Faculty Collaboration Database

Inducible endothelium-derived hyperpolarizing factor: role of the 15-lipoxygenase-EDHF pathway. J Cardiovasc Pharmacol 2013 Mar;61(3):176-87

Date

12/20/2012

Pubmed ID

23249676

Pubmed Central ID

PMC3594564

DOI

10.1097/FJC.0b013e31828165db

Scopus ID

2-s2.0-84875218727 (requires institutional sign-in at Scopus site)   32 Citations

Abstract

Endothelium-derived hyperpolarizing factors (EDHFs) regulate vascular tone by contributing to the vasorelaxations to shear stress and endothelial agonists such as bradykinin and acetylcholine. 15(S)-Hydroxy-11,12-epoxyeicosatrienoic acid (15-H-11,12-EETA) and 11(R),12(S),15(S)-trihydroxyeicosatrienoic acid (11,12,15-THETA) are endothelial metabolites of the 15-lipoxygenase (15-LO) pathway of arachidonic acid metabolism and are EDHFs. 11,12,15-THETA activates small conductance, calcium-activated potassium channels on smooth muscle cells causing membrane hyperpolarization, and relaxation. Expression levels of 15-LO in the endothelium regulate the activity of the 15-LO/15-H-11,12-EETA/11,12,15-THETA pathway and its contribution to vascular tone. Regulation of its expression is by transcriptional, translational, and epigenetic mechanisms. Hypoxia, hypercholesterolemia, atherosclerosis, anemia, estrogen, interleukins, and possibly other hormones increase 15-LO expression. An increase in 15-LO results in increased synthesis of 15-H-11,12-EETA and 11,12,15-THETA, increased membrane hyperpolarization, and enhanced contribution to relaxation by endothelial agonists. Thus, the 15-LO pathway represents the first example of an inducible EDHF. In addition to 15-LO metabolites, a number of chemicals have been identified as EDHFs and their contributions to vascular tone vary with species and vascular bed. The reason for multiple EDHFs has evaded explanation. However, EDHF functioning as constitutive EDHFs or inducible EDHFs may explain the need for chemically and biochemically distinct pathways for EDHF activity and the variation in EDHFs between species and vascular beds. This new EDHF classification provides a framework for understanding EDHF activity in physiological and pathological conditions.

Author List

Campbell WB, Gauthier KM

Author

William B. Campbell PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Arachidonate 15-Lipoxygenase
Arachidonic Acid
Biological Factors
Endothelium, Vascular
Humans
Natriuretic Peptide, C-Type
Signal Transduction
Up-Regulation
Vasodilation