Cytochrome P450 1B1

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K U Malik - One of the best experts on this subject based on the ideXlab platform.

Frank J Gonzalez - One of the best experts on this subject based on the ideXlab platform.

Anne M Estes - One of the best experts on this subject based on the ideXlab platform.

  • Cytochrome P450 1B1 is critical for neointimal growth in wire injured carotid artery of male mice
    Journal of the American Heart Association, 2018
    Co-Authors: Kamalika Mukherjee, Anne M Estes, Frank J Gonzalez, Chi Young Song, Ahmad N Dhodi, Benjamin H Ormseth, Ji Soo Shin, K U Malik
    Abstract:

    Background We have reported that Cytochrome P450 1B1 (CYP1B1), expressed in cardiovascular tissues, contributes to angiotensin II–induced vascular smooth muscle cell (VSMC) migration and proliferat...

  • 6β hydroxytestosterone a Cytochrome P450 1B1 metabolite of testosterone contributes to angiotensin ii induced hypertension and its pathogenesis in male mice
    Hypertension, 2015
    Co-Authors: Ajeeth K Pingili, Anne M Estes, Frank J Gonzalez, Mehmet Kara, Nayaab S Khan, Wei Li, K U Malik
    Abstract:

    Previously, we showed that Cyp1B1 gene disruption minimizes angiotensin II–induced hypertension and associated pathophysiological changes in male mice. This study was conducted to test the hypothesis that Cytochrome P450 1B1-generated metabolites of testosterone, 6β-hydroxytestosterone and 16α-hydroxytestosterone, contribute to angiotensin II–induced hypertension and its pathogenesis. Angiotensin II infusion for 2 weeks increased cardiac Cytochrome P450 1B1 activity and plasma levels of 6β-hydroxytestosterone, but not 16α-hydroxytestosterone, in Cyp1B1 +/+ mice without altering Cyp1B1 gene expression; these effects of angiotensin II were not observed in Cyp1B1 −/− mice. Angiotensin II–induced increase in systolic blood pressure and associated cardiac hypertrophy, and fibrosis, measured by intracardiac accumulation of α-smooth muscle actin, collagen, and transforming growth factor-β, and increased nicotinamide adenine dinucleotide phosphate oxidase activity and production of reactive oxygen species; these changes were minimized in Cyp1B1 −/− or castrated Cyp1B1 +/+ mice, and restored by treatment with 6β-hydroxytestoterone. In Cyp1B1 +/+ mice, 6β-hydroxytestosterone did not alter the angiotensin II–induced increase in systolic blood pressure; the basal systolic blood pressure was also not affected by this agent in either genotype. Angiotensin II or castration did not alter cardiac, angiotensin II type 1 receptor, angiotensin-converting enzyme, Mas receptor, or androgen receptor mRNA levels in Cyp1B1 +/+ or in Cyp1B1 −/− mice. These data suggest that the testosterone metabolite, 6β-hydroxytestosterone, contributes to angiotensin II–induced hypertension and associated cardiac pathogenesis in male mice, most probably by acting as a permissive factor. Moreover, Cytochrome P450 1B1 could serve as a novel target for developing agents for treating renin–angiotensin and testosterone-dependent hypertension and associated pathogenesis in males.

  • abstract 715 Cytochrome P450 1B1 gene disruption prevents neointimal growth in wire injured carotid artery of male mice
    Arteriosclerosis Thrombosis and Vascular Biology, 2015
    Co-Authors: Kamalika Mukherjee, Anne M Estes, Frank J Gonzalez, Fariborz A Yaghini, Tyler H Buckley, K U Malik
    Abstract:

