Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013 Jun;124(12):695-700.
doi: 10.1042/CS20120483.

Role of the CYP4A/20-HETE pathway in vascular dysfunction of the Dahl salt-sensitive rat

Kathleen M Lukaszewicz  1 , Julian H Lombard
Affiliations
Review

Role of the CYP4A/20-HETE pathway in vascular dysfunction of the Dahl salt-sensitive rat

Kathleen M Lukaszewicz et al. Clin Sci (Lond). 2013 Jun.

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Chemical structures of 20-HETE, the 20-HETE antagonist 20-HEDE and the CYP4A inhibitor DDMS
Figure 2
Figure 2. General conclusions summarized from studies demonstrating the role of the CYP4A/20-HETE pathway in the cerebral vasculature of the Dahl SS rat
The summary includes previous reports from our laboratory [12,16], illustrating the role of chronically suppressed plasma AngII on vascular function within the cerebral vasculature of Dahl SS rats.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Roman RJ. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev. 2002;82:131–185. - PubMed
    1. Ward NC, Tsai IJ, Barden A, van Bockxmeer FM, Puddey IB, Hodgson JM, Croft KD. A single nucleotide polymorphism in the CYP4F2 but not CYP4A11 gene is associated with increased 20-HETE excretion and blood pressure. Hypertension. 2008;51:1393–1398. - PubMed
    1. Liu H, Zhao Y, Nie D, Shi J, Fu L, Li Y, Yu D, Lu J. Association of a functional cytochrome P450 4F2 haplotype with urinary 20-HETE and hypertension. J Am Soc Nephrol. 2008;19:714–721. - PMC - PubMed
    1. Levere RD, Martasek P, Escalante B, Schwartzman ML, Abraham NG. Effect of heme arginate administration on blood pressure in spontaneously hypertensive rats. J Clin Invest. 1990;86:213–219. - PMC - PubMed
    1. Singh H, Cheng J, Deng H, Kemp R, Ishizuka T, Nasjletti A, Schwartzman ML. Vascular cytochrome P450 4A expression and 20-hydroxyeicosatetraenoic acid synthesis contribute to endothelial dysfunction in androgen-induced hypertension. Hypertension. 2007;50:123–129. - PubMed

MeSH terms

Substances

-