期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1864, 期 10, 页码 3195-3210出版社
ELSEVIER
DOI: 10.1016/j.bbadis.2018.07.007
关键词
Obesity; Pre-pregnancy; Endoplasmic reticulum stress; Endothelium; Arginine; Nitric oxide
资金
- Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT) [1150377, 1121145, 11150083]
- Servicio de Salud de Medicina Oriente, Hospital San Juan de Dios [Res. 1938-2016], Santiago, Chile
- Comision Nacional para la Investigacion en Ciencia y Tecnologia (CONICYT) (Chile)
- ViceRectorate of Research, PUC (Chile)
- Abel Tasman Talent Program
- University Medical Center Groningen (UMCG) (The Netherlands)
Obesity associates with the endoplasmic reticulum (ER) stress-induced endothelial dysfunction. Pregnant women with pre-pregnancy maternal obesity (PGMO) may transfer this potential risk to their offspring; however, whether ER stress occurs and associates with foetoplacental endothelial dysfunction in PGMO is unknown. We studied the L-arginine transport and nitric oxide (NO) synthesis in human umbilical vein endothelial cells (HUVECs) from women with PGMO or with a normal pre-pregnancy weight. We analysed the expression and activation of the ER stress sensors protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 alpha (IRE1 alpha), and activating transcription factor 6 (ATF6). PGMO associated with lower endothelial NO synthase activity due to increased Thr(495)-inhibitor and decreased Ser(1177)-stimulator phosphorylation. However, higher expression and activity of the human cationic amino acid transporter 1 was found. PGMO caused activation of PERK and its downstream targets eukaryotic initiation factor 2 (eIF2 alpha), C/EBP homologous protein 10 (CHOP), and tribbles-like protein 3 (TRB3). Increased IRE1 a protein abundance (but not its phosphorylation or X-box binding protein 1-mRNA splicing) and increased c-Jun N-terminal kinase 1 phosphorylation was seen in PGMO. A preferential nuclear location of the activating transcription factor 6 (ATF6) was found in HUVECs from PGMO. All the changes seen in PGMO were blocked by TUDCA but unaltered by tunicamycin. Thus, PGMO may determine a state of ER stress via upregulation of the PERK-eIP2 alpha-CHOP-TRB3 axis signalling in HUVECs. This phenomenon results in foetoplacental vascular endothelial dysfunction at birth.
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