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Endothelial GATA6 deficiency promotes pulmonary arterial hypertension (PAH) through ER stress‐mediated CHOP upregulation
Author(s) -
Chrobak Izabela Maria,
Ghatnekar Angela,
Lenna Stefania,
Deuren Rosanne,
Radstake Timothy,
FeghaliBostwick Carol,
Trojanowska Maria
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.254.5
Subject(s) - downregulation and upregulation , gata6 , unfolded protein response , hypoxia (environmental) , atf4 , chop , cancer research , pulmonary hypertension , medicine , endocrinology , chemistry , endoplasmic reticulum , biology , microbiology and biotechnology , transcription factor , biochemistry , organic chemistry , oxygen , gene
PAH is characterized by pulmonary vasculopathy, pulmonary artery pressure and RV failure. Previous studies have implicated endoplasmic reticulum (ER) stress in several disorders, including atherosclerosis, but its involvement in PAH has not yet been investigated. GATA6 is expressed in quiescent vasculature, but is lost in vascular injury. Our goal was to investigate the role of endothelial GATA6 in mediating ER stress in PAH. Gata6 flox/flox mice were bred with mice expressing Cre under the ECs‐specific VE‐cad promoter (Gata6 CKO). Gata6 CKO mice developed PAH and had severe changes in hemodynamics under hypoxia. Furthermore, loss of GATA6 resulted in worsened vascular remodeling and RV hypertrophy in hypoxia. The ER stress‐related markers BiP, PERK, ATF4 and XBP were moderately upregulated, whereas pro‐apoptotic marker CHOP was significantly upregulated in Gata6CKO mice. Furthermore, upregulation of BiP protein was observed in Gata6CKO lungs by immunohistochemistry. Consistent with in vivo observations, depletion of GATA6 in HPAECs via siRNA resulted in upregulation of ER stress mediators including BiP, ATF4 and CHOP. Our findings suggest that GATA6 deficiency in endothelial cells leads to development of PAH, in part via upregulation of ER stress/CHOP pathway. This study was supported by NIH grant RO1 AR42334 and Postdoctoral Fellowships NIH training grant T32 AR 050958.