on June 30, 2005
Published online before print June 30, 2005, doi: 10.1161/01.ATV.0000175749.41799.9b
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Submitted on March 14, 2005
Accepted on June 16, 2005
Signal-Crosstalk Between Rho/ROCK and JNK Mediates Migration of Vascular Smooth Muscle Cells Stimulated by Angiotensin II
Haruhiko Ohtsu ;
From the Cardiovascular Research Center (H.O., M.M., H.S., H.N., S.E.), Temple University School of Medicine, Philadelphia, Penn; the Department of Biochemistry (G.D.F., S.S., T.I.), Vanderbilt University School of Medicine, Nashville, Tenn; the Department of Pharmacology and Molecular Therapeutics (S.K.-M.), Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; the Department of Physiology (Y.T.), Kanazawa University School of Medicine, Ishikawa, Japan; the Department of Biochemistry (T.S.), Sapporo Medical University, Sapporo, Japan; the Department of Neurology and Neuroscience (J.D.R.), Johns Hopkins University, Baltimore, Md; and the Department of Anatomy and Physiology (E.A.W., E.D.M.), Meharry Medical College, Nashville, Tenn.
* To whom correspondence should be addressed. E-mail: seguchi{at}temple.edu.
Background--Rho and its effector Rho-kinase/ROCK mediate cytoskeletal reorganization as well as smooth muscle contraction. Recent studies indicate that Rho and ROCK are critically involved in vascular remodeling. Here, we tested the hypothesis that Rho/ROCK are critically involved in angiotensin II (Ang II)-induced migration of vascular smooth muscle cells (VSMCs) by mediating a specific signal cross-talk.
Methods and Results--Immunoblotting demonstrated that Ang II stimulated phosphorylation of a ROCK substrate, regulatory myosin phosphatase targeting subunit (MYPT)-1. Phosphorylation of MYPT-1 as well as migration of VSMCs induced by Ang II was inhibited by dominant-negative Rho (dnRho) or ROCK inhibitor, Y27632. Ang II-induced c-Jun NH2-terminal kinase (JNK) activation, but extracellular signal-regulated kinase (ERK) activation was not mediated through Rho/ROCK. Thus, infection of adenovirus encoding dnJNK inhibited VSMC migration by Ang II. We have further demonstrated that the Rho/ROCK activation by Ang II requires protein kinase C-
(PKC) and proline-rich tyrosine kinase 2 (PYK2) activation, but not epidermal growth factor receptor transactivation. Also, VSMCs express PDZ-Rho guanine nucleotide exchange factor (GEF) and Ang II stimulated PYK2 association with tyrosine phosphorylated PDZ-RhoGEF.
Conclusions--PKC/PYK2-dependent Rho/ROCK activation through PDZ-RhoGEF mediates Ang II-induced VSMC migration via JNK activation in VSMCs, providing a novel mechanistic role of the Rho/ROCK cascade that is involved in vascular remodeling.
Key words: angiotensin II • Rho kinase/ROCK • JNK • VSMC • migration
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