Y-Chromosome Gene, Uty , Protects Against Pulmonary Hypertension by Reducing Proinflammatory Chemokines

• Published in: American journal of respiratory and critical care medicine 2022-07, Vol.206 (2), p.186-196
• Main Authors: Cunningham, Christine M, Li, Min, Ruffenach, Gregoire, Doshi, Mitali, Aryan, Laila, Hong, Jason, Park, John, Hrncir, Haley, Medzikovic, Lejla, Umar, Soban, Arnold, Arthur P, Eghbali, Mansoureh
• Format: Article
• Language: English
• Subjects: Animals; Chemokines - metabolism; Disease Models, Animal; Endothelial Cells - metabolism; Familial Primary Pulmonary Hypertension - genetics; Female; Gene expression; Genes; Genes, Y-Linked; Humans; Hypertension, Pulmonary - genetics; Hypoxia; Male; Medical research; Mice; Minor Histocompatibility Antigens - genetics; Nuclear Proteins - genetics; Original; Pulmonary Artery; Pulmonary hypertension; Rats; Y chromosomes
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.202110-2309OC

Idiopathic pulmonary arterial hypertension (PAH) is a terminal pulmonary vascular disease characterized by increased pressure, right ventricular failure, and death. PAH exhibits a striking sex bias and is up to four times more prevalent in females. Understanding the molecular basis behind sex differences could help uncover novel therapies. We previously discovered that the Y chromosome is protective against hypoxia-induced experimental pulmonary hypertension (PH), which may contribute to sex differences in PAH. Here, we identify the gene responsible for Y-chromosome protection, investigate key downstream autosomal genes, and demonstrate a novel preclinical therapy. To test the effect of Y-chromosome genes on PH development, we knocked down each Y-chromosome gene expressed in the lung by means of intratracheal instillation of siRNA in gonadectomized male mice exposed to hypoxia and monitored changes in right ventricular and pulmonary artery hemodynamics. We compared the lung transcriptome of knockdown mouse lungs to those of male and female PAH patient lungs to identify common downstream pathogenic chemokines and tested the effects of these chemokines on human pulmonary artery endothelial cells. We further inhibited the activity of these chemokines in two preclinical pulmonary hypertension models to test the therapeutic efficacy. Knockdown of the Y-chromosome gene resulted in more severe PH measured by increased right ventricular pressure and decreased pulmonary artery acceleration time. RNA sequencing revealed an increase in proinflammatory chemokines and as a result of Uty knockdown. We found and significantly upregulated in human PAH lungs, with more robust upregulation in females with PAH. Treatment of human pulmonary artery endothelial cells with CXCL9 and CXCL10 triggered apoptosis. Inhibition of and expression in male Uty knockout mice and CXCL9 and CXCL10 activity in female rats significantly reduced PH severity. is protective against PH. Reduction of expression results in increased expression of proinflammatory chemokines Cxcl9 and Cxcl10, which trigger endothelial cell death and PH. Inhibition of CLXC9 and CXLC10 rescues PH development in multiple experimental models.