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Up-Regulation of the Long Noncoding RNA X-Inactive–Specific Transcript and the Sex Bias in Pulmonary Arterial Hypertension

Shanshan Qin, Dan Predescu, Brandon Carman, Priyam Patel, Jiwang Chen, Miran Kim, Tim Lahm, Mark Geraci, Sanda A. Predescu
Published: 1 June 2021
The American Journal of Pathology , Volume 191, pp 1135-1150; doi:10.1016/j.ajpath.2021.03.009

Abstract: Pulmonary arterial hypertension (PAH) is a sex-biased disease. Increased expression and activity of the long-noncoding RNA X-inactive–specific transcript (Xist), essential for X-chromosome inactivation and dosage compensation of X-linked genes, may explain the sex bias of PAH. The present studies used a murine model of plexiform PAH, the intersectin-1s (ITSN) heterozygous knockout (KOITSN+/–) mouse transduced with an ITSN fragment (EHITSN) possessing endothelial cell proliferative activity, in conjunction with molecular, cell biology, biochemical, morphologic, and functional approaches. The data demonstrate significant sex-centered differences with regard to EHITSN-induced alterations in pulmonary artery remodeling, lung hemodynamics, and p38/ETS domain containing protein/c-Fos signaling, altogether leading to a more severe female lung PAH phenotype. Moreover, the long-noncoding RNA–Xist is up-regulated in the lungs of female EHITSN-KOITSN+/– mice compared with that in female wild-type mice, leading to sex-specific modulation of the X-linked gene ETS domain containing protein and its target, two molecular events also characteristic to female human PAH lung. More importantly, cyclin A1 expression in the S and G2/M phases of the cell cycle of synchronized pulmonary artery endothelial cells of female PAH patients is greater versus controls, suggesting functional hyperproliferation. Thus, Xist up-regulation leading to female pulmonary artery endothelial cell sexual dimorphic behavior may provide a better understanding of the origin of sex bias in PAH. Notably, the EHITSN-KOITSN+/– mouse is a unique experimental animal model of PAH that recapitulates most of the sexually dimorphic characteristics of human disease.
Keywords: model / bias in PAH / ITSN / sex bias of PAH / Xist / X linked gene

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