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

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47 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1170-1179
Number of pages10
JournalCirculation research
Volume108
Issue number10
DOIs
Publication statusPublished - 13-05-2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Miyake, H., Maeda, K., Asai, N., Shibata, R., Ichimiya, H., Isotani-Sakakibara, M., Yamamura, Y., Kato, K., Enomoto, A., Takahashi, M., & Murohara, T. (2011). The actin-binding protein girdin and its akt-mediated phosphorylation regulate neointima formation after vascular injury. Circulation research, 108(10), 1170-1179. https://doi.org/10.1161/CIRCRESAHA.110.236174