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The Role of EBP50 in Regulating Endothelial-To-Mesenchymal Transition in Pulmonary Hypertension

Gorelova, Anastasiia (2020) The Role of EBP50 in Regulating Endothelial-To-Mesenchymal Transition in Pulmonary Hypertension. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Pulmonary hypertension (PH) is a cardiopulmonary disease that manifests in a chronic elevation of mean pulmonary arterial pressure, pulmonary vascular remodeling, and right ventricular hypertrophy, and arises from a combination of various factors including endothelial dysfunction. Among the many signs of endothelial dysfunction in PH, increased production of vasoconstrictive signaling molecules and growth factors, proinflammatory shift, and endothelial-to-mesenchymal transition (EndMT) are increasingly recognized as important events potentiating endothelial reprogramming and impaired vascular homeostasis. Despite a critical need to identify molecular players that regulate endothelial reprogramming and the process of EndMT in PH, progress in that direction has been limited.
By utilizing lung samples from PH patients as well as three experimental rodent models of PH, we show that expression of the scaffolding PDZ protein ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50, NHERF1) is downregulated in PH pulmonary vessels and isolated pulmonary vascular endothelial cells. Our in vitro studies indicate that PH-relevant downregulation of endothelial EBP50 expression can be induced by hypoxia and inflammatory cytokine interleukin-1 beta (IL-1β) in a time-dependent manner. Phenocopy of EBP50 reduction using siRNA was found to exert regulatory control over EndMT transcription factors Snail, Zeb1 and Slug, and mesenchymal phenotype transition in pulmonary endothelial cells, and to regulate endothelial cell proliferation and barrier function. Further, the downregulation of EBP50 appeared to potentiate hypoxia-driven EndMT transcription factor Slug upregulation. In vivo studies on EBP50+/- mice demonstrated that downregulation of EBP50 exacerbates hemodynamic manifestations of chronic hypoxia PH.
In our work, we identify EBP50 as a key regulator of EndMT in PH whose expression is downregulated in PH patient pulmonary endothelium as well as animal models of PH, and whose partial deletion exacerbates PH disease manifestations in rodents. Taken together, our findings support the importance of this protein in PH and highlight the rescue of EBP50 levels in this disease as a promising therapeutic approach.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Gorelova, Anastasiiaana.a.gorelova@gmail.comang123
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorAl Ghouleh, Imadima6@pitt.eduima6
Committee ChairFreeman, Bruce A.freerad@pitt.edufreerad
Committee MemberPagano, Patrick J.pagano@pitt.edupagano
Committee MemberGoncharova, Elenaeag59@pitt.edueag59
Committee MemberSt. Croix, Claudetteclaudette.stcroix@pitt.educlaudette.stcroix
Committee MemberChan, Stephen Y.chansy@pitt.educhansy
Committee MemberDeFranco, Donald B.dod1@pitt.edudod1
Date: 5 June 2020
Date Type: Publication
Defense Date: 7 April 2020
Approval Date: 5 June 2020
Submission Date: 19 May 2020
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 167
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: EBP50, EndMT, endothelial dysfunction, pulmonary arterial hypertension, pulmonary hypertension, pulmonary vascular remodeling
Date Deposited: 05 Jun 2020 14:14
Last Modified: 05 Jun 2020 14:14
URI: http://d-scholarship.pitt.edu/id/eprint/39058

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