Submitted on August 9, 2006
Accepted on March 14, 2007
Preserved Expression of GLUT4 Prevents Enhanced Agonist-Induced Vascular Reactivity and MYPT1 Phosphorylation in Hypertensive Mouse Aorta
Kevin B. Atkins1*, Antoine Przekop1, James L. Park1, Jharna Saha1, Damon Duquaine1, Maureen J Charron2, Ann Louise Olson3, and Frank C. Brosius4
1 Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
2 Biochemistry, Albert Einstein College of Medicine, Bronx, New York, United States
3 Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City,, Oklahoma, United States
4 Internal Medicine and Physiology, University of Michigan, United States
* To whom correspondence should be addressed. E-mail: katkins{at}umich.edu.
We have previously shown that GLUT4 expression is decreased in arterial smooth muscle of deoxycorticosterone acetate (DOCA)-salt hypertensive rats and that GLUT4-knockout mice have enhanced arterial reactivity. Therefore, we hypothesized that increased GLUT4 expression in VSM in vivo would prevent the enhanced arterial reactivity and possibly reduce blood pressure in DOCA-salt hypertensive mice. Adult wild-type (WT) and GLUT4 transgenic (GLUT4 TG) mice were subjected to DOCA-salt hypertension with uninephrectomy or underwent uninephrectomy and remained normotensive. GLUT4 expression was increased >2-fold in the aortae of GLUT4 TG mice compared to that in WT aortae. Eight weeks after implantation of the DOCA pellets, GLUT4 expression decreased by 75% in aortae of WT hypertensive mice, but not in the GLUT4 TG hypertensive aortae. Systolic blood pressure was significantly and similarly increased in WT and GLUT4 TG DOCA-salt mice compared to their respective Sham controls (159 vs. 111 mmHg). Responsiveness to the contractile agonist, 5-HT, was significantly increased in aortic rings from WT DOCA-salt mice but remained normal in the GLUT4 TG DOCA mice. Phosphorylation of the myosin phosphatase targeting subunit, MYPT1, was significantly enhanced in aortae of WT DOCA-salt mice and this increase was prevented in the GLUT4 TG mice. MYPT1 phosphorylation was also increased in non-hypertensive GLUT4 knockout mice. Myosin phosphatase, a major negative regulator of calcium sensitivity, is itself negatively regulated by phosphorylation of MYPT1. Therefore, our results show that preservation of GLUT4 expression prevents enhanced arterial reactivity in hypertension possibly via effects on myosin phosphatase activity.
