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 microosmotic 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. (Circ Heart Fail. 2014;7:327-339.)

Beneficial Effects of Angiotensin-(1–7) Against Deoxycorticosterone Acetate–Induced Diastolic Dysfunction Occur Independently of Changes in Blood Pressure

“…Consistent with these results, Mori et al 35 showed that Ang-(1-7) infusion prevented PKCα elevation in db/db mice.…”

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

“…Unoxidized FA accumulation in cardiac myocytes impairs energy metabolism and aggravates mitochondrial dysfunction, ROS overproduction, and lipoapoptosis (Drosatos & Schulze, 2013; Rodrigues et al., 1995). Several recent studies concluded that strategies to minimize ectopic fat accumulation and lipotoxicity have direct cardioprotective effects (Mori et al., 2014; Yang et al., 2007). To the best of our knowledge, the present study is the first to revealed that both exendin‐4 and saxagliptin significantly reduced lipid content in CMs both in vivo and in vitro by controlling the PPARa‐CD36 pathway, which is a major regulatory signal in cardiac FA metabolism.…”

Angiotensin 1–7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity

“…Dried samples were dissolved in 50 l of a 3:2 tert-butyl alcohol-Triton X-100-methyl alcohol mixture. TAG levels were quantitated colorimetrically as glycerol using an enzymatic assay (Wako Pure Chemical Industries, Osaka, Japan) (32). Plasma TAG levels were also quantified colorimetrically using the same enzymatic assay.…”