Abstract 388: Role Of The Antiapoptotic C-iap2 On The Generation Of An Endothelial Memory In Schistosomiasis-associated Pulmonary Arterial Hypertension

Abstract

Introduction: Schistosomiasis-associated Pulmonary Arterial Hypertension (Sch-PAH) is a life-threatening complication of chronic S. mansoni infection, which can evolve to heart failure and death. During PAH, hyperproliferation of apoptosis-resistant endothelial cells (ECs) has been extensively reported, but therapeutic approaches to reverse this pathological phenotype remain clinically challenging. Hypothesis: Thus, our hypothesis is that antigenic molecules from S. mansoni eggs amplify the secretion of inhibitor of apoptosis protein 2 (c-IAP2), leading to generation of an abnormal EC memory of survival and the development of PAH. Methods/Results: Previously, we showed that depletion of the anti-apoptotic protein Caveolin-1 (Cav-1) via shedding of extracellular vesicles (EVs) leads to the survival of an abnormal EC phenotype through an unclear mechanism. Analysis of survival-associated genes in isolated murine lung ECs from Flk1 +/GFP ;Cav1 -/- mice, revealed high expression of the anti-apoptotic genes BIRC3 and BIRC5 (which encodes cIAP2 and survivin, respectively) when compared to control ECs. Interesting, exposure to 1 μg/mL of the major S. mansoni egg antigen Sm-p40 induced time-dependent phosphorylation of Cav-1 at residue Tyr14 in human lung microvascular EC (HMVEC-L: 228.2 +/- 38.28% of control; p<0.05; n=4), culminating in c-IAP2 expression with no difference on the constitutive expression of c-IAP1. Furthermore, Sm-p40 treatment of HMVEC-L in the presence of pro-inflammatory mediators IL-6, TNF-α, and ATP induced a significant release of EVs containing c-IAP2. Finally, in vivo analysis of lungs from S. mansoni -infected mice confirmed a significant decrease in Cav-1 expression unique to the egg-dependent granuloma area, indicating that local inflammatory response due to egg-derived antigenic molecules is essential for reprogramming and survival of an abnormal EC phenotype during Sch-PAH. Conclusions: Our data suggest that S. mansoni -induced Cav-1 depletion promotes the secretion of the anti-apoptotic c-IAP2 protein, which may be critical for prolonged survival of a pathogenic EC phenotype during the development of Sch-PAH.