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.
authors.affiliation: Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Brett L
authors.initials: BL
authors.lastname: Jennings
authors.forename: Anne M
authors.initials: AM
authors.lastname: Estes
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Anderson
authors.forename: Xiao R
authors.initials: XR
authors.lastname: Fang
authors.forename: Fariborz A
authors.initials: FA
authors.lastname: Yaghini
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fan
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: William B
authors.initials: WB
authors.lastname: Campbell
authors.forename: Kafait U
authors.initials: KU
authors.lastname: Malik
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D003900:Desoxycorticosterone / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D017673:Sodium Chloride, Dietary / Q000009:adverse effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017673:Sodium Chloride, Dietary; D003900:Desoxycorticosterone; D001189:Aryl Hydrocarbon Hydroxylases; C585498:Cyp1b1 protein, mouse; C585499:Cyp1b1 protein, rat; D065633:Cytochrome P-450 CYP1B1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases