Angiotensin 1-7 Ameliorates Diabetic Cardiomyopathy and Diastolic Dysfunction in db/db Mice by Reducing Lipotoxicity and Inflammation
Background—The angiotensin converting enzyme 2 and Ang 1-7/MasR axis is 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 PKC levels and loss of phosphorylation of Erk1/2 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 (ATGL) expression. Changes in ATGL expression correlated with increased SIRT1 levels and deacetylation of FOXO1.
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 ATGL. 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.
- angiotensin 1-7
- heart failure with preserved ejection fraction
- diabetic cardiomyopathy
- diastolic dysfunction
- Received July 26, 2013.
- Accepted January 2, 2014.