Abstract 3132: Examining The Role Of The Lung Endothelial Cell Anti-apoptotic Protein C-iap2 In Schistosomiasis-associated Pulmonary Hypertension

Abstract

Introduction: Schistosomiasis-associated Pulmonary Hypertension (Sch-PH) is the most common form of group I PH worldwide and remains with no targeted therapy. Previously, we observed that the loss of the anti-inflammatory protein caveolin-1 (Cav-1) in lung endothelial cells (EC) contributed to the survival of the abnormal EC phenotype in Sch-PH. Abnormal cell survival has been associated with some members of the inhibitor of apoptosis protein (IAP) family, but their role in Sch-PH is unknown. Hypothesis: The major etiological agent of Sch-PH, i.e., S. mansoni , may contribute to the abnormal lung EC phenotype via altered IAP family expression, specifically the inducible member c-IAP2. Methods/Methods: To test this hypothesis, we first quantified constitutive c-IAP1 and inducible c-IAP2 expression on lung samples from male and female control and pre-clinical S. mansoni egg-exposed mice (240 eggs/gram body weight intraperitoneally followed by intravenous injection of 175 eggs/gram body weight). Then, the specific contribution of EC-c-IAP2 expression to the progression of the disease was evaluated in our new mouse model ( Cdh5.CreERT2;cIAP1 -/- ,cIAP2 fl/fl - Cdh5.CreERT2;cIAP1 +/- ,cIAP2 +/fl ). EC- Cav1 -/- mice were also evaluated to test the contribution of EC-Cav-1 to lung c-IAP2 expression. Results/Discussion: Western blot and immunohistochemistry analysis revealed a reduction in c-IAP2 expression in the whole lung tissue of S. mansoni egg-exposed mice compared to controls (1.21 ± 0.12; 0.88 ± 0.06, control and egg-exposed mice respectively; p<0.05; n=6). No difference was observed in c-IAP1 expression. Preliminary data indicate that genetic ablation of c-IAP2 in EC heterozygous mice promoted a mild increase in microvascular thickness and area in Masson’s Trichrome -stained lung sections. Consistent with our previous findings, c-IAP2 expression was also significantly impaired when Cav-1 expression was absent in lung ECs, suggesting that EC-Cav-1 may contribute to reduced lung c-IAP2 expression, leading to the severe vascular remodeling that underlies the development of Sch-PH. Conclusion: Our data is uncovering whether c-IAP2 expression is a novel and specific molecular target for future therapeutic approaches against chronic Sch-PH.