Abstract 12362: Association Between GP130 Signaling, Microtubule Regulation, and RV Function in Porcine RV Pressure Overload

Abstract

Introduction: Pulmonary arterial hypertension (PAH) is a rare but lethal disease, which results in rightventricle (RV) failure. Unfortunately, there are no available therapies to directly combat RV failure and improvesurvival in PAH. We previously showed antagonism of the GP130 signaling pathway prevents microtubuleremodeling and enhances RV function in rat PAH. However, rodent models does not always recapitulatehuman physiology, which may limit translatability of our finding. Therefore, we examined the relationshipsbetween GP130 activation, microtubule regulation, t-tubule structure, and RV function in porcine RV pressureoverload. Methods: Pulmonary artery banding (PAB) was performed on old Yorskhire piglets and animals wereevaluated 4 weeks after. Immunoblots of RV extracts were probed with GP130, STAT3, phosphorylatedSTAT3, α-tubulin, β-tubulin, and detyrosinated α-tubulin primary antibodies to quantify GP130 activation andmicrotubule remodeling respectively. T-tubule architecture was examined using confocal microscopy. Finally,cardiac MRI quantified RV structure and function. Results: PAB pigs exhibited induction of GP130 signaling with higher levels of GP130, STAT3, andpSTAT3. Additionally, there was evidence of microtubule remodeling with elevated expression of α-, β-, anddetyrosinated α-tubulin. Confocal microscopy revealed t-tubule derangements in PAB pigs. Cardiac MRIshowed PAB pigs had significantly increased RV end systolic volume, reduced RV ejection fraction, andimpaired RV-pulmonary artery coupling. Finally, GP130 and tubulin expression levels were inverselyassociated with RV ejection fraction and RV-pulmonary artery coupling. Conclusion: Increased expression of GP130 and tubulin is associated with lower RV ejection fraction andworse RV-PA coupling. Future studies are needed to determine if GP130 antagonism enhances RV function inporcine RV pressure overload.