Angiotensin 1–7 Ameliorates Diabetic Cardiomyopathy and Diastolic Dysfunction in db/db Mice by Reducing Lipotoxicity and InflammationCLINICAL PERSPECTIVE
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.
- Received July 26, 2013.
- Accepted January 2, 2014.
- © 2014 American Heart Association, Inc.