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Reduction of endoplasmic reticulum stress inhibits neointima formation after vascular injury.

Ishimura S, Furuhashi M, Mita T, Fuseya T, Watanabe Y, Hoshina K, Kokubu N, Inoue K, Yoshida H, Miura T - Sci Rep (2014)

Bottom Line: 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.Suppression of ER stress would be a novel strategy against post-angioplasty vascular restenosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan.

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.

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Effects of chemical chaperones on neointima formation, cell proliferation and cell migration.(A), (B). Representative staining of EVG in the wired-injured left femoral arteries of mice treated with daily intraperitoneal injection of a vehicle (n = 11), 100 mg/kg 4-PBA (n = 8) or 500 mg/kg TUDCA (n = 6) for 4 weeks (A). Scale bars: 50 µm. The extent of neointima formation was evaluated as intima-to-media ratio in the wire-injured femoral artery (B). *P < 0.05 vs. Vehicle. (C), (D). Cell proliferation was assessed by an MTS assay in chronic stimulation with 20 ng/ml PDGF-BB for 48 h in CASMC treated with 0-0.5 mM of 4-PBA (C) or 0–0.5 mM of TUDCA (D). *P < 0.05 vs. PDGF-BB(−); †P < 0.05 vs. PDGF-BB(+). (E), (F). Cell migration was assessed by a scratch wound assay in CASMC treated with 0.5 mM 4-PBA (E) or 0.5 mM TUDCA (F) upon stimulation with PDGF-BB for 5 h. Photographs were taken, and migration distance was measured by ImageJ. *P < 0.05.
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f3: Effects of chemical chaperones on neointima formation, cell proliferation and cell migration.(A), (B). Representative staining of EVG in the wired-injured left femoral arteries of mice treated with daily intraperitoneal injection of a vehicle (n = 11), 100 mg/kg 4-PBA (n = 8) or 500 mg/kg TUDCA (n = 6) for 4 weeks (A). Scale bars: 50 µm. The extent of neointima formation was evaluated as intima-to-media ratio in the wire-injured femoral artery (B). *P < 0.05 vs. Vehicle. (C), (D). Cell proliferation was assessed by an MTS assay in chronic stimulation with 20 ng/ml PDGF-BB for 48 h in CASMC treated with 0-0.5 mM of 4-PBA (C) or 0–0.5 mM of TUDCA (D). *P < 0.05 vs. PDGF-BB(−); †P < 0.05 vs. PDGF-BB(+). (E), (F). Cell migration was assessed by a scratch wound assay in CASMC treated with 0.5 mM 4-PBA (E) or 0.5 mM TUDCA (F) upon stimulation with PDGF-BB for 5 h. Photographs were taken, and migration distance was measured by ImageJ. *P < 0.05.

Mentions: Treatment with ER stress reducers known as chemical chaperones, 4-phenylbutyric acid (4-PBA) and tauroursodeoxycholic acid (TUDCA), for 4 weeks did not affect media thickness but significantly decreased intima thickness, resulting in a reduction in the intima-to-media ratio, a severity index of neointima formation, by 50.0% and 72.8%, respectively, compared with those after vehicle treatment (Figure 3A, B).


Reduction of endoplasmic reticulum stress inhibits neointima formation after vascular injury.

Ishimura S, Furuhashi M, Mita T, Fuseya T, Watanabe Y, Hoshina K, Kokubu N, Inoue K, Yoshida H, Miura T - Sci Rep (2014)

Effects of chemical chaperones on neointima formation, cell proliferation and cell migration.(A), (B). Representative staining of EVG in the wired-injured left femoral arteries of mice treated with daily intraperitoneal injection of a vehicle (n = 11), 100 mg/kg 4-PBA (n = 8) or 500 mg/kg TUDCA (n = 6) for 4 weeks (A). Scale bars: 50 µm. The extent of neointima formation was evaluated as intima-to-media ratio in the wire-injured femoral artery (B). *P < 0.05 vs. Vehicle. (C), (D). Cell proliferation was assessed by an MTS assay in chronic stimulation with 20 ng/ml PDGF-BB for 48 h in CASMC treated with 0-0.5 mM of 4-PBA (C) or 0–0.5 mM of TUDCA (D). *P < 0.05 vs. PDGF-BB(−); †P < 0.05 vs. PDGF-BB(+). (E), (F). Cell migration was assessed by a scratch wound assay in CASMC treated with 0.5 mM 4-PBA (E) or 0.5 mM TUDCA (F) upon stimulation with PDGF-BB for 5 h. Photographs were taken, and migration distance was measured by ImageJ. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4221790&req=5

f3: Effects of chemical chaperones on neointima formation, cell proliferation and cell migration.(A), (B). Representative staining of EVG in the wired-injured left femoral arteries of mice treated with daily intraperitoneal injection of a vehicle (n = 11), 100 mg/kg 4-PBA (n = 8) or 500 mg/kg TUDCA (n = 6) for 4 weeks (A). Scale bars: 50 µm. The extent of neointima formation was evaluated as intima-to-media ratio in the wire-injured femoral artery (B). *P < 0.05 vs. Vehicle. (C), (D). Cell proliferation was assessed by an MTS assay in chronic stimulation with 20 ng/ml PDGF-BB for 48 h in CASMC treated with 0-0.5 mM of 4-PBA (C) or 0–0.5 mM of TUDCA (D). *P < 0.05 vs. PDGF-BB(−); †P < 0.05 vs. PDGF-BB(+). (E), (F). Cell migration was assessed by a scratch wound assay in CASMC treated with 0.5 mM 4-PBA (E) or 0.5 mM TUDCA (F) upon stimulation with PDGF-BB for 5 h. Photographs were taken, and migration distance was measured by ImageJ. *P < 0.05.
Mentions: Treatment with ER stress reducers known as chemical chaperones, 4-phenylbutyric acid (4-PBA) and tauroursodeoxycholic acid (TUDCA), for 4 weeks did not affect media thickness but significantly decreased intima thickness, resulting in a reduction in the intima-to-media ratio, a severity index of neointima formation, by 50.0% and 72.8%, respectively, compared with those after vehicle treatment (Figure 3A, B).

Bottom Line: 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.Suppression of ER stress would be a novel strategy against post-angioplasty vascular restenosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan.

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.

Show MeSH
Related in: MedlinePlus