title: Role of IκB kinase-β in the growth-promoting effects of angiotensin II in vitro and in vivo.
abstract: OBJECTIVE
  Angiotensin II (Ang II) is implicated in processes underlying the development of arterial wall remodeling events, including cellular hypertrophy and inflammation. We previously documented the activation of IκB kinase-β (IKKβ) in Ang II-treated cells, a kinase involved in inflammatory reactions. In light of a study suggesting a role of IKKβ in angiogenesis through its effect on the tuberous sclerosis (TSC)1/2-mammalian target of rapamycin complex 1 pathway in cancer cells, we hypothesized that targeting IKKβ could reduce arterial remodeling events by affecting both the inflammatory and the growth-promoting response of Ang II.
  
  
  RESULTS
  Treatment of aortic vascular smooth muscle cells with Ang II induced the rapid and sustained phosphorylation of TSC1 on Ser511, which paralleled the activation of effectors of the mammalian target of rapamycin complex 1 pathway. Furthermore, we show that Ser511 of TSC1 acted as a phosphoacceptor site for Ang II-activated IKKβ. Consistent with this, the use of different short hairpin RNA constructs targeting IKKβ reduced Ang II-induced TSC1, S6 kinase, and eukaryotic translation initiation factor 4E-binding protein 1 phosphorylation and the rate of protein synthesis. Overexpression of TSC1 lacking Ser511 in vascular smooth muscle cells also exerted detrimental effects on the hypertrophic effect of Ang II. Furthermore, the selective IKKβ inhibitor N-(6-chloro-7-methoxy-9H-β-carbolin-8-yl)-2 methylnicotinamide reduced the inflammatory response and dose-dependently diminished Ang II-induced TSC1 phosphorylation and effectors of the mammalian target of rapamycin complex 1 pathway, leading to inhibition of protein synthesis in vitro and in rat arteries in vivo.
  
  
  CONCLUSIONS
  Our findings provide new insights into the molecular understanding of the pathological role of Ang II and assist in identifying the beneficial effects of IKKβ inhibition for the treatment of cardiovascular diseases.
authors.affiliation: From the Faculty of Pharmacy, Université de Montréal, Montréal, Canada.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Doyon
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: van Zuylen
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Servant
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006984:Hypertrophy; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D055104:Infusions, Subcutaneous; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D010750:Phosphoproteins; C000624652:Tsc1 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000804:Angiotensin II; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase
keywords: I-kappa B kinase β; angiotensin II; hypertrophy; mammalian target of rapamycin; protein translational initiation; tuberous sclerosis 1