Abstract P353: Attenuation of Cardiac Fibrosis, Hypertrophy and Myopathy by AT2R Agonist NP-6A4

Abstract

Adverse cardiac remodeling (hypertrophy, fibrosis and myopathy) underlies cardiac dysfunction and heart failure. Male Zucker obese (ZO:fa/fa) rat that suffers from cardiac dysfunction, adverse remodeling, and heart failure with preserved ejection fraction is a useful model to study the effects of cardioprotective drugs. We reported that NP-6A4 (Novopyxis Inc. Cambridge, MA), a peptide agonist of the Angiotensin II Type 2 Receptor (AT2R), protected mouse cardiomyoblast HL-1 cells and human coronary artery vascular smooth muscle cells (hCAVSMCs) from acute nutrient serum deficiency stress better than β-AR-Blockers, ARBs, and AT2R agonist CGP42112A. This effect was inhibited by AT2R-specific antagonist PD123319, confirming that NP-6A4 acts through AT2R. AT2R is a cardiac and vascular reparative molecule that protects the heart and vasculature from structural damage and fibrosis. No current drugs increase AT2R expression. We report that NP-6A4 treatment (1μM) increased AT2R mRNA (up to 4 fold; p≤0.05) in hCAVSMCs and human coronary artery endothelial cells (up to 8 fold; p≤0.05). This effect was inhibited by PD123319 (10 μM). Treatment of 11-week old male ZO rats with heart disease with NP-6A4 (1.8mg/kg/day in saline, delivered once daily subcutaneously; N=7) increased cardiac AT2R expression and mitigated cardiac dysfunction and adverse remodeling. Quantitative RT-PCR and immunohistochemistry analysis showed that 2 weeks of NP-6A4 treatment increased cardiac AT2R mRNA (up to 9 fold) and protein (1.5-3 fold) compared to controls (N=6) receiving saline (p<0.01). NP-6A4 treatment improved cardiac parameters; endocardial circumferential strain (p≤0.05), myocardial performance index (MPI) (p≤0.005), and E/E’ ratio (p≤0.002). NP-6A4 treatment also increased cardiac capillary density (118% compared to saline treatedl; p≤0.002), and reduced interstitial fibrosis (77% compared to saline treated; p≤0.039.) At 19-weeks (after 8 weeks of treatment), cardiac tissues from 5 out of 6 control rats exhibited regions of myopathy. Only 2 out 7 NP-6A4 treated rats exhibited similar levels of myopathy in the heart. We propose that NP-6A4 attenuates adverse remodeling and improves cardiac function by increasing AT2R expression in cardiac cells.