Introgression of brown norway CYP4A genes on to the dahl salt-sensitive background restores vascular function in SS-5BN consomic rats

Kathleen M. Lukaszewicz, J R Falck, Vijaya L. Manthati, Julian H. Lombard

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The present study tested the hypothesis that the Dahl SS (salt-sensitive) rat has vascular dysfunction due, in part, to the up-regulation of the CYP4A/20-HETE (cytochrome P450 ω-hydroxylase 4A)/20-hydroxyeicosatetraenoic acid) system. To assess the role of vascular 20-HETE, SS rats were compared with SS-5BN consomic rats, carrying CYP4A alleles on chromosome 5 from the normotensive BN (Brown Norway) introgressed on to the SS genetic background. Cerebral arteries from SS-5BN rats had less CYP4A protein than arteries from SS rats fed either NS (normal-salt, 0.4% NaCl) or HS (high-salt, 4.0% NaCl) diet. ACh (acetylcholine)-induced dilation of MCAs (middle cerebral arteries) from SS and SS-5BN rats was present in SS-5BN rats fed on either an NS or HS diet, but absent in SS rats. In SS rats fed on either diet, ACh-induced dilation was restored by acute treatment with the CYP4A inhibitor DDMS (N-methyl-sulfonyl-12,12-dibromododec-11-enamide) or the 20-HETE antagonist 20-HEDE [20-hydroxyeicosa-6(Z),15(Z)-dienoic acid]. The restored response to ACh in DDMS-treated SS rats was inhibited by L-NAME (NG-nitro-L-arginine methyl ester) and unaffected by indomethacin or MS-PPOH [N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide]. Vascular relaxation responses to the NO donor C5FeN6Na2O were intact in both SS and SS-5BN rats and unaffected by the acute addition of DDMS, indicating that the vascular dysfunction of the SS rat is due to a reduced bioavailability of NO instead of failure of the VSMCs (vascular smooth muscle cells) to respond to the vasodilator. Superoxide levels in cerebral arteries of SS-5BN rats [evaluated semi-quantitatively by DHE (dihydroethidium) fluorescence] were lower than those in the arteries of SS rats. These findings indicate that SS rats have an up-regulation of the CYP4A/20-HETE pathway resulting in elevated ROS (reactive oxygen species) and reduced NO bioavailability causing vascular dysfunction.

Original languageEnglish (US)
Pages (from-to)333-342
Number of pages10
JournalClinical Science
Volume124
Issue number5
DOIs
StatePublished - Mar 2013

Fingerprint

Cytochrome P-450 CYP4A
Norway
Blood Vessels
Salts
Genes
Acetylcholine
Cerebral Arteries
NG-Nitroarginine Methyl Ester
Diet
Biological Availability
Dilatation
Up-Regulation
Arteries

Keywords

  • 20-hydroxyeicosatetraenoic acid (20-HETE)
  • Cytochrome P450 4A ω-hydroxylase (CYP4A)
  • Oxidative stress
  • Salt-sensitive hypertension
  • Vascular dysfunction

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Introgression of brown norway CYP4A genes on to the dahl salt-sensitive background restores vascular function in SS-5BN consomic rats. / Lukaszewicz, Kathleen M.; Falck, J R; Manthati, Vijaya L.; Lombard, Julian H.

In: Clinical Science, Vol. 124, No. 5, 03.2013, p. 333-342.

