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Abstract P635: Improvement of Cardiovascular Outcomes in Diabetic Rats by a Novel Angiotensin II Receptor Peptide Agonist

Diabetes Mellitus (DM) is an independent predictor of cardiovascular disease (CVD). Recent reports show that Angiotensin II type 2 receptor (AT2R) promotes cardiac repair after myocardial infarction. Therefore, we hypothesized that activation of AT2R would improve cardiac function in diabetic rats. Male Zucker obese (ZO) rats are leptin receptor–deficient and exhibit hyperphagia, obesity, insulin resistance and hyperlipidemia. They are a widely used rodent model for early stage Type 2 DM (T2DM). We and others have reported that male ZO rats exhibit diastolic and systolic dysfunction. Therefore we investigated whether a two week treatment with an AT2R agonist could improve cardiac functions of young male ZO rats. Thirteen-week old male ZO rats were subjected to daily intraperitoneal injections (0.9mg/kg/day) with a novel peptide AT2R agonist, NP-6A4 (from Novopyxis, Inc.) dissolved in saline (n=7) or saline only (n=6) for two weeks. Conventional echocardiography and speckle tracking strain analysis were performed using a Vevo 2100 (visualsonics) small animal ultrasound system. Fasting (6 hours) plasma analysis showed that triglycerides (mg/dL) were significantly reduced in response to treatment (ZO+ Saline=1229±164; ZO+NP-6A4= 610±109; p<0.015). Importantly, NP-6A4 treatment improved E/E’ ratio (ZO+Saline= 32.3±2.06; ZO+NP-6A4= 26±2.1; p<0.005), which indicates a significant improvement in diastolic dysfunction. A unit rise in the E/E' ratio is associated with a 17% increment in risk of a cardiac event. Moreover, myocardial performance index of NP-6A4 treated rats was also reduced (ZO+ Saline= 0.516±0.03; ZO+ NP-6A4= 0.389±0.02; p<0.006). Finally, circumferential strain (deg/sec) of endocardium (short axis view) was also significantly improved in response to treatment, while no significant changes were observed in radial or longitudinal strains (ZO+ Saline= -20.56±1.65; ZO+ NP-6A4= -26.11±2.47; p<0.024). Collectively, these data suggest that activation of the AT2R by NP-6A4 had significant lipid lowering effect and improved diastolic and systolic functions in diabetic rats.