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.

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.

• Authors: Jun Mori, Vaibhav B Patel, Osama Abo Alrob, Ratnadeep Basu, Tariq Altamimi, Jessica Desaulniers, Cory S Wagg, Zamaneh Kassiri, Gary D Lopaschuk, Gavin Y Oudit
• Journal: Circulation. Heart failure (Circ Heart Fail) Vol. 7 Issue 2 Pg. 327-39 (Mar 01 2014) ISSN: 1941-3297 [Electronic] United States
• PMID: 24389129 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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