Deactivation of 12(S)-HETE through (-1)-hydroxylation and -oxidation in alternatively activated macrophages

Tamas Kriska, Michael J. Thomas, J R Falck, William B. Campbell

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Polarization of macrophages to proinflammatory M1 and to antiinflammatory alternatively activated M2 states has physiological implications in the development of experimental hypertension and other pathological conditions. 12/15-Lipoxygenase (12/15-LO) and its enzymatic products 12(S)- and 15(S)-hydroxyeicosatetraenoic acid (HETE) are essential in the process since disruption of the gene encoding 12/15-LO renders the mice unsusceptible to hypertension. The objective was to test the hypothesis that M2 macrophages catabolize 12(S)-HETE into products that are incapable of promoting vasoconstriction. Cultured M2 macrophages metabolized externally added [ 14 C]12(S)-HETE into more polar metabolites, while M1 macrophages had little effect on the catabolism. The major metabolites were identified by mass spectrometry as (-1)-hydroxylation and -oxidation products. The conversion was inhibited by both peroxisomal -oxidation inhibitor, thioridazine, and cytochrome P450 inhibitors. Quantitative PCR analysis confirmed that several cytochrome P450 enzymes (CYP2E1 and CYP1B1) and peroxisomal -oxidation markers were upregulated upon M2 polarization. The identified 12,19-dihydroxy-5,8,10,14-eicosatetraenoic acid and 8-hydroxy-6,10-hexadecadienoic acid metabolites were tested on abdominal aortic rings for biological activity. While 12(S)-HETE enhanced vasocon-strictions to angiotensin II from 15% to 25%, the metabolites did not. These results indicate that M2, but not M1, macrophages degrade 12(S)-HETE into products that no longer enhance the angiotensin II-induced vascular constriction, supporting a possible antihypertensive role of M2 macrophages.

Original languageEnglish (US)
Pages (from-to)615-624
Number of pages10
JournalJournal of lipid research
Volume59
Issue number4
DOIs
StatePublished - 2018

Keywords

  • 12(S)-HETE metabolism
  • 12/15-lipoxygenase
  • Angiotensin II
  • Cytochrome P450

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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