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(Circulation Research. 2005;96:1014.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Long-Term Inhibition of RhoA Attenuates Vascular Contractility by Enhancing Endothelial NO Production in an Intact Rabbit Mesenteric Artery

Noriko Shiga, Katsuya Hirano, Mayumi Hirano, Junji Nishimura, Hajime Nawata, Hideo Kanaide

From the Division of Molecular Cardiology, Research Institute of Angiocardiology (N.S., K.H., M.H., J.N., H.K.), and Department of Medicine and Bioregulatory Science (H.N.), Graduate School of Medical Sciences, and Kyushu University COE Program on Lifestyle-Related Diseases (H.N., H.K.), Kyushu University, Fukuoka, Japan.

Correspondence to Hideo Kanaide, MD, PhD, Professor, Division of Molecular Cardiology, Research Institute of Angiocardiology, Graduate School of Medical Sciences, Kyushu University. 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. E-mail kanaide{at}molcar.med.kyushu-u.ac.jp

RhoA plays a critical role in regulating NO production in cultured endothelial cells. To determine its role in in situ endothelial cells, we investigated the effects of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors and a RhoA-binding domain of Rho-kinase (RB) on vascular contractility in the isolated rabbit mesenteric artery. Ex vivo treatment of the strips with 3x10^–5 mol/L simvastatin and fluvastatin for 24 to 30 hours significantly attenuated the contractile response to phenylephrine and high K⁺ in the presence of endothelium. The addition of N-nitro-L-arginine methyl ester and the removal of endothelium abolished the attenuation of the contractile response. The cotreatment with geranylgeranyl pyrophosphate prevented the statin-induced attenuation of the contractile response, whereas geranylgeranyl transferase inhibitor mimicked the effect of simvastatin. Treatment with simvastatin enhanced the bradykinin-induced endothelium-dependent relaxation in the mesenteric artery, whereas it had no effect on the bradykinin-induced [Ca²⁺]_i elevation in endothelial cells of the aortic valves. Introduction of RB to the strips using a cell-penetrating peptide of Tat protein (TATHA-RB) attenuated the contractile responses in a NO-dependent manner. However, a Rac1/Cdc42-binding fragment of p21-activated protein kinase, RB without Tat peptide or TATHA-protein A had no effect. The in vivo treatment of rabbit with simvastatin and TATHA-RB attenuated the contractility in a NO-dependent manner. Simvastatin and TATHA-RB significantly upregulated eNOS in the rabbit mesenteric artery. The present study provides the first evidence that RhoA plays a physiological role in suppressing NO production in in situ endothelial cells.

Key Words: endothelial cells • RhoA • nitric oxide • statins • molecular biology

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Statin-Mediated Inhibition of Rho: Only to Get More NO?

Ralf P. Brandes
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