Research output: Contribution to journalArticle

Lukaszewicz, Kathleen M. ; Falck, J R ; Manthati, Vijaya L. ; Lombard, Julian H. / Introgression of brown norway CYP4A genes on to the dahl salt-sensitive background restores vascular function in SS-5BN consomic rats. In: Clinical Science. 2013 ; Vol. 124, No. 5. pp. 333-342.
@article{3bae44267dfa40a38f30320a5d64792c,
title = "Introgression of brown norway CYP4A genes on to the dahl salt-sensitive background restores vascular function in SS-5BN consomic rats",
abstract = "The present study tested the hypothesis that the Dahl SS (salt-sensitive) rat has vascular dysfunction due, in part, to the up-regulation of the CYP4A/20-HETE (cytochrome P450 ω-hydroxylase 4A)/20-hydroxyeicosatetraenoic acid) system. To assess the role of vascular 20-HETE, SS rats were compared with SS-5BN consomic rats, carrying CYP4A alleles on chromosome 5 from the normotensive BN (Brown Norway) introgressed on to the SS genetic background. Cerebral arteries from SS-5BN rats had less CYP4A protein than arteries from SS rats fed either NS (normal-salt, 0.4{\%} NaCl) or HS (high-salt, 4.0{\%} NaCl) diet. ACh (acetylcholine)-induced dilation of MCAs (middle cerebral arteries) from SS and SS-5BN rats was present in SS-5BN rats fed on either an NS or HS diet, but absent in SS rats. In SS rats fed on either diet, ACh-induced dilation was restored by acute treatment with the CYP4A inhibitor DDMS (N-methyl-sulfonyl-12,12-dibromododec-11-enamide) or the 20-HETE antagonist 20-HEDE [20-hydroxyeicosa-6(Z),15(Z)-dienoic acid]. The restored response to ACh in DDMS-treated SS rats was inhibited by L-NAME (NG-nitro-L-arginine methyl ester) and unaffected by indomethacin or MS-PPOH [N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide]. Vascular relaxation responses to the NO donor C5FeN6Na2O were intact in both SS and SS-5BN rats and unaffected by the acute addition of DDMS, indicating that the vascular dysfunction of the SS rat is due to a reduced bioavailability of NO instead of failure of the VSMCs (vascular smooth muscle cells) to respond to the vasodilator. Superoxide levels in cerebral arteries of SS-5BN rats [evaluated semi-quantitatively by DHE (dihydroethidium) fluorescence] were lower than those in the arteries of SS rats. These findings indicate that SS rats have an up-regulation of the CYP4A/20-HETE pathway resulting in elevated ROS (reactive oxygen species) and reduced NO bioavailability causing vascular dysfunction.",
keywords = "20-hydroxyeicosatetraenoic acid (20-HETE), Cytochrome P450 4A ω-hydroxylase (CYP4A), Oxidative stress, Salt-sensitive hypertension, Vascular dysfunction",
author = "Lukaszewicz, {Kathleen M.} and Falck, {J R} and Manthati, {Vijaya L.} and Lombard, {Julian H.}",
year = "2013",
month = "3",
doi = "10.1042/CS20120232",
language = "English (US)",
volume = "124",
pages = "333--342",
journal = "Clinical Science",
issn = "0143-5221",
publisher = "Portland Press Ltd.",
number = "5",

}

TY - JOUR

T1 - Introgression of brown norway CYP4A genes on to the dahl salt-sensitive background restores vascular function in SS-5BN consomic rats

AU - Lukaszewicz, Kathleen M.

AU - Falck, J R

AU - Manthati, Vijaya L.

AU - Lombard, Julian H.

