title: Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway.
abstract: BACKGROUND
  Angiotensin II (Ang II) has been reported to contribute to the pathogenesis of various human diseases including atherosclerosis, and inhibition of Ang II activity has been shown to reduce the morbidity and mortality of cardiovascular diseases. We have previously demonstrated that vascular cell senescence contributes to the pathogenesis of atherosclerosis; however, the effects of Ang II on vascular cell senescence have not been examined.
  
  
  RESULTS
  Ang II significantly induced premature senescence of human vascular smooth muscle cells (VSMCs) via the p53/p21-dependent pathway in vitro. Inhibition of this pathway effectively suppressed induction of proinflammatory cytokines and premature senescence of VSMCs by Ang II. Ang II also significantly increased the number of senescent VSMCs and induced the expression of proinflammatory molecules and of p21 in a mouse model of atherosclerosis. Loss of p21 markedly ameliorated the induction of proinflammatory molecules by Ang II, thereby preventing the development of atherosclerosis. Replacement of p21-deficient bone marrow cells with wild-type cells had little influence on the protective effect of p21 deficiency against the progression of atherogenesis induced by Ang II.
  
  
  CONCLUSIONS
  We demonstrated that Ang II promotes vascular inflammation by inducing premature senescence of VSMCs both in vitro and in vivo. Our results suggest a critical role of p21-dependent premature senescence of VSMCs in the pathogenesis of atherosclerosis.
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Takeshige
authors.initials: T
authors.lastname: Kunieda
authors.forename: Tohru
authors.initials: T
authors.lastname: Minamino
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Nishi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tateno
authors.forename: Tomomi
authors.initials: T
authors.lastname: Oyama
authors.forename: Taro
authors.initials: T
authors.lastname: Katsuno
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Miyauchi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Orimo
authors.forename: Sho
authors.initials: S
authors.lastname: Okada
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takamura
authors.forename: Toshio
authors.initials: T
authors.lastname: Nagai
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D019588:Aging, Premature / Q000503:physiopathology*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000503:physiopathology*; D001794:Blood Pressure; D002478:Cells, Cultured; D004195:Disease Models, Animal; D017930:Genes, Reporter; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000254:growth & development*; D014162:Transfection
chemical_list: D001057:Apolipoproteins E; D000804:Angiotensin II