Cytochrome P450 1B1 gene disruption minimizes deoxycorticosterone acetate-salt-induced hypertension and associated cardiac dysfunction and renal damage in mice

Brett L. Jennings, Anne M. Estes, Larry J. Anderson, Xiao R. Fang, Fariborz A. Yaghini, Zheng Fan, Frank J. Gonzalez, William B. Campbell, Kafait Malik

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Previously, we showed that the cytochrome P450 1B1 inhibitor 2,3′,4,5′-tetramethoxystilbene reversed deoxycorticosterone acetate (DOCA)-salt-induced hypertension and minimized endothelial and renal dysfunction in the rat. This study was conducted to test the hypothesis that cytochrome P450 1B1 contributes to cardiac dysfunction, and renal damage and inflammation associated with DOCA-salt-induced hypertension, via increased production of reactive oxygen species and modulation of neurohumoral factors and signaling molecules. DOCA-salt increased systolic blood pressure, cardiac and renal cytochrome P450 1B1 activity, and plasma levels of catecholamines, vasopressin, and endothelin-1 in wild-type (Cyp1b1+/+) mice that were minimized in Cyp1b1+/+ mice. Cardiac function, assessed by echocardiography, showed that DOCA-salt increased the thickness of the left ventricular posterior and anterior walls during diastole, the left ventricular internal diameter, and end-diastolic and end-systolic volume in Cyp1b1+/+ but not in Cyp1b1+/+ mice; stroke volume was not altered in either genotype. DOCA-salt increased renal vascular resistance and caused vascular hypertrophy and renal fibrosis, increased renal infiltration of macrophages and T lymphocytes, caused proteinuria, increased cardiac and renal nicotinamide adenine dinucleotide phosphate-oxidase activity, caused production of reactive oxygen species, and increased activities of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and cellular-Src; these were all reduced in DOCA-salt-treated Cyp1b1 mice. Renal and cardiac levels of eicosanoids were not altered in either genotype of mice. These data suggest that, in DOCA-salt hypertension in mice, cytochrome P450 1B1 plays a pivotal role in cardiovascular dysfunction, renal damage, and inflammation, and increased levels of catecholamines, vasopressin, and endothelin-1, consequent to generation of reactive oxygen species and activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and cellular-Src independent of eicosanoids.

Original languageEnglish (US)
Pages (from-to)1510-1516
Number of pages7
JournalHypertension
Volume60
Issue number6
DOIs
StatePublished - Dec 1 2012

Fingerprint

Desoxycorticosterone
Cytochrome P-450 Enzyme System
Acetates
Salts
Hypertension
Kidney
Genes
Reactive Oxygen Species
Mitogen-Activated Protein Kinase 3
Eicosanoids
Mitogen-Activated Protein Kinase 1
Endothelin-1
p38 Mitogen-Activated Protein Kinases
Vasopressins
Catecholamines
Genotype
Blood Pressure
Inflammation
Diastole
NADP

All Science Journal Classification (ASJC) codes

  • Internal Medicine

Cite this

Cytochrome P450 1B1 gene disruption minimizes deoxycorticosterone acetate-salt-induced hypertension and associated cardiac dysfunction and renal damage in mice. / Jennings, Brett L.; Estes, Anne M.; Anderson, Larry J.; Fang, Xiao R.; Yaghini, Fariborz A.; Fan, Zheng; Gonzalez, Frank J.; Campbell, William B.; Malik, Kafait.

In: Hypertension, Vol. 60, No. 6, 01.12.2012, p. 1510-1516.

Research output: Contribution to journalArticle

Jennings, Brett L. ; Estes, Anne M. ; Anderson, Larry J. ; Fang, Xiao R. ; Yaghini, Fariborz A. ; Fan, Zheng ; Gonzalez, Frank J. ; Campbell, William B. ; Malik, Kafait. / Cytochrome P450 1B1 gene disruption minimizes deoxycorticosterone acetate-salt-induced hypertension and associated cardiac dysfunction and renal damage in mice. In: Hypertension. 2012 ; Vol. 60, No. 6. pp. 1510-1516.
@article{cafa44d3b9ad40e3b8b15554404fc4eb,
title = "Cytochrome P450 1B1 gene disruption minimizes deoxycorticosterone acetate-salt-induced hypertension and associated cardiac dysfunction and renal damage in mice",
abstract = "Previously, we showed that the cytochrome P450 1B1 inhibitor 2,3′,4,5′-tetramethoxystilbene reversed deoxycorticosterone acetate (DOCA)-salt-induced hypertension and minimized endothelial and renal dysfunction in the rat. This study was conducted to test the hypothesis that cytochrome P450 1B1 contributes to cardiac dysfunction, and renal damage and inflammation associated with DOCA-salt-induced hypertension, via increased production of reactive oxygen species and modulation of neurohumoral factors and signaling molecules. DOCA-salt increased systolic blood pressure, cardiac and renal cytochrome P450 1B1 activity, and plasma levels of catecholamines, vasopressin, and endothelin-1 in wild-type (Cyp1b1+/+) mice that were minimized in Cyp1b1+/+ mice. Cardiac function, assessed by echocardiography, showed that DOCA-salt increased the thickness of the left ventricular posterior and anterior walls during diastole, the left ventricular internal diameter, and end-diastolic and end-systolic volume in Cyp1b1+/+ but not in Cyp1b1+/+ mice; stroke volume was not altered in either genotype. DOCA-salt increased renal vascular resistance and caused vascular hypertrophy and renal fibrosis, increased renal infiltration of macrophages and T lymphocytes, caused proteinuria, increased cardiac and renal nicotinamide adenine dinucleotide phosphate-oxidase activity, caused production of reactive oxygen species, and increased activities of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and cellular-Src; these were all reduced in DOCA-salt-treated Cyp1b1 mice. Renal and cardiac levels of eicosanoids were not altered in either genotype of mice. These data suggest that, in DOCA-salt hypertension in mice, cytochrome P450 1B1 plays a pivotal role in cardiovascular dysfunction, renal damage, and inflammation, and increased levels of catecholamines, vasopressin, and endothelin-1, consequent to generation of reactive oxygen species and activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and cellular-Src independent of eicosanoids.",
author = "Jennings, {Brett L.} and Estes, {Anne M.} and Anderson, {Larry J.} and Fang, {Xiao R.} and Yaghini, {Fariborz A.} and Zheng Fan and Gonzalez, {Frank J.} and Campbell, {William B.} and Kafait Malik",
year = "2012",
month = "12",
day = "1",
doi = "10.1161/HYPERTENSIONAHA.112.202606",
language = "English (US)",
volume = "60",
pages = "1510--1516",
journal = "Hypertension",
issn = "0194-911X",
publisher = "Lippincott Williams and Wilkins",
number = "6",

