RGD Reference Report - Endothelial GATA-6 deficiency promotes pulmonary arterial hypertension. - Rat Genome Database

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Endothelial GATA-6 deficiency promotes pulmonary arterial hypertension.

Authors: Ghatnekar, Angela  Chrobak, Izabela  Reese, Charlie  Stawski, Lukasz  Seta, Francesca  Wirrig, Elaine  Paez-Cortez, Jesus  Markiewicz, Margaret  Asano, Yoshihide  Harley, Russell  Silver, Richard  Feghali-Bostwick, Carol  Trojanowska, Maria 
Citation: Ghatnekar A, etal., Am J Pathol. 2013 Jun;182(6):2391-406. doi: 10.1016/j.ajpath.2013.02.039. Epub 2013 Apr 11.
RGD ID: 13208869
Pubmed: PMID:23583651   (View Abstract at PubMed)
PMCID: PMC3668018   (View Article at PubMed Central)
DOI: DOI:10.1016/j.ajpath.2013.02.039   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
pulmonary hypertension  ISOGata6 (Mus musculus)13208869; 13208869 RGD 
pulmonary hypertension  IEP 13208869protein:decreased expression:lung more ...RGD 
pulmonary hypertension  ISOGATA6 (Homo sapiens)13208869; 13208869protein:decreased expression:lung more ...RGD 
pulmonary hypertension  IMP 13208869 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Gata6  (GATA binding protein 6)

Genes (Mus musculus)
Gata6  (GATA binding protein 6)

Genes (Homo sapiens)
GATA6  (GATA binding protein 6)


Additional Information