title: Angiotensin 1-7 ameliorates diabetic cardiomyopathy and diastolic dysfunction in db/db mice by reducing lipotoxicity and inflammation.
abstract: BACKGROUND
  The angiotensin-converting enzyme 2 and angiotensin-(1-7) (Ang 1-7)/MasR (Mas receptor) axis are emerging as a key pathway that can modulate the development of diabetic cardiomyopathy. We studied the effects of Ang 1-7 on diabetic cardiomyopathy in db/db diabetic mice to elucidate the therapeutic effects and mechanism of action.
  
  
  RESULTS
  Ang 1-7 was administered to 5-month-old male db/db mice for 28 days via implanted micro-osmotic pumps. Ang 1-7 treatment ameliorated myocardial hypertrophy and fibrosis with normalization of diastolic dysfunction assessed by pressure-volume loop analysis and echocardiography. The functional improvement by Ang 1-7 was accompanied by a reduction in myocardial lipid accumulation and systemic fat mass and inflammation and increased insulin-stimulated myocardial glucose oxidation. Increased myocardial protein kinase C levels and loss of phosphorylation of extracellular signal-regulated kinase 1/2 were prevented by Ang 1-7. Furthermore, Ang 1-7 treatment decreased cardiac triacylglycerol and ceramide levels in db/db mice, concomitantly with an increase in myocardial adipose triglyceride lipase expression. Changes in adipose triglyceride lipase expression correlated with increased SIRT1 (silent mating type information regulation 2 homolog 1) levels and deacetylation of FOXO1 (forkhead box O1).
  
  
  CONCLUSIONS
  We identified a novel beneficial effect of Ang 1-7 on diabetic cardiomyopathy that involved a reduction in cardiac hypertrophy and lipotoxicity, adipose inflammation, and an upregulation of adipose triglyceride lipase. Ang 1-7 completely rescued the diastolic dysfunction in the db/db model. Ang 1-7 represents a promising therapy for diabetic cardiomyopathy associated with type 2 diabetes mellitus.
authors.affiliation: Department of Pediatrics, Department of Pharmacology, Mazankowski Alberta Heart Institute, Department of Physiology, and Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Mori
authors.forename: Vaibhav B
authors.initials: VB
authors.lastname: Patel
authors.forename: Osama
authors.initials: O
authors.lastname: Abo Alrob
authors.forename: Ratnadeep
authors.initials: R
authors.lastname: Basu
authors.forename: Tariq
authors.initials: T
authors.lastname: Altamimi
authors.forename: Jessica
authors.initials: J
authors.lastname: Desaulniers
authors.forename: Cory S
authors.initials: CS
authors.lastname: Wagg
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D000803:Angiotensin I / Q000627:therapeutic use*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D058065:Diabetic Cardiomyopathies / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D003971:Diastole; D015150:Echocardiography, Doppler; D005500:Follow-Up Studies; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000627:therapeutic use; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D016276:Ventricular Function / Q000502:physiology*; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D008055:Lipids; D010446:Peptide Fragments; D014665:Vasodilator Agents; D000803:Angiotensin I; C118790:angiotensin I (1-7)
keywords: diabetic cardiomyopathies