SmgGDS as a crucial mediator of the inhibitory effects of statins on cardiac hypertrophy and fibrosis: Novel mechanism of the pleiotropic effects of statins

Shun Kudo, Kimio Satoh, Masamichi Nogi, Kota Suzuki, Shinichiro Sunamura, Junichi Omura, Nobuhiro Kikuchi, Ryo Kurosawa, Taijyu Satoh, Tatsuro Minami, Shohei Ikeda, Satoshi Miyata, Hiroaki Shimokawa

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

The detailed molecular mechanisms of the pleiotropic effects of statins remain to be fully elucidated. Here, we hypothesized that cardioprotective effects of statins are mediated by small GTP-binding protein GDP dissociation stimulator (SmgGDS). SmgGDS+/- and wild-type (WT) mice were treated with continuous infusion of angiotensin II (Ang II) for 2 weeks with and without oral treatment with atorvastatin or pravastatin. At 2 weeks, the extents of Ang II-induced cardiac hypertrophy and fibrosis were comparable between the 2 genotypes. However, statins significantly attenuated cardiomyocyte hypertrophy and fibrosis in WT mice, but not in SmgGDS+/- mice. In SmgGDS+/- cardiac fibroblasts (CFs), Rac1 expression, extracellular signal-regulated kinases 1/2 activity, Rho-kinase activity, and inflammatory cytokines secretion in response to Ang II were significantly increased when compared with WT CFs. Atorvastatin significantly reduced Rac1 expression and oxidative stress in WT CFs, but not in SmgGDS+/- CFs. Furthermore, Bio-plex analysis revealed significant upregulations of inflammatory cytokines/chemokines and growth factors in SmgGDS+/- CFs when compared with WT CFs. Importantly, conditioned medium from SmgGDS+/- CFs increased B-type natriuretic peptide expression in rat cardiomyocytes to a greater extent than that from WT CFs. Furthermore, atorvastatin significantly increased SmgGDS secretion from mouse CFs. Finally, treatment with recombinant SmgGDS significantly reduced Rac1 expression in SmgGDS+/- CFs. These results indicate that both intracellular and extracellular SmgGDS play crucial roles in the inhibitory effects of statins on cardiac hypertrophy and fibrosis, partly through inhibition of Rac1, Rho kinase, and extracellular signal-regulated kinase 1/2 pathways, demonstrating the novel mechanism of the pleiotropic effects of statins.

Original languageEnglish
Pages (from-to)878-889
Number of pages12
JournalHypertension
Volume67
Issue number5
DOIs
Publication statusPublished - 2016 May 1

Keywords

  • angiotensin II
  • chemokines
  • oxidative stress
  • pravastatin
  • statin

ASJC Scopus subject areas

  • Internal Medicine

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