Journal
VASCULAR PHARMACOLOGY
Volume 130, Issue -, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.vph.2020.106678
Keywords
Omics; Diabetes; Hyperosmotic stress; Insulin resistance; Endothelial cells
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Funding
- Italian Ministry of University and Scientific Research (PRIN)
- CARIPLO Foundation
- Istituto Nazionale Ricerche Cardiovascolari (INRC)
- Incyte s.r.l.
- Italian Ministry of University and Scientific Research
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Background: Hyperglycemia plays a role in promoting insulin resistance in adipocytes, hepatocytes and myocytes. Its effects on insulin signaling in endothelial cells remain, however, incompletely understood. Aim: To investigate the proteomic and metabolomic profiles of human aortic endothelial cells (HAECs) exposed to insulin, normal glucose (NG), high glucose (HG) or its hyperosmolar control high mannitol (HM), and to examine whether and how HG or HM may promote insulin resistance. Methods and results: We exposed HAECs to HG and HM in shorter (3 h) and longer-term experiments (24 h), followed by insulin treatment for 45 min. Label-free proteomics and network analysis showed a downregulation of proteins linked to the PI3K-Akt/mTOR/eNOS signaling pathway in HAECs. Metabolomic profiling showed decreased levels of odd-chain acylcarnitines such as C3. At immunoblotting, HG or HM blunted insulin ability to activate the PI3K/AKT/eNOS pathway, which was reverted through a silencing of aquaporin 1 (AQP1) and Tonicity enhancer binding protein (TonEBP), while inducing p-P38 and pERK1/2. Conclusions: HG impairs the PI3K/AKT/eNOS pathway and shifts insulin signaling towards the activation of mitogenic and pro-inflammatory effectors, such as p38 and ERK1/2. These effects may explain the progression of insulin resistance as a result of endothelial glucotoxicity.
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