title: Enhanced sterol response element-binding protein in postintervention restenotic blood vessels plays an important role in vascular smooth muscle proliferation.
abstract: Postintervention restenosis (PIRS) after balloon angioplasty or stent implantation is a limitation for these interventional procedures even with the advent of new drug-eluting stents. Sterol regulatory element-binding proteins (SREBP) are transcription factors governing cellular lipid biosynthesis and thus critical in the regulation of the lipid-rich cell membranes. PIRS following injury results partially from newly proliferating cells expressing vascular smooth muscle cell (VSMC) markers. Platelet-derived growth factor (PDGF), lysophosphatidic acid (LPA) and alpha(1)-adrenergic receptor stimulation are well recognized diverse mitogens for VSMC activation in PIRS. We examined whether PDGF, LPA and alpha(1)-adrenergic receptor stimulation with phenylephrine (PE) regulate SREBP expression and subsequently, VSMC proliferation. Our results show that PDGF, LPA and PE upregulate SREBP-1 in a time- and dose-dependent manner. PDGF, LPA and PE-mediated proliferation is dependent on SREBP since inhibition of SREBP expression using targeted knockdown of the SREBP precursor SREBP activating protein (SCAP) by siRNA led to an attenuation of SREBP expression and decreased PDGF, LPA and PE induced proliferation. In two different in vivo PIRS models we found that SREBP-1 was enhanced in the injured blood vessel wall, especially within the neointima and co-localized with alpha-smooth muscle actin positive cells. Thus, SREBP is enhanced in the vessel wall following PIRS and is important in the regulation of pro-hyperplasia molecular signaling. SREBP inhibition may be a powerful tool to limit PIRS.
authors: Eugene Feiner Laboratory of Vascular Biology and Thrombosis, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors: Rui-Hai
authors: RH
authors: Zhou
authors: Stéphanie
authors: S
authors: Pesant
authors: Heather I
authors: HI
authors: Cohn
authors: Andrea D
authors: AD
authors: Eckhart
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism*; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000378:metabolism*; D004195:Disease Models, Animal; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1; D015607:Stents; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D008565:Membrane Proteins; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; D018340:Receptors, Adrenergic, alpha-1; C102196:SREBP cleavage-activating protein; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D010656:Phenylephrine; C032881:lysophosphatidic acid