FKBPL and SIRT-1 Are Downregulated by Diabetes.....pdf (3.68 MB)

FKBPL and SIRT-1 are downregulated by diabetes in pregnancy impacting on angiogenesis and endothelial function

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posted on 09.08.2021, 10:21 by Abdelrahim Alqudah, Kelly-Ann Eastwood, Djurdja Jerotic, Naomi Todd, Denise Hoch, Ross McNally, Danilo Obradovic, Stefan Dugalic, Alyson J Hunter, Valerie A Holmes, David R McCance, Ian S Young, Chris J Watson, Tracy RobsonTracy Robson, Gernot Desoye, David J Grieve, Lana McClements
Diabetes in pregnancy is associated with adverse pregnancy outcomes including preterm birth. Although the mechanisms leading to these pregnancy complications are still poorly understood, aberrant angiogenesis and endothelial dysfunction play a key role. FKBPL and SIRT-1 are critical regulators of angiogenesis, however, their roles in pregnancies affected by diabetes have not been examined before in detail. Hence, this study aimed to investigate the role of FKBPL and SIRT-1 in pre-gestational (type 1 diabetes mellitus, T1D) and gestational diabetes mellitus (GDM). Placental protein expression of important angiogenesis proteins, FKBPL, SIRT-1, PlGF and VEGF-R1, was determined from pregnant women with GDM or T1D, and in the first trimester trophoblast cells exposed to high glucose (25 mM) and varying oxygen concentrations [21%, 6.5%, 2.5% (ACH-3Ps)]. Endothelial cell function was assessed in high glucose conditions (30 mM) and following FKBPL overexpression. Placental FKBPL protein expression was downregulated in T1D (FKBPL; p<0.05) whereas PlGF/VEGF-R1 were upregulated (p<0.05); correlations adjusted for gestational age were also significant. In the presence of GDM, only SIRT-1 was significantly downregulated (p<0.05) even when adjusted for gestational age (r=-0.92, p=0.001). Both FKBPL and SIRT-1 protein expression was reduced in ACH-3P cells in high glucose conditions associated with 6.5%/2.5% oxygen concentrations compared to experimental normoxia (21%; p<0.05). FKBPL overexpression in endothelial cells (HUVECs) exacerbated reduction in tubule formation compared to empty vector control, in high glucose conditions (junctions; p<0.01, branches; p<0.05). In conclusion, FKBPL and/or SIRT-1 downregulation in response to diabetic pregnancies may have a key role in the development of vascular dysfunction and associated complications affected by impaired placental angiogenesis.

Funding

Hashemite University, Jordan and the Department for the Economy (DfE) - Global Challenge Research Fund (GCRF)

History

Comments

The original article is available at https://www.frontiersin.org

Published Citation

Alqudah A. et al. FKBPL and SIRT-1 are downregulated by diabetes in pregnancy impacting on angiogenesis and endothelial function. Front Endocrinol (Lausanne). 2021;12:650328.

Publication Date

2 June 2021

PubMed ID

34149611

Department/Unit

  • Irish Centre for Vascular Biology
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Immunity, Infection and Inflammation
  • Vascular Biology
  • Cancer

Publisher

Frontiers Media SA

Version

  • Published Version (Version of Record)