Targeting the Angiotensin AT2 Receptor to Treat Cardiac Fibrosis and Heart Failure

Background Cardiac fibrosis underpins all types of heart failure although there is generally a lack of effective anti-fibrotic therapies. Activation of the angiotensin type 2 receptor (AT2R) evokes anti-fibrotic effects in multiple organs [1]. Our lab has synthesised a library of AT2R-selective ligands that exhibit greater AT2R to AT1R selectivity than gold standard, C21. The aim of this study is to determine the anti-fibrotic effects of 3 novel AT2R-selective agonists (β-Pro7-Trp8-AngIII, D-Arg2-β-Pro7-Trp8-AngIII and N-Ac-β-Pro7-Trp8-AngIII) in mouse fibrotic models as well as in human cardiac fibroblast (HCFs). Methods and Results High salt diet (HSD) (5% NaCl) for 8 weeks increased left ventricular fibrosis (by both picrosirius red and hydroxyproline analysis) (all p<0.05 vs NS group), which was associated with increased myofibroblast differentiation and cardiac inflammation. Each AT2R-selective agonist (intervention given at 0.1mg/kg/day by sc-minipump, weeks 5-8) normalised HSD-induced cardiac fibrosis, which was companied by reduced myofibroblast differentiation and cardiac inflammation (all p<0.05 vs HS group). In HCFs, both C21 and N-Ac-β-Pro7-Trp8-AngIII dose dependently inhibited TGF-β1-induced pSMAD3 production and fibronectin production. Using a novel MI-surgical model of heart failure (which does not require intubation [2]), C21 (0.3 mg/kg/day SC) prevented MI-induced increase in cardiac fibrosis and improved cardiac function at 28 days. Conclusions Collectively, these findings demonstrate that activation of cardiac AT2R is anti-fibrotic in both repetitive and reparative models of cardiac fibrosis and in human cardiac fibroblasts, highlighting a potential therapeutic strategy of stimulating AT2R in cardiac fibrosis and heart failure. References [1] Wang Y, Del Borgo M, Lee H W, et al. Anti-fibrotic potential of AT2 receptor antagonists. Front Pharmacol 2017;8:564.[2] Gao E, Lei YH, Shang X, et al. A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse. Circ Res. 2010;107(12):1445-53.