Abstract 4141414: Glycoprotein 130 Antagonism Counteracts Autophagy-Mediated Mitochondrial Metabolic Derangements and Improves Right Ventricle Function in Pulmonary Artery Banded Pigs

Background: Right ventricular dysfunction (RVD) is a risk factor for death in PAH, but RV-specific therapies are lacking. We showed inhibition of glycoprotein 130 (GP130) signaling with the small molecule SC144 improved RV function in rodent RVD. However, SC144’s efficacy in a translational large animal model of RVD is untested. Methods: Ten 4-week-old castrated male pigs underwent pulmonary artery banding (PAB). After 3 weeks, PAB pigs were randomized into 2 groups (daily injections of SC144 [2 mg/kg, PAB-SC144, n =5] or vehicle [PAB-VEH, n =5] for 3 weeks). Five pigs of a similar age served as controls. Cardiac MRI quantified RV function, mass, and volume. Mitochondrial morphology was examined from electron micrographs of RV free wall cardiomyocytes. Wheat Germ Agglutinin stained RV cross sections were used to calculate cardiomyocyte remodeling. Lipidomics and metabolomics quantified lipid species and metabolites in whole RV tissue. Quantitative proteomics evaluated RV mitochondrial enrichments. Results: SC144 significantly improved RV ejection fraction (CONTROL: 60±4%, PAB-VEH: 23±11%, PAB-SC144: 38±6%) despite identical RV afterload. SC144 normalized RV cardiomyocyte size (CONTROL: 131±54 µm 2 , PAB-VEH 200±70 µm 2 , PAB-SC144: 129±62 µm 2 ), mitochondrial dimensions, and cristae morphology. Integrated lipidomics, metabolomics, and proteomics revealed changes in lipid metabolism in PAB pigs, which was counteracted by SC144. In particular, the accumulation of acylcarnitines, the mitochondrial form of fatty acids, and the downregulation of fatty acid oxidation proteins was mitigated by SC144. The improvements in mitochondrial structure, protein regulation, and metabolic activity were likely due to the restoration of autophagy as SC144 mitigated the reduction in numerous autophagy proteins. Conclusion: SC144 improves RV function in porcine RV failure, likely by maintaining autophagy, which ultimately preserves mitochondrial fatty acid oxidation.