Abstract 13406: The Novel Biased Apelin Receptor Agonist MM07 Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension

Abstract

Introduction: Apelin, a ligand of the G protein-coupled apelin receptor, is a vasodilator and a positive cardiac inotrope. Apelin expression is reduced in pulmonary arterial hypertension (PAH) and administration is reported to be beneficial in animal models of PAH. A synthetic biased apelin receptor agonist (MM07) that preferentially activates G protein-dependent signalling could be used to reduce the detrimental cardiac hypertrophy that contributes to heart failure whilst retaining the beneficial actions of apelin. The effect of MM07 has not been tested in an animal model of PAH. Hypothesis: We hypothesised that MM07 would attenuate PAH pathogenesis in the rat model of monocrotaline (MCT)-induced PAH. Methods: Male Sprague Dawley rats (187±2g) were randomly assigned to receive MCT (60mg/kg body weight) or saline subcutaneously on day 0. From day 1, animals in both groups were given daily intraperitoneal injections of either MM07 (1mg/kg body weight) or saline for 20 days. On day 21, the animals were anaesthetized and right ventricular systolic pressure (RVSP) was measured as a surrogate of pulmonary arterial pressure. Subsequently, hearts were dissected and the weight ratio of right ventricle compared to left ventricle and septum (RV/(LV+S)) was determined as an indicator of right ventricular hypertrophy. Data between groups were compared using one-way ANOVA with Tukey’s post-test. Results: Compared to saline control, as expected, the MCT group showed elevated RVSP (19.8±2.0mmHg, n=4 vs 45.8±8.4mmHg, n=5, p≤0.01) and RV/(LV+S) (0.22±0.01 vs 0.41±0.02, p≤0.001). Compared to the MCT group both parameters were significantly reduced in MCT-injected rats treated with MM07 (RVSP 28.8±2.7mmHg p≤0.05; RV/(LV+S) 0.29±0.01, p≤0.001, n=6). MM07 alone (n=4) did not alter right ventricular parameters (RVSP 20.6±1.2mmHg, p≥0.05; RV/(LV+S) 0.23±0.01, p≥0.05) in control animals. Conclusions: In this proof principle study we have shown for the first time that a biased apelin receptor agonist, MM07, significantly attenuated the development of PAH in an animal model. The predicted additional benefit of a G protein-biased agonist used chronically for PAH is less receptor desensitisation and cardiac remodelling that are mediated via β-arrestin pathways.