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

Roberto Villalobos-Labra, Pablo J. Saez, Mario Subiabre, Luis Silva, Fernando Toledo, Francisco Westermeier, Fabian Pardo, Marcelo Farias, Luis Sobrevia

    Research output: Contribution to journalArticleAcademicpeer-review

    18 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)3195-3210
    Number of pages16
    JournalBiochimica et biophysica acta-Molecular basis of disease
    Volume1864
    Issue number10
    DOIs
    Publication statusPublished - Oct-2018

    Keywords

    • Obesity
    • Pre-pregnancy
    • Endoplasmic reticulum stress
    • Endothelium
    • Arginine
    • Nitric oxide
    • UNFOLDED PROTEIN RESPONSE
    • NITRIC-OXIDE SYNTHASE
    • L-ARGININE TRANSPORT
    • GESTATIONAL DIABETES-MELLITUS
    • BODY-MASS INDEX
    • ER STRESS
    • INSULIN-RESISTANCE
    • CARDIOVASCULAR-DISEASE
    • WEIGHT-GAIN
    • DYSFUNCTION

    Cite this