Pre-pregnancy maternal obesity associates with endoplasmic reticulum stress in human umbilical vein endothelium

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1864

Article

Villalobos-Labra, Roberto¹  Saez, Pablo J.²  Subiabre, Mario¹  Silva, Luis^1,3  Toledo, Fernando^1,4  Westermeier, Francisco⁵  Pardo, Fabian^1,6  Farias, Marcelo¹  Sobrevia, Luis^1,7,8 

[1] Pontificia Univ Catolica Chile, Fac Med, Sch Med, CMPL,Dept Obstet,Div Obstet & Gynaecol, POB 114-D, Santiago 8330024, Chile

[2] Paris Sci & Lettres Res Univ, Inst Curie, CNRS, UMR 144, F-75005 Paris, France

[3] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, Immunoendocrinol,Div Med Biol, NL-9700 RB Groningen, Netherlands

[4] Univ Bio Bio, Fac Sci, Dept Basic Sci, Chillan 3780000, Chile

[5] FH JOANNEUM Gesell mbH Univ Appl Sci, Inst Biomed Sci, Eggenberger Allee 13, A-8020 Graz, Austria

[6] Univ Valparaiso, Fac Med, Metab Dis Res Lab,Fac Med, Ctr Res Dev & Innovat Hlth Aconcagua Valley,Sch M, San Felipe Campus, San Felipe 2172972, Chile

[7] Univ Seville, Fac Pharm, Dept Physiol, E-41012 Seville, Spain

[8] Univ Queensland, Fac Med & Biomed Sci, UQCCR, Herston, Qld 4029, Australia

关键词: Obesity;    Pre-pregnancy;    Endoplasmic reticulum stress;    Endothelium;    Arginine;    Nitric oxide;   

DOI  :  10.1016/j.bbadis.2018.07.007

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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