    We have previously reported that Cytochrome P450 1B1 (CYP1B1), a heme-thiolate monooxygenase expressed in cardiovascular tissues, contributes to the development of hypertension and its associated pathogenesis in various experimental animal models. The current study was conducted to determine the contribution of CYP1B1 in neointimal growth following wire injury of carotid artery in 8 week-old male Cyp1B1+/+ and Cyp1B1-/- mice. The left carotid artery was injured with a metal wire and denudation of the endothelial layer was confirmed by the absence of von Willebrand factor staining cells, 1 day after the injury in both Cyp1B1+/+ and Cyp1B1-/- mice. After 14 days of injury, the mice were sacrificed, and both injured and uninjured contralateral carotid arteries were collected for histological and immunohistochemical analysis. The wire injury caused neointimal growth as indicated by increased intimal area, intima/media ratio and elastin disorganization in carotid arteries of Cyp1B1+/+ mice; these changes were minimized in the carotid arteries of Cyp1B1-/- mice. Vascular smooth muscle cells (VSMCs) were found to be the major cellular component of these neointima, as evident by positive staining for α-smooth muscle actin. We also found increased infiltration of inflammatory and immune cells as indicated by expression of CD68+ macrophages and CD3+ T-cells, respectively, in the wire-injured carotid arteries of Cyp1B1+/+ mice but not Cyp1B1-/- mice. Administration of 4-Hydroxy-2, 2, 6, 6-tetramethylpiperidine 1-oxyl (TEMPOL), a superoxide dismutase mimetic, in drinking water (2 mmoles/l), attenuated the neointimal growth in wire-injured carotid arteries of Cyp1B1+/+ mice. Furthermore, in vitro studies showed significant reduction of angiotensin II-induced migration, proliferation and protein synthesis in VSMCs from Cyp1B1-/- compared to Cyp1B1+/+ mice. These data suggest that Cyp1B1-dependent oxidative stress contributes to the neointimal growth caused by wire injury of carotid arteries of male mice. Therefore, inhibitors of Cyp1B1 could be useful in the treatment of restenosis caused by vascular injury including balloon angioplasty, atherosclerosis and diabetes in males.

  • Abstract 250: 6β-hydroxytestosterone, A Cytochrome P450 1B1-derived Metabolite Of Testosterone, Mediates Increase In Thirst, Renal Dysfunction, And End Organ Damage Associated With Angiotensin II-induced Hypertension In Male Mice
    Hypertension, 2014
    Co-Authors: Ajeeth K Pingili, Brett L Jennings, Anne M Estes, Mehmet Kara, K U Malik
    Abstract:

    Recently, we showed that 6β-hydroxytestosterone (6β-OHT), a Cytochrome P450 1B1 (CYP1B1)-derived metabolite of testosterone, contributes to the development of angiotensin II (Ang II)-induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of Ang II in renal homeostasis and end organ damage, we determined the contribution of 6β-OHT to Ang II actions on water consumption and renal function in male Cyp1B1 +/+ and Cyp1B1 -/- mice. Eight weeks old male Cyp1B1 +/+ and Cyp1B1 -/- intact or castrated mice were injected with 6β-OHT (15 μg/g, i.p. every 3 rd day) or vehicle (DMSO, 50 μl), and infused with Ang II (700 ng/kg/min) or vehicle for 2 weeks. Urine was collected for 24 hours on the final day of experiment. Castration attenuated Ang II-induced increase in water consumption and urine output, proteinuria and decrease in osmolality in both Cyp1B1 +/+ , and Cyp1B1 -/- mice (Table 1). 6β-OHT did not alter Ang II-induced increase in water intake, urine output, proteinuria and decrease in osmolality in Cyp1B1 +/+ mice, but restored these effects of Ang II in Cyp1B1 -/- or castrated mice (Table 1). Cyp1B1 gene disruption or castration prevented Ang II-induced renal fibrosis, inflammation, and oxidative stress. 6β-OHT did not alter Ang II-induced renal fibrosis, inflammation or oxidative stress in Cyp1B1 +/+ mice, however in Cyp1B1 -/- or castrated mice it restored these effects of Ang II. These data suggest that 6β-OHT, contributes to increased thirst, impairment of renal function and end organ damage associated with Ang II-induced hypertension in male mice, and that CYP1B1 could serve as a novel target for the treatment of renal disease and hypertension.

