RNA interference targeting STIM1 suppresses vascular smooth muscle cell proliferation and neointima formation in the rat

Fleur C. Aubart; Yassine Sassi; Nathalie Mougenot; Nathalie Mougenot; Cédric Vrignaud; Pascal Leprince; Philippe Lechat; Anne Marie Lompré; Jean Sébastien Hulot

doi:10.1038/mt.2008.291

RNA interference targeting STIM1 suppresses vascular smooth muscle cell proliferation and neointima formation in the rat

Fleur C. Aubart, Yassine Sassi, Nathalie Mougenot, Nathalie Mougenot, Cédric Vrignaud, Pascal Leprince, Philippe Lechat, Anne Marie Lompré, Jean Sébastien Hulot

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82 Scopus citations

Abstract

Our objective was to study the expression and function of stromal interaction molecule 1 (STIM1), an endoplasmic reticulum protein recently identified as the calcium sensor that regulated Ca²⁺ -released activated channels in T cells. STIM1 was found to be upregulated in serum-induced proliferating human coronary artery smooth muscle cells (hCASMCs) as well as in the neointima of injured rat carotid arteries. Growth factors-induced proliferation was significantly lower in hCASMC transfected with STIM1 siRNA than in those transfected with scrambled siRNA (increase relative to 0.1% S: 116 ± 12% and 184 ± 16%, respectively, P < 0.01). To assess the role of STIM1 in preventing vascular smooth muscle cells (VSMCs) proliferation in vivo, we infected balloon-injured rat carotid arteries with an adenoviral vector expressing a short hairpin (sh) RNA against rat STIM1 mRNA (Ad-shSTIM1). Intima/media ratios reflecting the degree of restenosis were significantly lower in Ad-shSTIM1- infected arteries than in Ad-shLuciferase-infected arteries (0.34 ± 0.02 vs. 0.92 ± 0.11, P < 0.006). Finally, we demonstrated that silencing STIM1 prevents activation of the transcription factor NFAT (nuclear factor of activated T cell). In conclusion, STIM1 appears as a major regulator of in vitro and in vivo VSMC proliferation, representing a novel and original pharmacological target for prominent vascular proliferative diseases.

Original language	English
Pages (from-to)	455-462
Number of pages	8
Journal	Molecular Therapy
Volume	17
Issue number	3
DOIs	https://doi.org/10.1038/mt.2008.291
State	Published - 2009
Externally published	Yes

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@article{1291aebfaba4436d82d9c2eec71e9373,

title = "RNA interference targeting STIM1 suppresses vascular smooth muscle cell proliferation and neointima formation in the rat",

abstract = "Our objective was to study the expression and function of stromal interaction molecule 1 (STIM1), an endoplasmic reticulum protein recently identified as the calcium sensor that regulated Ca2+ -released activated channels in T cells. STIM1 was found to be upregulated in serum-induced proliferating human coronary artery smooth muscle cells (hCASMCs) as well as in the neointima of injured rat carotid arteries. Growth factors-induced proliferation was significantly lower in hCASMC transfected with STIM1 siRNA than in those transfected with scrambled siRNA (increase relative to 0.1% S: 116 ± 12% and 184 ± 16%, respectively, P < 0.01). To assess the role of STIM1 in preventing vascular smooth muscle cells (VSMCs) proliferation in vivo, we infected balloon-injured rat carotid arteries with an adenoviral vector expressing a short hairpin (sh) RNA against rat STIM1 mRNA (Ad-shSTIM1). Intima/media ratios reflecting the degree of restenosis were significantly lower in Ad-shSTIM1- infected arteries than in Ad-shLuciferase-infected arteries (0.34 ± 0.02 vs. 0.92 ± 0.11, P < 0.006). Finally, we demonstrated that silencing STIM1 prevents activation of the transcription factor NFAT (nuclear factor of activated T cell). In conclusion, STIM1 appears as a major regulator of in vitro and in vivo VSMC proliferation, representing a novel and original pharmacological target for prominent vascular proliferative diseases.",

author = "Aubart, {Fleur C.} and Yassine Sassi and Nathalie Mougenot and Nathalie Mougenot and C{\'e}dric Vrignaud and Pascal Leprince and Philippe Lechat and Lompr{\'e}, {Anne Marie} and Hulot, {Jean S{\'e}bastien}",

note = "Funding Information: We thank Dr Jack Ross (La Jolla, CA) for providing the polyclonal anti human STIM1 antibody. This work is supported by Fondation Leducq through the CAERUS network (research agreement 05CVD03 to AML). YS is the recipient of a PhD fellowship from the French MENRS.",

year = "2009",

doi = "10.1038/mt.2008.291",

language = "English",

volume = "17",

pages = "455--462",

journal = "Molecular Therapy",

issn = "1525-0016",

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T1 - RNA interference targeting STIM1 suppresses vascular smooth muscle cell proliferation and neointima formation in the rat

AU - Aubart, Fleur C.

