title: Endothelial GATA-6 deficiency promotes pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) is a chronic and progressive disease characterized by pulmonary vasculopathy with elevation of pulmonary artery pressure, often culminating in right ventricular failure. GATA-6, a member of the GATA family of zinc-finger transcription factors, is highly expressed in quiescent vasculature and is frequently lost during vascular injury. We hypothesized that endothelial GATA-6 may play a critical role in the molecular mechanisms underlying endothelial cell (EC) dysfunction in PAH. Here we report that GATA-6 is markedly reduced in pulmonary ECs lining both occluded and nonoccluded vessels in patients with idiopathic and systemic sclerosis-associated PAH. GATA-6 transcripts are also rapidly decreased in rodent PAH models. Endothelial GATA-6 is a direct transcriptional regulator of genes controlling vascular tone [endothelin-1, endothelin-1 receptor type A, and endothelial nitric oxide synthase (eNOS)], pro-inflammatory genes, CX3CL1 (fractalkine), 5-lipoxygenease-activating protein, and markers of vascular remodeling, including PAI-1 and RhoB. Mice with the genetic deletion of GATA-6 in ECs (Gata6-KO) spontaneously develop elevated pulmonary artery pressure and increased vessel muscularization, and these features are further exacerbated in response to hypoxia. Furthermore, innate immune cells including macrophages (CD11b(+)/F4/80(+)), granulocytes (Ly6G(+)/CD45(+)), and dendritic cells (CD11b(+)/CD11c(+)) are significantly increased in normoxic Gata6-KO mice. Together, our findings suggest a critical role of endothelial GATA-6 deficiency in development and disease progression in PAH.
authors.affiliation: Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Ghatnekar
authors.forename: Izabela
authors.initials: I
authors.lastname: Chrobak
authors.forename: Charlie
authors.initials: C
authors.lastname: Reese
authors.forename: Lukasz
authors.initials: L
authors.lastname: Stawski
authors.forename: Francesca
authors.initials: F
authors.lastname: Seta
authors.forename: Elaine
authors.initials: E
authors.lastname: Wirrig
authors.forename: Jesus
authors.initials: J
authors.lastname: Paez-Cortez
authors.forename: Margaret
authors.initials: M
authors.lastname: Markiewicz
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Asano
authors.forename: Russell
authors.initials: R
authors.lastname: Harley
authors.forename: Richard
authors.initials: R
authors.lastname: Silver
authors.forename: Carol
authors.initials: C
authors.lastname: Feghali-Bostwick
authors.forename: Maria
authors.initials: M
authors.lastname: Trojanowska
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000096:biosynthesis / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D016022:Case-Control Studies; D002908:Chronic Disease; D018450:Disease Progression; D015536:Down-Regulation / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism*; D065627:Familial Primary Pulmonary Hypertension; D050993:GATA6 Transcription Factor / Q000172:deficiency* / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism*; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications; D008168:Lung / Q000098:blood supply; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011014:Pneumonia / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012595:Scleroderma, Systemic / Q000150:complications; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D050993:GATA6 Transcription Factor; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1; C497397:Arnt protein, mouse