title: ACE2 Deficiency Worsens Epicardial Adipose Tissue Inflammation and Cardiac Dysfunction in Response to Diet-Induced Obesity.
abstract: Obesity is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; angiotensin (Ang)-converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. We studied the role of ACE2 in obesity-mediated cardiac dysfunction. ACE2 null (ACE2KO) and wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet and studied at 6 months of age. Loss of ACE2 resulted in decreased weight gain but increased glucose intolerance, epicardial adipose tissue (EAT) inflammation, and polarization of macrophages into a proinflammatory phenotype in response to HFD. Similarly, human EAT in patients with obesity and heart failure displayed a proinflammatory macrophage phenotype. Exacerbated EAT inflammation in ACE2KO-HFD mice was associated with decreased myocardial adiponectin, decreased phosphorylation of AMPK, increased cardiac steatosis and lipotoxicity, and myocardial insulin resistance, which worsened heart function. Ang 1-7 (24 µg/kg/h) administered to ACE2KO-HFD mice resulted in ameliorated EAT inflammation and reduced cardiac steatosis and lipotoxicity, resulting in normalization of heart failure. In conclusion, ACE2 plays a novel role in heart disease associated with obesity wherein ACE2 negatively regulates obesity-induced EAT inflammation and cardiac insulin resistance.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Vaibhav B
authors.initials: VB
authors.lastname: Patel
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada Departments of Pediatrics and Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Mori
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Brent A
authors.initials: BA
authors.lastname: McLean
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Ratnadeep
authors.initials: R
authors.lastname: Basu
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Subhash K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Tharmarajan
authors.initials: T
authors.lastname: Ramprasath
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Nirmal
authors.initials: N
authors.lastname: Parajuli
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.affiliation: Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada Departments of Pediatrics and Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada Department of Physiology, University of Alberta, Edmonton, Alberta, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada gavin.oudit@ualberta.ca.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue / Q000276:immunology*; D000803:Angiotensin I / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D059305:Diet, High-Fat; D004797:Enzyme-Linked Immunosorbent Assay; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007333:Insulin Resistance / Q000235:genetics; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D009765:Obesity / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency* / Q000235:genetics; D010496:Pericardium / Q000276:immunology*; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D013318:Stroke Volume; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014665:Vasodilator Agents / Q000494:pharmacology; D015430:Weight Gain / Q000235:genetics
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D000803:Angiotensin I; D055372:AMP-Activated Protein Kinases; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)