Aldose reductase regulates acrolein-induced cytotoxicity in human small airway epithelial cells

Umesh C.S. Yadav, K. V. Ramana, Satish K. Srivastava

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Aldose reductase (AR), a glucose-metabolizing enzyme, reduces lipid aldehydes and their glutathione conjugates with more than 1000-fold efficiency (Km aldehydes 5-30 μM) relative to glucose. Acrolein, a major endogenous lipid peroxidation product as well as a component of environmental pollutants and cigarette smoke, is known to be involved in various pathologies including atherosclerosis, airway inflammation, COPD, and age-related disorders, but the mechanism of acrolein-induced cytotoxicity is not clearly understood. We have investigated the role of AR in acrolein-induced cytotoxicity in primary human small airway epithelial cells (SAECs). Exposure of SAECs to varying concentrations of acrolein caused cell death in a concentration- and time-dependent manner. AR inhibition by fidarestat prevented the low-dose (5-10 μM) but not the high-dose (>10 μM) acrolein-induced SAEC death. AR inhibition protected SAECs from low-dose (5 μM) acrolein-induced cellular reactive oxygen species (ROS). Inhibition of acrolein-induced apoptosis by fidarestat was confirmed by decreased condensation of nuclear chromatin, DNA fragmentation, comet tail moment, and annexin V fluorescence. Further, fidarestat inhibited acrolein-induced translocation of the proapoptotic proteins Bax and Bad from the cytosol to the mitochondria and that of Bcl2 and Bcl XL from the mitochondria to the cytosol. Acrolein-induced cytochrome c release from mitochondria was also prevented by AR inhibition. The mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinases 1 and 2, stress-activated protein kinase/c-Jun NH 2-terminal kinase, and p38MAPK, and c-Jun were transiently activated in airway epithelial cells by acrolein in a concentration- and time-dependent fashion, which was significantly prevented by AR inhibition. These results suggest that AR inhibitors could prevent acrolein-induced cytotoxicity in the lung epithelial cells.

Original languageEnglish (US)
Pages (from-to)15-25
Number of pages11
JournalFree Radical Biology and Medicine
StatePublished - 2013
Externally publishedYes


  • Acrolein
  • Airway epithelial cells
  • Aldose reductase
  • Apoptosis
  • COPD
  • Cytotoxicity
  • Free radicals

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


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