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.


Journal Details

This article was published in the following journal.

Name: Journal of molecular endocrinology
ISSN: 1479-6813


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

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