GP130 Antagonism in Porcine RV Pressure Overload

Project Summary Pulmonary arterial hypertension (PAH) is a lethal disease with a median survival of only 5-7 years. Pathophysiologically, PAH is a progressive vasculopathy of the precapillary pulmonary vessels that increases pulmonary arterial pressures and pulmonary vascular resistance while reducing pulmonary arterial compliance. The changes in the pulmonary vasculature augment the work load of the right ventricle, which ultimately results in right ventricular dysfunction (RVD). The presence of RVD is the greatest risk factor for death in PAH; however, no current PAH therapies actually target the RV directly. In this proposal, we will investigate the hypothesis that GP130 activation in RV cardiomyocytes promotes cardiomyocyte dysfunction via microtubule remodeling which causes t-tubule derangements and mitochondrial metabolic dysfunction. We will use state- of-the-art approaches to probe the molecular and physiological effects of GP130 antagonism on right ventricular function in porcine RV failure.