Published online before print December 6, 2007, doi: 10.1161/CIRCRESAHA.107.163253
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Submitted on September 25, 2006
Revised on November 19, 2007
Accepted on November 27, 2007
Thromboxane Receptor Activates the AMP-Activated Protein Kinase in Vascular Smooth Muscle Cells via Hydrogen Peroxide
Miao Zhang ;
From the Division of Endocrinology and Diabetes (M.Z., Y.-Z.D., J.X., Z.-L.X., Y.W., P.S., M.G., M.-H.Z.), Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City; and Department of Pharmacology (J.W.), Xianning College, Hubei, China.
* To whom correspondence should be addressed. E-mail: ming-hui-zou{at}ouhsc.edu.
Thromboxane A2 receptor (TPr) stimulation induces cellular hypertrophy in vascular smooth muscle cells (VSMCs); however, regulation of VSMC hypertrophy remains poorly understood. Here we show that TPr stimulation activates AMP-activated kinase (AMPK), which in turn limits TPr-induced protein synthesis in VSMCs. Exposure of cultured VSMCs to either TPr agonists, IBOP and U46619, or exogenous hydrogen peroxide (H2O2) caused time- and dose-dependent AMPK activation, as evidenced by increased phosphorylation of both AMPK-Thr172 and acetyl-coenzyme A carboxylase–Ser79, a downstream enzyme of AMPK, whereas SQ29548, a selective TPr antagonist, significantly attenuated TPr-enhanced AMPK activation. In parallel, both IBOP and U46619 significantly increased the production of reactive oxygen species such as H2O2. Furthermore, adenoviral overexpression of catalase (an H2O2 scavenger) abolished, whereas superoxide dismutase (which catalyzes H2O2 formation) enhanced, IBOP-induced AMPK activation, suggesting that TPr-activated AMPK was mediated by H2O2. Consistently, exposure of VSMCs to either TPr agonists or exogenous H2O2 dose-dependently increased the phosphorylation of LKB1 (at serines 428 and 307), an AMPK kinase, as well as coimmunoprecipitation of AMPK with LKB1. In addition, direct mutagenesis of either Ser428 or Ser307 of LKB1 into alanine, like the kinase-dead LKB1 mutant, abolished both TPr-stimulated AMPK activation and coimmunoprecipitation. Finally, genetic inhibition of AMPK significantly accentuated IBOP-enhanced protein synthesis, whereas adenoviral overexpression of constitutively active AMPK abolished IBOP-enhance protein synthesis in VSMCs. We conclude that TPr stimulation triggers reactive oxygen species–mediated LKB1-dependent AMPK activation, which in return inhibits cellular protein synthesis in VSMCs.
Key words: thromboxane receptor • AMPK • oxidative stress • vascular smooth muscle cells
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