Angiotensin 1-7 ameliorates diabetic cardiomyopathy and diastolic dysfunction in db/db mice by reducing lipotoxicity and inflammation

Circ Heart Fail. 2014 Mar 1;7(2):327-39. doi: 10.1161/CIRCHEARTFAILURE.113.000672. Epub 2014 Jan 3.


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.

Methods and 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.

Keywords: diabetic cardiomyopathies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / therapeutic use*
  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Experimental*
  • Diabetic Cardiomyopathies / complications
  • Diabetic Cardiomyopathies / diagnosis
  • Diabetic Cardiomyopathies / drug therapy*
  • Diastole
  • Echocardiography, Doppler
  • Follow-Up Studies
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Insulin Resistance
  • Lipids / blood*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Peptide Fragments / therapeutic use*
  • Vasodilator Agents / therapeutic use
  • Ventricular Dysfunction, Left / blood
  • Ventricular Dysfunction, Left / drug therapy*
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Function / physiology*
  • Ventricular Pressure / drug effects


  • Blood Glucose
  • Lipids
  • Peptide Fragments
  • Vasodilator Agents
  • Angiotensin I
  • angiotensin I (1-7)