Preserved expression of GLUT4 prevents enhanced agonist-induced vascular reactivity and MYPT1 phosphorylation in hypertensive mouse aorta.
We previously showed 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 vascular smooth muscle in vivo would prevent enhanced arterial reactivity and possibly reduce blood pressure in DOCA-salt hypertensive mice. Adult wild-type (WT) and GLUT4 transgenic (TG) mice were subjected to DOCA-salt hypertension with uninephrectomy or underwent uninephrectomy and remained normotensive. GLUT4 expression was increased more than twofold in the aortas of GLUT4 TG mice compared with WT aortas. Eight weeks after implantation of the DOCA pellets, GLUT4 expression decreased by 75% in aortas of WT hypertensive mice, but not in GLUT4 TG hypertensive aortas. Systolic blood pressure was significantly and similarly increased in WT and GLUT4 TG DOCA-salt mice compared with their respective sham-treated 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 GLUT4 TG DOCA mice. Phosphorylation of the myosin phosphatase targeting subunit MYPT1 was significantly enhanced in aortas of WT DOCA-salt mice, and this increase was prevented in GLUT4 TG mice. MYPT1 phosphorylation was also increased in nonhypertensive 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.
Atkins
Kevin B
KB
Department of Internal Medicine, University of Michigan Medical School, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0676, USA. katkins@umich.edu
Prezkop
Antoine
A
Park
James L
JL
Saha
Jharna
J
Duquaine
Damon
D
Charron
Maureen J
MJ
Olson
Ann Louise
AL
Brosius
Frank C
FC
D000818:Animals; D001011:Aorta / Q000503:physiopathology*; D001794:Blood Pressure; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism*; D043263:Myosin-Light-Chain Phosphatase; D010766:Phosphorylation
D051275:Glucose Transporter Type 4; C495693:Slc2a4 protein, mouse; D009219:Myosin-Light-Chain Kinase; D043263:Myosin-Light-Chain Phosphatase; C510645:Ppp1r12a protein, mouse