The actin-binding protein girdin and its akt-mediated phosphorylation regulate neointima formation after vascular injury

Hiroshi Miyake, Kengo Maeda, Naoya Asai, Rei Shibata, Hitoshi Ichimiya, Mayu Isotani-Sakakibara, Yumiko Yamamura, Katsuhiro Kato, Atsushi Enomoto, Masahide Takahashi, Toyoaki Murohara

研究成果: Article査読

49 被引用数 (Scopus)

抄録

Rationale: It is well established that the migration and proliferation of vascular smooth muscle cells (VSMCs) have major roles in the vascular remodeling process. Our previous study showed that the Akt substrate Girdin, which is expressed in VSMCs and endothelial cells, is essential for postnatal angiogenesis. However, the function of Girdin and its Akt-mediated phosphorylation in VSMCs and their in vivo roles in vascular remodeling remain to be elucidated. Objective: We investigated the function of Girdin and its Akt-mediated phosphorylation using cultured VSMCs and animal models of vascular remodeling. Methods and Results: The depletion of Girdin by RNA interference disrupted the rearrangement of the actin cytoskeleton in VSMCs, resulting in impaired cell migration. The depletion of Girdin also inhibited VSMC proliferation. Girdin expression was highly upregulated and its serine at position 1416 was phosphorylated in the neointima of carotid arteries after balloon injury in a rat model. The introduction of an adenovirus harboring short hairpin RNA against Girdin attenuated the proliferation of VSMCs and neointima formation without affecting reendothelialization. Furthermore, we found that neointima formation after femoral wire injury was significantly attenuated in Girdin S1416A knock-in mice, in which the Akt phosphorylation site of Girdin was mutated, thus indicating a major role for Girdin phosphorylation in vascular remodeling. Conclusions: These findings indicate that Girdin and its Akt-mediated phosphorylation have major roles in the migration and proliferation of VSMCs and vascular remodeling, making the Akt/Girdin signaling pathway a potential target for the development of new therapeutics for vascular diseases.

本文言語English
ページ(範囲)1170-1179
ページ数10
ジャーナルCirculation research
108
10
DOI
出版ステータスPublished - 13-05-2011
外部発表はい

All Science Journal Classification (ASJC) codes

  • 生理学
  • 循環器および心血管医学

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