Cyclic GMP kinase and RhoA Ser188 phosphorylation integrate pro- and antifibrotic signals in blood vessels

Naoki Sawada, Hiroshi Itoh, Kazutoshi Miyashita, Hirokazu Tsujimoto, Masakatsu Sone, Kenichi Yamahara, Zoltan P. Arany, Franz Hofmann, Kazuwa Nakao

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Abstract

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.

Original languageEnglish
Pages (from-to)6018-6032
Number of pages15
JournalMolecular and cellular biology
Volume29
Issue number22
DOIs
Publication statusPublished - 2009 Nov 1

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Sawada, N., Itoh, H., Miyashita, K., Tsujimoto, H., Sone, M., Yamahara, K., Arany, Z. P., Hofmann, F., & Nakao, K. (2009). Cyclic GMP kinase and RhoA Ser188 phosphorylation integrate pro- and antifibrotic signals in blood vessels. Molecular and cellular biology, 29(22), 6018-6032. https://doi.org/10.1128/MCB.00225-09