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Introduction:Pulmonary hypertension (PH) is a progressive and fatal disorder characterized by high blood pressure in the pulmonary vasculature. This results in prolonged pressure overload on the right ventricle (RV) of the heart leading to remodeling and eventual dysfunction and failure. While current PH drugs target the pulmonary vasculature, RV failure remains the leading cause of death for which no therapies exist. We recently showed that the scaffolding PDZ protein EBP50 (ERM-binding phosphoprotein 50) induces vascular cell hypertrophy and our preliminary studies implicated EBP50 in RV cardiomyocyte and fibroblast subcellular processes in vitro.However, whether EBP50 plays a role in RV responses to pressure overload in vivoremains unknown. This study aims to evaluate whether genetic interruption of EBP50 exacerbates RV pressure overload responses.Method:Wild type (WT) and EBP50 knockout (KO) mice were subjected to pulmonary artery (PA) banding (PAB), a procedure that constricts the PA inducing pressure overload similar to that observed in PH. Invasive hemodynamics were used for RV pressure-volume functional assessment. To glean mechanistic insight, we obtained gene expression profile (128 genes), utilizing a PCR array custom designed using in siliconetwork analyses of the intersection of curated PH-related and cardiomyopathy-related gene networks.Results:PAB induced a significant increase in systolic RV pressure (RVP) and hypertrophy (Fulton index: RV/(left ventricle+septrum) weights) in WT mice. These parameters were further exacerbated in KO mice under PAB (RVP, mmHg: 43.98?2.65 vs. 58.90?2.36; Fulton index: 0.39?0.02 vs.0.5?0.02, for WT PAB vs. KO PAB). RV gene expression arrays showed 7 upregulated and 36 downregulated genes in WT PAB, some of which have not been previously connected to RV. Importantly, 5 of the 7 upregulated genes were further enhanced in KO PAB, and 3 of the 36 downregulated genes were further attenuated in KO PAB.Conclusion:Taken together our data demonstrate a novel role for EBP50 in modulating RV responses to PH-related pressure overload and offer mechanistic insight through identifying potential downstream targets. These findings have the potential to educate future development of RV targeted therapies.

Introduction:Splenectomy is a relatively common surgical procedure in hematologic disorders, such as thalassemia, to improve anemia. However, clinical studies indicate that splenectomy is a strong risk factor for the development of pulmonary hypertension (PH) and cardiac dysfunction in thalassemia. The underlying mechanisms have not been well established. FGF23 is an independent marker for cardiovascular risk in various patient populations, which directly promotes cardiac remodeling and endothelial dysfunction. We hypothesize that FGF23 plays a role in the pathogenesis of post-splenectomy cardiovascular complications.Methods:Thalassemia (Hbbth-3) mice were bred and maintained at the University of Pittsburgh. Splenectomy was performed at 4 weeks of age and right ventricular maximum systolic pressure (RVSP) was measured at 10 weeks post-splenectomy using a closed chest right heart catheterization approach. Cardiac structure and functions were evaluated using echocardiography using Vevo 3100 ultrasound system. Wire myography was conducted to test the vascular function of pulmonary arteries. Circulating levels of FGF23 were determined in plasma using ELISA.Results:We found that Hbbth-3mice with surgical splenectomy developed significant PH, along with biventricular cardiac hypertrophy, impaired diastolic function as well as pulmonary vascular endothelial dysfunction. We also found significant liver iron overload in Hbbth-3mice, along with strong upregulation of hepatic HO-1, the major enzyme for heme degradation. Circulating levels of intact FGF23 were dramatically elevated in splenectomised Hbbth-3mice. Despite that FGF23 expression was barely detected in WT mouse livers, it was induced in thalassemia mice and dramatically upregulated in splenectomised mice.Conclusions:Our findings suggest a pivotal pathological role of the liver in the post-splenectomy state by supporting erythrocyte removal and iron recycling. Liver derived FGF23 may play a role in the development of post-splenectomy cardiovascular complications in thalassemia.