Dysregulation of the Long Noncoding RNA X-Inactive-Specific Transcript Expression in Male Patients with Pulmonary Arterial Hypertension.

Autor: Carman BL; Division of Pulmonary, Critical Care and Sleep Medicine, Rush University Medical Center, Chicago, Illinois., Qin S; Division of Pulmonary, Critical Care and Sleep Medicine, Rush University Medical Center, Chicago, Illinois., Predescu DN; Division of Pulmonary, Critical Care and Sleep Medicine, Rush University Medical Center, Chicago, Illinois., Jana M; Department of Neurological Science, Rush University Medical Center, Chicago, Illinois., Cortese R; Child Health Research Institute, University of Missouri, Columbia, Missouri., Aldred MA; Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine, Indianapolis, Indiana., Gozal D; Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia., Mokhlesi B; Division of Pulmonary, Critical Care and Sleep Medicine, Rush University Medical Center, Chicago, Illinois., Predescu SA; Division of Pulmonary, Critical Care and Sleep Medicine, Rush University Medical Center, Chicago, Illinois. Electronic address: sanda_predescu@rush.edu.
Jazyk: angličtina
Zdroj: The American journal of pathology [Am J Pathol] 2024 Aug; Vol. 194 (8), pp. 1592-1606. Date of Electronic Publication: 2024 May 03.
DOI: 10.1016/j.ajpath.2024.04.005
Abstrakt: Pulmonary arterial hypertension (PAH) is a sex-biased disease with female sex as a significant risk factor. Increased expression of the long noncoding RNA X-inactive-specific transcript (Xist), as induced by an intersectin-1s protein fragment with proliferative potential (EH ITSN ), may explain the sexual dimorphism of female pulmonary artery endothelial cells (ECs) and at least in part, the imbalance sex/ratio of PAH. Xist is essential for X-chromosome inactivation and dosage compensation of X-linked genes. Herein, increased Xist expression was detected in a subset of ECs and lung tissue samples of male patients with PAH. The role of different Xist expression levels in ECs of male patients with PAH (EC PAH ) was studied in several lines of male EC PAH in conjunction with molecular, biochemical, morphologic, and functional approaches. Male EC PAH showed on average 10.3-fold increase in high Xist versus low Xist, a significant association between Xist levels and their proliferative potential, and a heterogeneous methylation of the Xist/XIST antisense RNA (Tsix) locus. Interestingly, Xist up-regulation in male EC PAH decreased the expression of Krueppel-like factor 2 (Klf2), via EH ITSN interaction with enhancer of zeste polycomb repressive complex 2 subunit (EZH2), the catalytic subunit of the polycomb repressive complex 2. Moreover, the studies demonstrate that EH ITSN -triggered p38/ETS domain-containing protein Elk1/AP-1 transcription factor subunit (c-Fos) signaling is a pathologic mechanism central to EC PAH proliferation and the dynamic crosstalk with cell cycle regulatory proteins cyclin A1/cyclin D2 and Xist-EZH2-Klf2 interaction participate directly and differentially in establishing the proliferative profile of male EC PAH .
Competing Interests: Disclosure Statement None declared.
(Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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