
authors.initials: HC
authors.lastname: Choi
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis*; D000199:Actins / Q000378:metabolism; D000818:Animals; D001011:Aorta; D001794:Blood Pressure / Q000187:drug effects; D004789:Enzyme Activation; D006973:Hypertension / Q000201:enzymology*; D008687:Metformin / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D018994:Myosin Light Chains / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D000199:Actins; D018994:Myosin Light Chains; D010656:Phenylephrine; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; C488755:Stk11 protein, rat; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases