Abstract 230: AT2 Receptor Agonist, Compound 21, Attenuates Pulmonary Hypertension and Associated Cardiac Pathophysiology via the Vasoprotective ACE2/Ang-(1-7)/Mas axis

Abstract

Pulmonary hypertension (PH) is a devastating disease affecting the lung vasculature. Recently, we determined that increased activation of the ACE2/Ang-(1-7)/Mas axis attenuates much of the associated pathophysiology. In other models of cardiovascular disease, the beneficial effects seen with ACE2/Ang-(1-7)/Mas activation are similar to those seen by AT2 receptor (AT2R) activation. We hypothesize that activation of the AT2R, via selective agonist Compound 21 (C21), will be an effective treatment against PH. SD rats were injected with 50mg/kg of monocrotaline (MCT) at 8 weeks of age, to induce PH. Control animals were given saline. Two weeks post MCT injection, when right ventricular systolic pressures (RVSP) were significantly elevated (MCT 48.3±8.8; Control 32.0 ±2.4 mmHg), animals received 0.03mg/kg/day C21 ip (MCT+C21) or vehicle for 2 weeks. Two weeks later, RV hemodynamic parameters were measured and tissues collected. Treatment with C21 significantly reduced PH and associated cardiac pathophysiologies. The mechanism by which C21 attenuates PH may be the restored balance between the RAS vasodeleterious and vasoprotective arms. Relative quantitation of lung mRNA expression showed C21 treatment normalized the ACE/ACE2 and AT1R/AT2R ratios, and increased Mas receptors. C21 also attenuated the increase in pro-inflammatory cytokines TGF-β, TNF-α, and Il-1b. The increased expression of the vasoprotective axis and resulting decrease in inflammatory cytokines may account for reduced PH and associated cardiopathophysiology. The increases in ACE2/Mas receptor expression may indicate an underlying connection between the AT2R and the vasoprotective axis of the RAS.