title: Renin inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques.
abstract: OBJECTIVE
  The interaction between the renin-angiotensin system and toll-like receptors (TLRs) in the pathogenesis of advanced atherosclerotic plaques is not well understood. We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E-deficient (ApoE(-/-)) mice with a special focus on plaque neovessel formation.
  
  
  RESULTS
  Four-wk-old ApoE(-/-) mice were fed a high-fat diet for 8 wks, and the mice were randomly assigned to one of three groups and administered a vehicle, hydralazine, or aliskiren for an additional 12 wks. Aliskiren reduced the atherosclerotic plaque area and plaque neovessel density. It increased the plaque collagen and elastin contents, and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S (CatS) protein. Aliskiren also decreased the levels of AT1R, gp91phox, TLR2, monocyte chemotactic protein-1, and CatS mRNAs in the aortic roots. Hydralazine had no beneficial vascular effects, although its administration resulted in the same degree of blood pressure reduction as aliskiren. CatS deficiency mimicked the aliskiren-mediated vasculoprotective effect in the ApoE(-/-) mice, but aliskiren showed no further benefits in ApoE(-/-) CatS(-/-) mice. In vitro, TLR2 silencing reduced CatS expression induced by angiotensin II. Moreover, aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or/and ex vivo.
  
  
  CONCLUSIONS
  Renin inhibition appears to inhibit advanced plaque neovessel formation in ApoE(-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation, partly by reducing AT1R/TLR2-mediated CatS activation and activity, thus regressing advanced atherosclerosis.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hongxian
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Cardiology, Yanbian University Hospital, Yanji, China. Electronic address: xianwu@med.nagoya-u.ac.jp.
authors.forename: Xian Wu
authors.initials: XW
authors.lastname: Cheng
authors.affiliation: Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Lina
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Chang-Ning
authors.initials: CN
authors.lastname: Hao
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Mutsuharu
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Takeshita
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Mohammad Shoaib
authors.initials: MS
authors.lastname: Hamrah
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, United States.
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
authors.affiliation: Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kuzuya
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: murohara@med.nagoya-u.ac.jp.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood* / Q000188:drug therapy*; D001794:Blood Pressure; D002352:Carrier Proteins / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005650:Fumarates / Q000494:pharmacology*; D020868:Gene Silencing; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D009687:Nuclear Proteins; D058226:Plaque, Atherosclerotic / Q000473:pathology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D016896:Treatment Outcome; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000804:Angiotensin II; D001057:Apolipoproteins E; D002352:Carrier Proteins; D002403:Cathepsins; D018932:Chemokine CCL2; D005650:Fumarates; D006830:Hydralazine; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D044140:Receptor, Angiotensin, Type 1; D051195:Toll-Like Receptor 2; D019010:Vascular Cell Adhesion Molecule-1; D000092502:Renin Inhibitors; C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; C512398:PIMREG protein, human; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; C446481:aliskiren
keywords: Aliskiren; Angiotensin II; Atherosclerosis; Cathepsin S; Toll-like receptor 2