THU0351 LOW ER? EXPRESSION MIGHT BE IMPLICATED IN THE DEVELOPMENT OF PULMONARY HYPERTENSION IN FEMALE MICE LACKING PSGL-1. (June 2019)

• Record Type: Journal Article
• Authors: Gonzlez-Tajuelo, Rafael; Fuente-Fernndez, Mara De la; Morales-Cano, Daniel; Muoz-Callejas, Antonio; Manuel Serrador, Juan; Barreira, Bianca; Silvn, Javier; Gamallo, Carlos; Vicente, Esther; Castaeda, Santos; Prez-Vizcano, Francisco; Cogolludo, Angel; Urzainqui, Ana
• Is Part Of: Annals of the rheumatic diseases. Volume 78(2019)Supplement 2
• Page Start: 457
• Page End: 457
• Publication Date: 2019-06
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2019-eular.2813
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Pulmonary arterial hypertension (PAH) is a rare disease with unknown etiopathogenesis and no curative treatment [1]. PAH is one of the major complications of connective tissue diseases, and 7-15% of patients with systemic sclerosis (SSc) develop PAH [2]. Mice deficient for the leukocytic receptor P-selectin glycoprotein ligand-1 ( PSGL-1 -/- ) spontaneously develop a SSc-like autoimmune syndrome with ageing [3]. Objectives: To check whether PSGL1 -/- mice may develop PAH and the molecular mechanisms that might be implicated in the initiation and establishment of the disease. Methods: Doppler pulse echochardiography was used to evaluate pulmonary artery flow acceleration time/ejection time (PAAT/ET) ratio in WT and PSGL-1 -/- C57BL/6 mice. Isolated pulmonary artery rings were incubated with acetylcholine and responses were registered with a wire myograph coupled to an isometric force transducer. Expression levels of the NO-sensing probe DAR-4M AM by fluorescence microscopy and flow cytometry. Angiotensin II lung concentration was quantified by ELISA. eNOS, p-ENOS, AT1R and AT2R expression was evaluated by western blot. In all cases, data are expressed as the meanSD. Results: Aged PSGL-1 -/- females showed reduced flow PAAT/ET ratio indicating PAH. Moreover, pulmonary arterial rings from aged PSGL-1 -/- females presented ROS-independent reduced vasodilation response to acetylcholine. Importantly, eNOS phosphorylation was impaired and NO production by lung EC was reduced in aged PSGL-1 -/- females. Vascular remodeling and reduced expression of AT2R were observed in lungs of PSGL-1 -/- females from a younger age. With ageing, the levels of angiotensin II and the percentages of IFN?-producing interstitial macrophages, T and B lymphocytes were increased in PSGL-1 -/- females. The differences in the gender-biased genotype could be explained by the reduced expression of ERa in the lungs of aged PSGL-1 -/- females while WT and PSGL-1 -/- males showed similar expression. Conclusion: PSGL-1 deficiency leads to pulmonary hypertension in >18-months-old female mice, involving various mechanisms: Lung vessel wall remodeling and reduced AT2R expression. Reduced eNOS phosphorylation and reduced NO production with the subsequent specific lung endothelial dysfunction in PSGL-1 -/- females. Importantly, ROS production is not increased nor help to NO reduction. Increased pulmonary AngII levels with ageing in PSGL-1 -/- females. Increased Th1 polarization, reduced Treg population and increased IFN-? production by interstitial macrophages. Impaired ageing up-regulation of ERa expression in the lungs of PSGL-1 -/- females. References: [1] Montani et al. Orphanet Journal of Rare Diseases. 2013, 8 (97). [2] Tedford et al. Circ Heart Fail. 2013, 6 (5): 953-63. [3] Prez-Fras et al. Arthritis Rheumatol. 2014, 66 (11): 3178-89. Disclosure of Interests: Rafael Gonzlez-Tajuelo: None declared, Mara De la Fuente-Fernndez: None declared, Daniel Morales-Cano: None declared, Antonio Muoz-Callejas: None declared, Juan Manuel Serrador: None declared, Bianca Barreira: None declared, Javier Silvn: None declared, Carlos Gamallo: None declared, Esther Vicente: None declared, Santos Castaeda Consultant for: Amgen, BMS, Pfizer, Lilly, MSD, Roche, Sanofi, UCB, Francisco Prez-Vizcano: None declared, Angel Cogolludo: None declared, Ana Urzainqui: None declared