RNA interference targeting STIM1 suppresses vascular smooth muscle cell proliferation and neointima formation in the rat.
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 Ca(2+)-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.
Aubart
Fleur C
FC
INSERM UMR S 956, Paris, France.
Sassi
Yassine
Y
Coulombe
Alain
A
Mougenot
Nathalie
N
Vrignaud
Cédric
C
Leprince
Pascal
P
Lechat
Philippe
P
Lompré
Anne-Marie
AM
Hulot
Jean-Sébastien
JS
D021581:Active Transport, Cell Nucleus; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000293:injuries / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels / Q000378:metabolism; D046509:Tissue Culture Techniques; D017539:Tunica Intima / Q000166:cytology* / Q000378:metabolism*; D015854:Up-Regulation
D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C103530:STIM1 protein, human; C518857:Stim1 protein, rat; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels