Reduction of endoplasmic reticulum stress inhibits neointima formation after vascular injury

Shutaro Ishimura,Takahiro Fuseya,Tomohiro Mita,Hideaki Yoshida,Nobuaki Kokubu,Kyoko Hoshina,Masato Furuhashi,Yuki Watanabe,Tetsuji Miura,Katsumi Inoue

doi:10.1038/srep06943

Shutaro Ishimura, Takahiro Fuseya + Show 8 more

Open Access

https://doi.org/10.1038/srep06943

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Abstract

Endoplasmic reticulum (ER) stress and inappropriate adaptation through the unfolded protein response (UPR) are predominant features of pathological processes. However, little is known about the link between ER stress and endovascular injury. We investigated the involvement of ER stress in neointima hyperplasia after vascular injury. The femoral arteries of 7-8-week-old male mice were subjected to wire-induced vascular injury. After 4 weeks, immunohistological analysis showed that ER stress markers were upregulated in the hyperplastic neointima. Neointima formation was increased by 54.8% in X-box binding protein-1 (XBP1) heterozygous mice, a model of compromised UPR. Knockdown of Xbp1 in human coronary artery smooth muscle cells (CASMC) in vitro promoted cell proliferation and migration. Furthermore, treatment with ER stress reducers, 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA), decreased the intima-to-media ratio after wire injury by 50.0% and 72.8%, respectively. Chronic stimulation of CASMC with PDGF-BB activated the UPR, and treatment with 4-PBA and TUDCA significantly suppressed the PDGF-BB-induced ER stress markers in CASMC and the proliferation and migration of CASMC. In conclusion, increased ER stress contributes to neointima formation after vascular injury, while UPR signaling downstream of XBP1 plays a suppressive role. Suppression of ER stress would be a novel strategy against post-angioplasty vascular restenosis.

Highlights

Endoplasmic reticulum (ER) stress and inappropriate adaptation through the unfolded protein response (UPR) are predominant features of pathological processes
We demonstrated for the first time that activation of all branches of the UPR, including inositolrequiring enzyme-1a (IRE1a)-X-box binding protein-1 (XBP1), activating transcription factor 6 (ATF6) and PKR-like ER kinase (PERK) pathways, and accompanying inflammation are associated with neointima formation in the artery after wire injury
Overall suppression of UPRs by use of 4-PBA or tauroursodeoxycholic acid (TUDCA) suppressed neointima hyperplasia after wire injury in vivo and proliferation and migration of CASMAC in vitro. These findings suggest that ER stress contributes to vascular remodeling following intravascular injury, while UPR signaling downstream of XBP1 plays a suppressive role in neointima formation

Summary

Introduction

Endoplasmic reticulum (ER) stress and inappropriate adaptation through the unfolded protein response (UPR) are predominant features of pathological processes. Neointima hyperplasia in coronary lesions subjected to PCI is a pathologic hallmark of restenosis, and it is widely accepted that vascular injury activates vascular smooth muscle cells in the media and induces neointima formation by cell migration into intima and proliferation[5]. A compensational reaction to ER stress is called an unfolded protein response (UPR), which has mainly three signaling pathways by sensor proteins: PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6) and inositolrequiring enzyme-1a (IRE1a)-X-box binding protein-1 (XBP1) pathways, through the mechanism of arresting translation to alleviate additional sources of ER stress, induction of chaperones to increase protein folding capacity and degradation of unfolded or misfolded proteins[6]. We investigated the involvement of ER stress in neointima hyperplasia after endovascular injury by use of a model of wire-induced femoral artery injury, which mimics vascular remodeling following coronary angioplasty[11]

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