title: Heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease.
abstract: Angiotensin-converting enzyme 2 (ACE2) metabolizes Ang II into Ang 1-7 thereby negatively regulating the renin-angiotensin system. However, heart disease in humans and in animal models is associated with only a partial loss of ACE2. ACE2 is an X-linked gene; and as such, we tested the clinical relevance of a partial loss of ACE2 by using female ACE2(+/+) (wildtype) and ACE2(+/-) (heterozygote) mice. Pressure overload in ACE2(+/-) mice resulted in greater LV dilation and worsening systolic and diastolic dysfunction. These changes were associated with increased myocardial fibrosis, hypertrophy, and upregulation of pathological gene expression. In response to Ang II infusion, there was increased NADPH oxidase activity and myocardial fibrosis resulting in the worsening of Ang II-induced diastolic dysfunction with a preserved systolic function. Ang II-mediated cellular effects in cultured adult ACE2(+/-) cardiomyocytes and cardiofibroblasts were exacerbated. Ang II-mediated pathological signaling worsened in ACE2(+/-) hearts characterized by an increase in the phosphorylation of ERK1/2 and JNK1/2 and STAT-3 pathways. The ACE2(+/-) mice showed an exacerbated pressor response with increased vascular fibrosis and stiffness. Vascular superoxide and nitrotyrosine levels were increased in ACE2(+/-) vessels consistent with increased vascular oxidative stress. These changes occurred with increased renal fibrosis and superoxide production. Partial heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease secondary to pressure overload and Ang II infusion.
  
  
  CONCLUSIONS
  Heart disease in humans with idiopathic dilated cardiomyopathy is associated with a partial loss of ACE2. Heterozygote female ACE2 mutant mice showed enhanced susceptibility to pressure overload-induced heart disease. Heterozygote female ACE2 mutant mice showed enhanced susceptibility to Ang II-induced heart and vascular diseases. Partial loss of ACE2 is sufficient to enhance the susceptibility to heart disease.
authors.affiliation: Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, T6G 2S2, Canada.
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.forename: Vaibhav B
authors.initials: VB
authors.lastname: Patel
authors.forename: Nirmal
authors.initials: N
authors.lastname: Parajuli
authors.forename: Dong
authors.initials: D
authors.lastname: Fan
authors.forename: Ratnadeep
authors.initials: R
authors.lastname: Basu
authors.forename: Zuocheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Tharmarajan
authors.initials: T
authors.lastname: Ramprasath
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004452:Echocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D006321:Heart / Q000187:drug effects; D006331:Heart Diseases / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2
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