PY - 2013/3

Y1 - 2013/3

N2 - The present study tested the hypothesis that the Dahl SS (salt-sensitive) rat has vascular dysfunction due, in part, to the up-regulation of the CYP4A/20-HETE (cytochrome P450 ω-hydroxylase 4A)/20-hydroxyeicosatetraenoic acid) system. To assess the role of vascular 20-HETE, SS rats were compared with SS-5BN consomic rats, carrying CYP4A alleles on chromosome 5 from the normotensive BN (Brown Norway) introgressed on to the SS genetic background. Cerebral arteries from SS-5BN rats had less CYP4A protein than arteries from SS rats fed either NS (normal-salt, 0.4% NaCl) or HS (high-salt, 4.0% NaCl) diet. ACh (acetylcholine)-induced dilation of MCAs (middle cerebral arteries) from SS and SS-5BN rats was present in SS-5BN rats fed on either an NS or HS diet, but absent in SS rats. In SS rats fed on either diet, ACh-induced dilation was restored by acute treatment with the CYP4A inhibitor DDMS (N-methyl-sulfonyl-12,12-dibromododec-11-enamide) or the 20-HETE antagonist 20-HEDE [20-hydroxyeicosa-6(Z),15(Z)-dienoic acid]. The restored response to ACh in DDMS-treated SS rats was inhibited by L-NAME (NG-nitro-L-arginine methyl ester) and unaffected by indomethacin or MS-PPOH [N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide]. Vascular relaxation responses to the NO donor C5FeN6Na2O were intact in both SS and SS-5BN rats and unaffected by the acute addition of DDMS, indicating that the vascular dysfunction of the SS rat is due to a reduced bioavailability of NO instead of failure of the VSMCs (vascular smooth muscle cells) to respond to the vasodilator. Superoxide levels in cerebral arteries of SS-5BN rats [evaluated semi-quantitatively by DHE (dihydroethidium) fluorescence] were lower than those in the arteries of SS rats. These findings indicate that SS rats have an up-regulation of the CYP4A/20-HETE pathway resulting in elevated ROS (reactive oxygen species) and reduced NO bioavailability causing vascular dysfunction.

AB - The present study tested the hypothesis that the Dahl SS (salt-sensitive) rat has vascular dysfunction due, in part, to the up-regulation of the CYP4A/20-HETE (cytochrome P450 ω-hydroxylase 4A)/20-hydroxyeicosatetraenoic acid) system. To assess the role of vascular 20-HETE, SS rats were compared with SS-5BN consomic rats, carrying CYP4A alleles on chromosome 5 from the normotensive BN (Brown Norway) introgressed on to the SS genetic background. Cerebral arteries from SS-5BN rats had less CYP4A protein than arteries from SS rats fed either NS (normal-salt, 0.4% NaCl) or HS (high-salt, 4.0% NaCl) diet. ACh (acetylcholine)-induced dilation of MCAs (middle cerebral arteries) from SS and SS-5BN rats was present in SS-5BN rats fed on either an NS or HS diet, but absent in SS rats. In SS rats fed on either diet, ACh-induced dilation was restored by acute treatment with the CYP4A inhibitor DDMS (N-methyl-sulfonyl-12,12-dibromododec-11-enamide) or the 20-HETE antagonist 20-HEDE [20-hydroxyeicosa-6(Z),15(Z)-dienoic acid]. The restored response to ACh in DDMS-treated SS rats was inhibited by L-NAME (NG-nitro-L-arginine methyl ester) and unaffected by indomethacin or MS-PPOH [N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide]. Vascular relaxation responses to the NO donor C5FeN6Na2O were intact in both SS and SS-5BN rats and unaffected by the acute addition of DDMS, indicating that the vascular dysfunction of the SS rat is due to a reduced bioavailability of NO instead of failure of the VSMCs (vascular smooth muscle cells) to respond to the vasodilator. Superoxide levels in cerebral arteries of SS-5BN rats [evaluated semi-quantitatively by DHE (dihydroethidium) fluorescence] were lower than those in the arteries of SS rats. These findings indicate that SS rats have an up-regulation of the CYP4A/20-HETE pathway resulting in elevated ROS (reactive oxygen species) and reduced NO bioavailability causing vascular dysfunction.

KW - 20-hydroxyeicosatetraenoic acid (20-HETE)

KW - Cytochrome P450 4A ω-hydroxylase (CYP4A)

KW - Oxidative stress

KW - Salt-sensitive hypertension

KW - Vascular dysfunction

UR - http://www.scopus.com/inward/record.url?scp=84872249355&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84872249355&partnerID=8YFLogxK

U2 - 10.1042/CS20120232

DO - 10.1042/CS20120232

M3 - Article

C2 - 22938512

AN - SCOPUS:84872249355

VL - 124

SP - 333

EP - 342

JO - Clinical Science

JF - Clinical Science

SN - 0143-5221

IS - 5

ER -