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

Pabitra B. Pal, Himangshu Sonowal, Kirtikar Shukla, Satish K. Srivastava, Kota Ramana

Research output: Contribution to journalArticle

Abstract

Although hyperglycemia-mediated death and dysfunction of endothelial cells have been reported to be a major cause of diabetes associated vascular complications, the mechanisms through which hyperglycemia cause 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 well known. In this study, we have investigated the mechanism(s) by which AR regulates hyperglycemia-induced endothelial dysfunction. Incubation of human umbilical vein endothelial cells (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, BAX and 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 a decrease in phosphorylation of mTOR in HG-treated HUVECs. Fidarestat decreased SIRT1 expression in HUVECs pre-treated with specific SIRT1 inhibitor but not with the AMPKα1 inhibitor. Similarly, knockdown of AR in HUVECs by siRNA prevented the HG-induced HUVECs cell death, THP-1 monocyte adhesion and SIRT1 depletion. Furthermore, fidarestat regulated the phosphorylation of AMPKα1 and mTOR, and expression of SIRT1 in STZ-induced diabetic mice heart and aorta tissues. Collectively, our data suggest that AR regulates hyperglycemia-induced endothelial death and dysfunction by altering the ROS/SIRT1/AMPKα1/mTOR pathway.

Original languageEnglish (US)
Pages (from-to)11-25
Number of pages15
JournalJournal of Molecular Endocrinology
Volume63
Issue number1
DOIs
StatePublished - Jan 1 2019

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Aldehyde Reductase
AMP-Activated Protein Kinases
Human Umbilical Vein Endothelial Cells
Hyperglycemia
Glucose
Phosphorylation
Monocytes
Vascular Cell Adhesion Molecule-1
Intercellular Adhesion Molecule-1
Caspase 3
Small Interfering RNA
Blood Vessels
Aorta
Cell Survival
Intercellular Signaling Peptides and Proteins
Cell Death
Endothelial Cells
Cytokines

Keywords

  • Aldose reductase
  • Endothelial cells
  • Hyperglycemia
  • Oxidative stress
  • Sirt1

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Aldose reductase regulates hyperglycemia-induced huvec death via SIRT1/AMPK-α1/mTOR pathway. / Pal, Pabitra B.; Sonowal, Himangshu; Shukla, Kirtikar; Srivastava, Satish K.; Ramana, Kota.

In: Journal of Molecular Endocrinology, Vol. 63, No. 1, 01.01.2019, p. 11-25.

Research output: Contribution to journalArticle

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