title: Deletion of angiotensin-converting enzyme 2 promotes the development of atherosclerosis and arterial neointima formation.
abstract: OBJECTIVE
  Angiotensin-converting enzyme 2 (ACE2) is known as a negative regulator of the renin-angiotensin system. We aimed to determine the roles of ACE2 on the development of vascular diseases.
  
  
  RESULTS
  Using two diversely different models of vascular diseases, hyperlipidaemia-induced atherosclerosis in apolipoprotein E knockout (KO) mice and mechanical injury-induced arterial neointimal hyperplasia in C57Bl6 mice, we examined whether ACE2 deficiency could affect formation of the vascular lesions. ACE2 deficiency resulted in significantly larger vascular lesions in both aortic atherosclerotic plaques and arterial neointima formation, compared with ACE2(+) control. These ACE2-deficient vascular lesions exhibited enhanced accumulation of macrophages into the lesions and proliferation of vascular smooth muscle cells (VSMCs), accompanied with increased angiotensin-II (Ang-II) levels and enhanced expression of vascular inflammation-related genes, including vascular cell adhesion molecule (VCAM)-1, monocyte chemoattractant protein (MCP)-1, and matrix metalloproteinase (MMP)9 in aorta/artery tissues. Primary bone marrow macrophages and aortic VSMCs isolated from ACE2 KO mice also displayed enhanced pro-inflammatory responsiveness such as up-regulated gene/protein expression of VCAM-1, MCP-1, and MMP9 to stimulation with tumour necrosis factor-α and Ang-II. The similar phenotype was shown in human macrophages and aortic VSMCs that were transfected with ACE2-specific siRNA. In ACE2-deficient VSMCs, inhibition of c-Jun N-terminal kinase (JNK) by pharmacological blockade with SP600125 or genetic knockdown with JNK-specific siRNA significantly attenuated their pro-inflammatory phenotype.
  
  
  CONCLUSIONS
  ACE2 deficiency promotes the development of vascular diseases associated with Ang-II-mediated vascular inflammation and activation of the JNK signalling, leading to the notion that ACE2 potentially confers protection against vascular diseases.
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sahara
authors.forename: Masayasu
authors.initials: M
authors.lastname: Ikutomi
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Morita
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Minami
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakajima
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Hirata
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001011:Aorta / Q000201:enzymology* / Q000473:pathology; D001018:Aortic Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D018836:Inflammation Mediators / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000473:pathology; D058426:Neointima; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency* / Q000235:genetics; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D057772:Vascular System Injuries / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D000804:Angiotensin II; D048031:JNK Mitogen-Activated Protein Kinases; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2
keywords: Angiotensin II; Angiotensin-converting enzyme 2 remodelling; Atherosclerosis; Vascular disease; c-Jun N-terminal kinase