}

TY - JOUR

T1 - Cytochrome P450 1B1 gene disruption minimizes deoxycorticosterone acetate-salt-induced hypertension and associated cardiac dysfunction and renal damage in mice

AU - Jennings, Brett L.

AU - Estes, Anne M.

AU - Anderson, Larry J.

AU - Fang, Xiao R.

AU - Yaghini, Fariborz A.

AU - Fan, Zheng

AU - Gonzalez, Frank J.

AU - Campbell, William B.

AU - Malik, Kafait

PY - 2012/12/1

Y1 - 2012/12/1

N2 - Previously, we showed that the cytochrome P450 1B1 inhibitor 2,3′,4,5′-tetramethoxystilbene reversed deoxycorticosterone acetate (DOCA)-salt-induced hypertension and minimized endothelial and renal dysfunction in the rat. This study was conducted to test the hypothesis that cytochrome P450 1B1 contributes to cardiac dysfunction, and renal damage and inflammation associated with DOCA-salt-induced hypertension, via increased production of reactive oxygen species and modulation of neurohumoral factors and signaling molecules. DOCA-salt increased systolic blood pressure, cardiac and renal cytochrome P450 1B1 activity, and plasma levels of catecholamines, vasopressin, and endothelin-1 in wild-type (Cyp1b1+/+) mice that were minimized in Cyp1b1+/+ mice. Cardiac function, assessed by echocardiography, showed that DOCA-salt increased the thickness of the left ventricular posterior and anterior walls during diastole, the left ventricular internal diameter, and end-diastolic and end-systolic volume in Cyp1b1+/+ but not in Cyp1b1+/+ mice; stroke volume was not altered in either genotype. DOCA-salt increased renal vascular resistance and caused vascular hypertrophy and renal fibrosis, increased renal infiltration of macrophages and T lymphocytes, caused proteinuria, increased cardiac and renal nicotinamide adenine dinucleotide phosphate-oxidase activity, caused production of reactive oxygen species, and increased activities of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and cellular-Src; these were all reduced in DOCA-salt-treated Cyp1b1 mice. Renal and cardiac levels of eicosanoids were not altered in either genotype of mice. These data suggest that, in DOCA-salt hypertension in mice, cytochrome P450 1B1 plays a pivotal role in cardiovascular dysfunction, renal damage, and inflammation, and increased levels of catecholamines, vasopressin, and endothelin-1, consequent to generation of reactive oxygen species and activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and cellular-Src independent of eicosanoids.

AB - Previously, we showed that the cytochrome P450 1B1 inhibitor 2,3′,4,5′-tetramethoxystilbene reversed deoxycorticosterone acetate (DOCA)-salt-induced hypertension and minimized endothelial and renal dysfunction in the rat. This study was conducted to test the hypothesis that cytochrome P450 1B1 contributes to cardiac dysfunction, and renal damage and inflammation associated with DOCA-salt-induced hypertension, via increased production of reactive oxygen species and modulation of neurohumoral factors and signaling molecules. DOCA-salt increased systolic blood pressure, cardiac and renal cytochrome P450 1B1 activity, and plasma levels of catecholamines, vasopressin, and endothelin-1 in wild-type (Cyp1b1+/+) mice that were minimized in Cyp1b1+/+ mice. Cardiac function, assessed by echocardiography, showed that DOCA-salt increased the thickness of the left ventricular posterior and anterior walls during diastole, the left ventricular internal diameter, and end-diastolic and end-systolic volume in Cyp1b1+/+ but not in Cyp1b1+/+ mice; stroke volume was not altered in either genotype. DOCA-salt increased renal vascular resistance and caused vascular hypertrophy and renal fibrosis, increased renal infiltration of macrophages and T lymphocytes, caused proteinuria, increased cardiac and renal nicotinamide adenine dinucleotide phosphate-oxidase activity, caused production of reactive oxygen species, and increased activities of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and cellular-Src; these were all reduced in DOCA-salt-treated Cyp1b1 mice. Renal and cardiac levels of eicosanoids were not altered in either genotype of mice. These data suggest that, in DOCA-salt hypertension in mice, cytochrome P450 1B1 plays a pivotal role in cardiovascular dysfunction, renal damage, and inflammation, and increased levels of catecholamines, vasopressin, and endothelin-1, consequent to generation of reactive oxygen species and activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and cellular-Src independent of eicosanoids.

UR - http://www.scopus.com/inward/record.url?scp=84870242580&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870242580&partnerID=8YFLogxK

U2 - 10.1161/HYPERTENSIONAHA.112.202606

DO - 10.1161/HYPERTENSIONAHA.112.202606

M3 - Article

VL - 60

SP - 1510

EP - 1516

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 6

ER -