AU - Sassi, Yassine

AU - Mougenot, Nathalie

AU - Vrignaud, Cédric

AU - Leprince, Pascal

AU - Lechat, Philippe

AU - Lompré, Anne Marie

AU - Hulot, Jean Sébastien

N1 - Funding Information: We thank Dr Jack Ross (La Jolla, CA) for providing the polyclonal anti human STIM1 antibody. This work is supported by Fondation Leducq through the CAERUS network (research agreement 05CVD03 to AML). YS is the recipient of a PhD fellowship from the French MENRS.

PY - 2009

Y1 - 2009

N2 - Our objective was to study the expression and function of stromal interaction molecule 1 (STIM1), an endoplasmic reticulum protein recently identified as the calcium sensor that regulated Ca2+ -released activated channels in T cells. STIM1 was found to be upregulated in serum-induced proliferating human coronary artery smooth muscle cells (hCASMCs) as well as in the neointima of injured rat carotid arteries. Growth factors-induced proliferation was significantly lower in hCASMC transfected with STIM1 siRNA than in those transfected with scrambled siRNA (increase relative to 0.1% S: 116 ± 12% and 184 ± 16%, respectively, P < 0.01). To assess the role of STIM1 in preventing vascular smooth muscle cells (VSMCs) proliferation in vivo, we infected balloon-injured rat carotid arteries with an adenoviral vector expressing a short hairpin (sh) RNA against rat STIM1 mRNA (Ad-shSTIM1). Intima/media ratios reflecting the degree of restenosis were significantly lower in Ad-shSTIM1- infected arteries than in Ad-shLuciferase-infected arteries (0.34 ± 0.02 vs. 0.92 ± 0.11, P < 0.006). Finally, we demonstrated that silencing STIM1 prevents activation of the transcription factor NFAT (nuclear factor of activated T cell). In conclusion, STIM1 appears as a major regulator of in vitro and in vivo VSMC proliferation, representing a novel and original pharmacological target for prominent vascular proliferative diseases.

AB - Our objective was to study the expression and function of stromal interaction molecule 1 (STIM1), an endoplasmic reticulum protein recently identified as the calcium sensor that regulated Ca2+ -released activated channels in T cells. STIM1 was found to be upregulated in serum-induced proliferating human coronary artery smooth muscle cells (hCASMCs) as well as in the neointima of injured rat carotid arteries. Growth factors-induced proliferation was significantly lower in hCASMC transfected with STIM1 siRNA than in those transfected with scrambled siRNA (increase relative to 0.1% S: 116 ± 12% and 184 ± 16%, respectively, P < 0.01). To assess the role of STIM1 in preventing vascular smooth muscle cells (VSMCs) proliferation in vivo, we infected balloon-injured rat carotid arteries with an adenoviral vector expressing a short hairpin (sh) RNA against rat STIM1 mRNA (Ad-shSTIM1). Intima/media ratios reflecting the degree of restenosis were significantly lower in Ad-shSTIM1- infected arteries than in Ad-shLuciferase-infected arteries (0.34 ± 0.02 vs. 0.92 ± 0.11, P < 0.006). Finally, we demonstrated that silencing STIM1 prevents activation of the transcription factor NFAT (nuclear factor of activated T cell). In conclusion, STIM1 appears as a major regulator of in vitro and in vivo VSMC proliferation, representing a novel and original pharmacological target for prominent vascular proliferative diseases.

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U2 - 10.1038/mt.2008.291

DO - 10.1038/mt.2008.291

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SN - 1525-0016

VL - 17

SP - 455

EP - 462

JO - Molecular Therapy

JF - Molecular Therapy

IS - 3

ER -

RNA interference targeting STIM1 suppresses vascular smooth muscle cell proliferation and neointima formation in the rat

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