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

Autor: Lakshmi Pulakat, Madhavi Gavini, Abuzar Mahmood, Anthony Belechia, Ryan Toedebusch, Paige Beauparlant, Vincent DeMarco, Senthil Kumar, Sivakumar Ardhanari
Rok vydání: 2017
Předmět:
Zdroj: Hypertension. 70
ISSN: 1524-4563
0194-911X
DOI: 10.1161/hyp.70.suppl_1.p353
Popis: 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
Databáze: OpenAIRE
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