Dataset Information

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

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 (KO^ITSN+/-) mouse transduced with an ITSN fragment (EH_ITSN) 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 EH_ITSN-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 EH_ITSN-KO^ITSN+/- 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 EH_ITSN-KO^ITSN+/- mouse is a unique experimental animal model of PAH that recapitulates most of the sexually dimorphic characteristics of human disease.

SUBMITTER: Qin S

PROVIDER: S-EPMC8176134 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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

Qin Shanshan S Predescu Dan D Carman Brandon B Patel Priyam P Chen Jiwang J Kim Miran M Lahm Tim T Geraci Mark M Predescu Sanda A SA

The American journal of pathology 20210406 6

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 (KO<sup>ITSN+/-</sup>) mouse transduced with an ITSN fragment (EH<sub>ITSN</sub>) possessing endothelial cell prolif ...[more]

PMID: 33836164

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Project description:Rationale: Sex-based differences in pulmonary arterial hypertension (PAH) are known, but the contribution to disease measures is understudied. Objectives: We examined whether sex was associated with baseline 6-minute-walk distance (6MWD), hemodynamics, and functional class. Methods: We conducted a secondary analysis of participant-level data from randomized clinical trials of investigational PAH therapies conducted between 1998 and 2014 and provided by the U.S. Food and Drug Administration. Outcomes were modeled as a function of an interaction between sex and age or sex and body mass index (BMI), respectively, with generalized mixed modeling. Results: We included a total of 6,633 participants from 18 randomized clinical trials. A total of 5,197 (78%) were female, with a mean age of 49.1 years and a mean BMI of 27.0 kg/m2. Among 1,436 males, the mean age was 49.7 years, and the mean BMI was 26.4 kg/m2. The most common etiology of PAH was idiopathic. Females had shorter 6MWD. For every 1 kg/m2 increase in BMI for females, 6MWD decreased 2.3 (1.6-3.0) meters (P < 0.001), whereas 6MWD did not significantly change with BMI in males (0.31 m [-0.30 to 0.92]; P = 0.32). Females had lower right atrial pressure (RAP) and mean pulmonary artery pressure, and higher cardiac index than males (all P < 0.03). Age significantly modified the sex by RAP and mean pulmonary artery pressure relationships. For every 10-year increase in age, RAP was lower in males (0.5 mm Hg [0.3-0.7]; P < 0.001), but not in females (0.13 [-0.03 to 0.28]; P = 0.10). There was a significant decrease in pulmonary vascular resistance (PVR) with increasing age regardless of sex (P < 0.001). For every 1 kg/m2 increase in BMI, there was a 3% decrease in PVR for males (P < 0.001), compared with a 2% decrease in PVR in females (P < 0.001). Conclusions: Sexual dimorphism in subjects enrolled in clinical trials extends to 6MWD and hemodynamics; these relationships are modified by age and BMI. Sex, age, and body size should be considered in the evaluation and interpretation of surrogate outcomes in PAH.

Dataset Information

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

Publications

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

Similar Datasets

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