Abstract 16277: Glycoprotein 130 Antagonism Improves Right Ventricle Function in Pulmonary Artery Banded Piglets

Introduction: Right ventricular dysfunction (RVD) is a risk factor for death in multiple cardiovascular diseases, but RV-specific therapies are lacking. We recently showed inhibition of glycoprotein 130 (GP130) signaling with the small molecule SC144 improved RV function via modulation of microtubules and mitochondria metabolism in rodent RVD. However, SC144’s efficacy in a translational large animal model of RVD is untested.

Methods: Ten 4-week-old castrated male piglets 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 control [PAB-Veh, n =5] for 3 weeks). Five pigs of a similar age served as controls. Cardiac MRI evaluated RV function, mass, and volume. Immunoblots of RV extracts quantified microtubule and GP130 pathway protein levels. Quantitative proteomics evaluated RV mitochondrial enrichments. KEGG pathway analysis delineated the biochemical pathways associated with RV ejection fraction.

Results: SC144 significantly improved RV ejection fraction ( A , Control: 59.5±4.2, PAB-Veh: 22.6±10.8, PAB-SC144: 37.6±6.4) without changing RV afterload ( B-C ). Molecularly, GP130 antagonism normalized abundances of microtubule proteins and increased levels of suppressor of cytokine signaling 3 (SOCS3), an endogenous GP130 antagonist. Mitochondrial proteomics analysis revealed amino acid metabolism and oxidative phosphorylation suppression was mitigated by SC144 ( D ).

Conclusions: SC144 improves RV function in porcine RV failure, potentially by maintaining oxidative phosphorylation, amino acid metabolism, and microtubule regulation.