Faculty Collaboration Database

Role of the CYP4A/20-HETE pathway in vascular dysfunction of the Dahl salt-sensitive rat. Clin Sci (Lond) 2013 Jun;124(12):695-700

Date

02/27/2013

Pubmed ID

23438293

Pubmed Central ID

PMC4106241

DOI

10.1042/CS20120483

Scopus ID

2-s2.0-84875507515 (requires institutional sign-in at Scopus site)   31 Citations

Abstract

20-HETE (20-hydroxyeicosatetraenoic acid), a vasoconstrictor metabolite of arachidonic acid formed through the action of CYP4A (cytochrome P450-4A) in vascular smooth muscle cells, has been implicated in the development of hypertension and vascular dysfunction. There have been a number of reports in human subjects demonstrating an association between elevated urinary excretion of 20-HETE and hypertension, as well as increased 20-HETE production and vascular dysfunction. The Dahl SS (salt-sensitive) rat is a genetic model of salt-sensitive hypertension that exhibits vascular dysfunction, even when maintained on a normal-salt diet and before the development of hypertension. This mini-review highlights our current research on the role of CYP4A and 20-HETE in the vascular dysfunction of the Dahl SS rat. In our studies, the SS rat is compared with the consomic SS-5BN rat, having chromosome 5 from the salt-resistant Brown Norway rat (carrying all CYP4A genes) introgressed on to the SS genetic background. Our laboratory has demonstrated restoration of normal vascular function in the SS rat with inhibition of the CYP4A/20-HETE pathway, suggesting a direct role for this pathway in the vascular dysfunction in this animal model. Our studies have also shown that the SS rat has an up-regulated CYP4A/20-HETE pathway within their cerebral vasculature compared with the SS-5BN consomic rat, which causes endothelial dysfunction through the production of ROS (reactive oxygen species). Our data shows that ROS influences the expression of the CYP4A/20-HETE pathway in the SS rat in a feed-forward mechanism whereby elevated ROS stimulates production of 20-HETE. The presence of this vicious cycle offers a possible explanation for the spiralling effects of elevated 20-HETE on the development of vascular dysfunction in this animal model.

Author List

Lukaszewicz KM, Lombard JH

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

Animals
Blood Pressure
Cerebral Arteries
Cytochrome P-450 CYP4A
Disease Models, Animal
Hydroxyeicosatetraenoic Acids
Hypertension
Muscle, Smooth, Vascular
Rats
Rats, Inbred BN
Rats, Inbred Dahl
Reactive Oxygen Species
Signal Transduction
Sodium Chloride, Dietary
Up-Regulation
Vasoconstriction