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Aldose reductase regulates hyperglycemia-induced HUVEC death via SIRT1/AMPK-α1/mTOR pathway.

08:00 EDT 1st April 2019 | BioPortfolio

Summary of "Aldose reductase regulates hyperglycemia-induced HUVEC death via SIRT1/AMPK-α1/mTOR pathway."

Although hyperglycemia-mediated death and dysfunction of endothelial cells has been reported to be a major cause of diabetes associated vascular complications, the mechanism(s) through which hyperglycemia causes endothelial dysfunction is not well understood. We have recently demonstrated that aldose reductase (AR; AKR1B1) is an obligatory mediator of oxidative and inflammatory signals induced by growth factors, cytokines and hyperglycemia. However, the molecular mechanisms by which AR regulates hyperglycemia -induced endothelial dysfunction is not known. In this study, we have investigated the mechanism(s) by which AR regulates hyperglycemia-induced endothelial dysfunction. Incubation of HUVECs with high glucose (HG) decreased the cell viability and inhibition of AR prevented it. Further, AR inhibition prevented the HG-induced ROS generation and expression of Bcl-2 and Baxand activation of Caspase-3 in HUVECs. AR inhibition also prevented the adhesion of THP-1 monocytes on HUVECs, expression of iNOS and eNOS and adhesion molecules ICAM-1 and VCAM-1 in HG-treated HUVECs. Further, AR inhibition restored the HG-induced depletion of Sirt1 in HUVECS and increased the phosphorylation of AMPKα1 along-with decrease in phosphorylation of mTOR in HG-treated HUVECs. Fidarestat decreased Sirt1 expression in HUVECs pre-treated with specific Sirt1 inhibitorbut not in the AMPKα1 inhibitor-treated HUVECs. Similarly, knockdown of AR in HUVECs by siRNAprevented the HG-induced HUVECs cell death, THP-1 monocyte adhesion and Sirt1 depletion. Furthermore, fidarestat prevented the decrease in phosphorylation of AMPKα1 and increase in mTOR phosphorylation alongwith decrease in the expression of Sirt1 in STZ-induced diabetic mice heart tissues. Collectively, our data suggest that AR regulates hyperglycemia-induced endothelial death and dysfunction by altering the ROS/Sirt1/AMPKα1/mTOR pathway.

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This article was published in the following journal.

Name: Journal of molecular endocrinology
ISSN: 1479-6813
Pages:

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Medical and Biotech [MESH] Definitions

An enzyme that catalyzes reversibly the oxidation of an aldose to an alditol. It possesses broad specificity for many aldoses. EC 1.1.1.21.

Aldo-keto reductase that functions as an all-trans-retinaldehyde reductase. It also reduces aromatic and aliphatic ALDEHYDES.

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A subtype of DIABETES MELLITUS that is characterized by INSULIN deficiency. It is manifested by the sudden onset of severe HYPERGLYCEMIA, rapid progression to DIABETIC KETOACIDOSIS, and DEATH unless treated with insulin. The disease may occur at any age, but is most common in childhood or adolescence.

A forkhead box transcription factor and transcriptional activator which triggers type 1 programmed cell death (APOPTOSIS) in the absence of APOPTOSIS INHIBITING PROTEINS, including neuronal cell death induced by OXIDATIVE STRESS. It recognizes and binds to the DNA sequence 5'-(AG)TAAA(TC)A-3' and also functions in post-transcriptional regulation of the c-MYC PROTO-ONCOGENE.

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