  • Cytochrome P450 1B1 gene disruption minimizes doca salt induced hypertension and associated cardiac dysfunction and renal damage in mice
    Hypertension, 2012
    Co-Authors: Brett L Jennings, Anne M Estes, Xiao R Fang, Frank J Gonzalez, Fariborz A Yaghini, William B Campbell, Larry J Anderson, K U Malik
    Abstract:

    Previously, we showed that the Cytochrome P450 1B1 inhibitor, 2,3´,4,5´-tetramethoxystilbene, reversed 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 Cyp1B1−/− mice; stroke volume was not altered in either genotype. DOCA-salt increased renal vascular resistance and caused vascular hypertrophy, renal fibrosis, increased renal infiltration of macrophages and T-lymphocytes, caused proteinuria, increased cardiac and renal NADPH oxidase activity, production of reactive oxygen species, and activities of ERK1/2, p38 MAPK and c-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 ERK1/2, p38 MAPK, and c-Src independent of eicosanoids.

Fariborz A Yaghini - One of the best experts on this subject based on the ideXlab platform.

  • abstract 715 Cytochrome P450 1B1 gene disruption prevents neointimal growth in wire injured carotid artery of male mice
    Arteriosclerosis Thrombosis and Vascular Biology, 2015
    Co-Authors: Kamalika Mukherjee, Anne M Estes, Frank J Gonzalez, Fariborz A Yaghini, Tyler H Buckley, K U Malik
    Abstract:

    We have previously reported that Cytochrome P450 1B1 (CYP1B1), a heme-thiolate monooxygenase expressed in cardiovascular tissues, contributes to the development of hypertension and its associated pathogenesis in various experimental animal models. The current study was conducted to determine the contribution of CYP1B1 in neointimal growth following wire injury of carotid artery in 8 week-old male Cyp1B1+/+ and Cyp1B1-/- mice. The left carotid artery was injured with a metal wire and denudation of the endothelial layer was confirmed by the absence of von Willebrand factor staining cells, 1 day after the injury in both Cyp1B1+/+ and Cyp1B1-/- mice. After 14 days of injury, the mice were sacrificed, and both injured and uninjured contralateral carotid arteries were collected for histological and immunohistochemical analysis. The wire injury caused neointimal growth as indicated by increased intimal area, intima/media ratio and elastin disorganization in carotid arteries of Cyp1B1+/+ mice; these changes were minimized in the carotid arteries of Cyp1B1-/- mice. Vascular smooth muscle cells (VSMCs) were found to be the major cellular component of these neointima, as evident by positive staining for α-smooth muscle actin. We also found increased infiltration of inflammatory and immune cells as indicated by expression of CD68+ macrophages and CD3+ T-cells, respectively, in the wire-injured carotid arteries of Cyp1B1+/+ mice but not Cyp1B1-/- mice. Administration of 4-Hydroxy-2, 2, 6, 6-tetramethylpiperidine 1-oxyl (TEMPOL), a superoxide dismutase mimetic, in drinking water (2 mmoles/l), attenuated the neointimal growth in wire-injured carotid arteries of Cyp1B1+/+ mice. Furthermore, in vitro studies showed significant reduction of angiotensin II-induced migration, proliferation and protein synthesis in VSMCs from Cyp1B1-/- compared to Cyp1B1+/+ mice. These data suggest that Cyp1B1-dependent oxidative stress contributes to the neointimal growth caused by wire injury of carotid arteries of male mice. Therefore, inhibitors of Cyp1B1 could be useful in the treatment of restenosis caused by vascular injury including balloon angioplasty, atherosclerosis and diabetes in males.

