Inhibition of aldose reductase prevents endotoxin-induced inflammation by regulating the arachidonic acid pathway in murine macrophages

Mohammad Shoeb, Umesh C.S. Yadav, Satish K. Srivastava, Kota V. Ramana

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

The bacterial endotoxin lipopolysaccharide (LPS) is known to induce release of arachidonic acid (AA) and its metabolic products, which play important roles in the inflammatory process. We have shown earlier that LPS-induced signals in macrophages are mediated by aldose reductase (AR). Here we have investigated the role of AR in LPS-induced release of AA metabolites and their modulation using a potent pharmacological inhibitor, fidarestat, and AR siRNA ablation in RAW264.7 macrophages and AR-knockout mouse peritoneal macrophages and heart tissue. Inhibition or genetic ablation of AR prevented the LPS-induced synthesis and release of AA metabolites such as PGE2, TXB, PGI2, and LTBs in macrophages. LPS-induced activation of cPLA2 was also prevented by AR inhibition. Similarly, AR inhibition also prevented the calcium ionophore A23187-induced cPLA2 and LTB4 in macrophages. Further, AR inhibition by fidarestat prevented the expression of AA-metabolizing enzymes such as COX-2 and LOX-5 in RAW264.7 cells and AR-knockout mouse-derived peritoneal macrophages. LPS-induced expression of AA-metabolizing enzymes and their catalyzed metabolic products was significantly lower in peritoneal macrophages and heart tissue from AR-knockout mice. LPS-induced activation of redox-sensitive signaling intermediates such as MAPKs, transcription factor NF-κB, and EGR-1, a transcriptional regulator of mPGES-1, which in collaboration with COX-2 leads to the production of PGE2, was also significantly prevented by AR inhibition. Taken together, our results indicate that AR mediates LPS-induced inflammation by regulating the AA-metabolic pathway and thus provide a novel role for AR inhibition in preventing inflammatory complications such as sepsis.

Original languageEnglish (US)
Pages (from-to)1686-1696
Number of pages11
JournalFree Radical Biology and Medicine
Volume51
Issue number9
DOIs
StatePublished - Nov 1 2011

Keywords

  • Aldose reductase
  • Arachidonic acid
  • COX-2
  • Free radicals
  • Inflammation
  • LOX-5
  • LPS

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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