Abstract 10715: Therapeutic Efficacy of Drpitor1a, a Novel Dynamin-Related Protein 1 (DRP1) Inhibitor, in Preclinical Pulmonary Arterial Hypertension

Abstract

Introduction: Dynamin-related protein 1 (DRP1) is a large GTPase that mediates mitotic fission (the division of mitochondria which is coordinated with mitosis, ensuring equitable distribution of mitochondria to daughter cells). In pulmonary arterial hypertension (PAH) pulmonary artery smooth muscle cells (PASMC), mitotic fission, and DRP1 activity are increased, contributing to its hyperproliferative phenotype. We investigated the therapeutic efficacy of Drpitor1a, a novel, small molecule, Drp1 GTPase inhibitor, in a rat PAH model. Methods: A single dose of monocrotaline (MCT, 60mg/kg, SC) or PBS was injected to female Sprague-Dawley rats on day 0 (n=20 for MCT and n=15 for PBS). On day 14, the development of PAH was confirmed by echocardiography and the rats were randomized for treatments. An indwelling catheter was implanted through the left jugular vein on day 15. Drpitor1a (1mg/kg) or normal saline (NS) was administered by IV every 48 hours from day 17 to day 27. Right ventricular (RV) structure and function were assessed on day 28 with echocardiography. Pulmonary hemodynamics was evaluated on day 29 using right heart catheterization (RHC). Results: MCT rats developed PAH with RV dysfunction on day 14. There was no statistical difference between the Drpitor1a and NS groups at randomization. At the endpoint, MCT+Drpitor1a rats, vs. MCT+NS rats, had a significantly reduced severity of pulmonary hypertension evident as longer pulmonary artery acceleration time (PAAT) and lower pulmonary vascular resistance index. Drpitor1a also improved RV function, evident as greater RV free wall thickening (RVFWT%), increased tricuspid annular plane systolic excursion (TAPSE), and increased cardiac index (CI). Drpitor1a regressed pulmonary artery medial thickening and inhibited RV hypertrophy without hepatological, renal or hepatic toxicities. Conclusion: Drpitor1a is a safe and effective treatment for preclinical PAH.