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Inducible Endothelium‐Derived Hyperpolarizing Factor (iEDHF): A New Role for the Endothelial 15‐Lipoxygenase Pathway
Author(s) -
Campbell William B,
Gauthier Kathryn M,
Pfister Sandra L
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.880.3
Subject(s) - hyperpolarization (physics) , arachidonic acid , acetylcholine , mesenteric arteries , chemistry , endothelium , endothelium derived hyperpolarizing factor , endocrinology , lipoxygenase , epoxygenase , medicine , vasodilation , vascular smooth muscle , membrane potential , microbiology and biotechnology , biochemistry , enzyme , biology , stereochemistry , resting potential , artery , smooth muscle , nuclear magnetic resonance spectroscopy
Endothelium‐derived hyperpolarizing factors (EDHFs) mediate a portion of the vasorelaxations to agonists such as acetylcholine (ACh). In rabbit aorta and mesenteric arteries, ACh and arachidonic acid (AA) caused endothelium‐dependent relaxations that were inhibited by lipoxygenase (LO) inhibitors. Arteries metabolized AA to 15(S)‐hydroxy‐11,12‐epoxyeicosatrienoic acid (HEETA) and 11(R),12(S),15(S)‐trihydroxyeicosatrienoic acid (THETA). LO inhibitors reduced their synthesis. HEETA and THETA are EDHFs that activate smooth muscle cell 24 pS, calcium‐activated potassium channels causing membrane hyperpolarization and relaxation. Endothelial 15‐LO expression was increased by adenoviral transduction of arteries and resulted in increased synthesis of HEETA and THETA and increased relaxations to AA and ACh. Hypoxia, hypercholesterolemia, estrogen and interleukin‐13 increased the endothelial expression of 15‐LO. These increases in endothelial 15‐LO expression enhanced HEETA and THETA synthesis, increased membrane hyperpolarization and increased relaxations to ACh and AA. 15‐ LO is an inducible enzyme and changes in its expression regulate EDHF activity. Thus, the 15‐LO/HEETA/THETA pathway represents the first example of an inducible EDHF. (Supported by HL‐37981, HL‐93181 and HL‐103673)