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Molecular and Cellular Biology, November 2009, p. 6018-6032, Vol. 29, No. 22
0270-7306/09/$08.00+0     doi:10.1128/MCB.00225-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cyclic GMP Kinase and RhoA Ser188 Phosphorylation Integrate Pro- and Antifibrotic Signals in Blood Vessels {triangledown} ,{dagger}

Naoki Sawada,1,2,3 Hiroshi Itoh,1* Kazutoshi Miyashita,1 Hirokazu Tsujimoto,1 Masakatsu Sone,1 Kenichi Yamahara,1 Zoltan P. Arany,2 Franz Hofmann,4 and Kazuwa Nakao1

Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan,1 Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115,2 Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, Tokyo 113-8510, Japan,3 Institut für Pharmakologie und Toxikologie, Technische Universität München, 80802 Munich, Germany4

Received 19 February 2009/ Returned for modification 3 April 2009/ Accepted 23 July 2009

Vascular fibrosis is a major complication of hypertension and atherosclerosis, yet it is largely untreatable. Natriuretic peptides (NPs) repress fibrogenic activation of vascular smooth muscle cells (VSMCs), but the intracellular mechanism mediating this effect remains undetermined. Here we show that inhibition of RhoA through phosphorylation at Ser188, the site targeted by the NP effector cyclic GMP (cGMP)-dependent protein kinase I (cGK I), is critical to fully exert antifibrotic potential. cGK I+/– mouse blood vessels exhibited an attenuated P-RhoA level and concurrently increased RhoA/ROCK signaling. Importantly, cGK I insufficiency caused dynamic recruitment of ROCK into the fibrogenic programs, thereby eliciting exaggerated vascular hypertrophy and fibrosis. Transgenic expression of cGK I-unphosphorylatable RhoAA188 in VSMCs augmented ROCK activity, vascular hypertrophy, and fibrosis more prominently than did that of wild-type RhoA, consistent with the notion that RhoAA188 escapes the intrinsic inhibition by cGK I. Additionally, VSMCs expressing RhoAA188 became refractory to the antifibrotic effects of NPs. Our results identify cGK I-mediated Ser188 phosphorylation of RhoA as a converging node for pro- and antifibrotic signals and may explain how diminished cGMP signaling, commonly associated with vascular malfunction, predisposes individuals to vascular fibrosis.

* Corresponding author. Present address: Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Phone: 81-3-5363-3795. Fax: 81-3-3354-7446. E-mail: hiito{at}kuhp.kyoto-u.ac.jp

{triangledown} Published ahead of print on 8 September 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2009, p. 6018-6032, Vol. 29, No. 22
0270-7306/09/$08.00+0     doi:10.1128/MCB.00225-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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