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J Appl Physiol 91: 1475-1482, 2001;
8750-7587/01 $5.00
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Vol. 91, Issue 3, 1475-1482, September 2001

HIGHLIGHTED TOPICS
Signal Transduction in Smooth Muscle
Selected Contribution: Insulin utilizes NO/cGMP pathway to activate myosin phosphatase via Rho inhibition in vascular smooth muscle

Oana A. Sandu1, Masaaki Ito2, and Najma Begum1,3

1 The Diabetes Research Laboratory, Winthrop University Hospital, Mineola 11501; 3 School of Medicine, State University of New York, Stony Brook, New York 11794; and 2 First Department of Internal Medicine, Mie University School of Medicine, Mie 514-8507, Japan

Our laboratory has recently demonstrated that insulin induces relaxation of vascular smooth muscle cells (VSMCs) by activating myosin-bound phosphatase (MBP) and by inhibiting Rho kinase (Begum N, Duddy N, Sandu OA, Reinzie J, and Ragolia L. Mol Endocrinol 14: 1365-1376, 2000). In this study, we tested the hypothesis that insulin via the nitric oxide (NO)/cGMP pathway may inactivate Rho, resulting in a decrease in phosphorylation of the myosin-bound subunit (MBSThr695) of MBP and in its activation. Treatment of confluent serum-starved VSMCs with insulin prevented thrombin-induced increases in membrane-associated RhoA, Rho kinase activation, and site-specific phosphorylation of MBSThr695 of MBP and caused MBP activation. Preexposure to NG-monomethyl-L-arginine, a NO synthase inhibitor, and R-p-8-(4-chlorophenylthio)cGMP, a cGMP antagonist, attenuated insulin's inhibitory effect on Rho translocation and restored thrombin-mediated Rho kinase activation and site-specific MBSThr695 phosphorylation, resulting in MBP inactivation. In contrast, 8-bromo-cGMP, a cGMP agonist, mimicked insulin's inhibitory effects by abolishing thrombin-mediated Rho signaling and promoted dephosphorylation of MBSThr695. Furthermore, expression of a dominant-negative RhoA decreased basal as well as thrombin-induced MBSThr695 phosphorylation and caused insulin activation of MBP. Collectively, these results indicate that insulin inhibits Rho signaling by decreasing RhoA translocation via the NO/cGMP signaling pathway to cause MBP activation via site-specific dephosphorylation of its regulatory subunit MBS.

myosin-bound phosphatase site-specific phosphorylation; myosin-bound phosphatase activation; vasodilation; Rho kinase; hypertension


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