  • Cytochrome P450 1B1 gene disruption minimizes doca salt induced hypertension and associated cardiac dysfunction and renal damage in mice
    Hypertension, 2012
    Co-Authors: Brett L Jennings, Anne M Estes, Xiao R Fang, Frank J Gonzalez, Fariborz A Yaghini, William B Campbell, Larry J Anderson, K U Malik
    Abstract:

    Previously, we showed that the Cytochrome P450 1B1 inhibitor, 2,3´,4,5´-tetramethoxystilbene, reversed 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 Cyp1B1−/− mice; stroke volume was not altered in either genotype. DOCA-salt increased renal vascular resistance and caused vascular hypertrophy, renal fibrosis, increased renal infiltration of macrophages and T-lymphocytes, caused proteinuria, increased cardiac and renal NADPH oxidase activity, production of reactive oxygen species, and activities of ERK1/2, p38 MAPK and c-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 ERK1/2, p38 MAPK, and c-Src independent of eicosanoids.

  • Cytochrome P450 1B1 gene disruption minimizes deoxycorticosterone acetate salt induced hypertension and associated cardiac dysfunction and renal damage in mice
    Hypertension, 2012
    Co-Authors: Brett L Jennings, Anne M Estes, Xiao R Fang, Frank J Gonzalez, Fariborz A Yaghini, William B Campbell, Larry J Anderson, K U Malik
    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.

  • Cytochrome P450 1B1 Gene Disruption Minimizes Deoxycorticosterone Acetate-Salt–Induced Hypertension and Associated Cardiac Dysfunction and Renal Damage in MiceNovelty and Significance
    Hypertension, 2012
    Co-Authors: Brett L Jennings, Anne M Estes, Xiao R Fang, Frank J Gonzalez, Fariborz A Yaghini, William B Campbell, Larry J Anderson, K U Malik
    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.

  • Cytochrome P450 1B1 contributes to renal dysfunction and damage caused by angiotensin ii in mice
    Hypertension, 2012
    Co-Authors: Brett L Jennings, Anne M Estes, Xiao R Fang, Frank J Gonzalez, Fariborz A Yaghini, William B Campbell, Larry J Anderson, Jason Porter, K U Malik
    Abstract:

    Cytochrome P450 1B1 contributes to the development of angiotensin II–induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of angiotensin II in the kidney, as well as in salt and water homeostasis, and blood pressure regulation, we determined the contribution of Cytochrome P450 1B1 to renal dysfunction and injury associated with angiotensin II–induced hypertension in male Cyp1B1 +/+ and Cyp1B1 − / − mice. Angiotensin II infusion (700 ng/kg per minute) given by miniosmotic pumps for 13 and 28 days increased systolic blood pressure in Cyp1B1 +/+ mice; this increase was significantly reduced in Cyp1B1 − / − mice. Angiotensin II increased renal Cyp1B1 activity, vascular resistance, and reactivity to vasoconstrictor agents and caused endothelial dysfunction in Cyp1B1 +/+ but not Cyp1B1 − / − mice. Angiotensin II increased water consumption and urine output, decreased urine osmolality, increased urinary Na + and K + excretion, and caused proteinuria and albuminuria in Cyp1B1 +/+ mice that was diminished in Cyp1B1 − / − mice. Infusion of angiotensin II for 28 but not 13 days caused renal fibrosis, tubular damage, and inflammation in Cyp1B1 +/+ mice, which was minimized in Cyp1B1 − / − mice. Angiotensin II increased levels of 12- and 20-hydroxyeicosatetraenoic acids; reactive oxygen species; and activity of NADPH oxidase, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-Src in the kidneys of Cyp1B1 +/+ but not Cyp1B1 − / − mice. These data suggest that increased thirst, renal dysfunction, and injury and inflammation associated with angiotensin II–induced hypertension in mice depend on Cytochrome P450 1B1 activity, thus indicating that Cytochrome P450 1B1 could serve as a novel target for treating renal disease and hypertension.

Brett L Jennings - One of the best experts on this subject based on the ideXlab platform.

  • Abstract 250: 6β-hydroxytestosterone, A Cytochrome P450 1B1-derived Metabolite Of Testosterone, Mediates Increase In Thirst, Renal Dysfunction, And End Organ Damage Associated With Angiotensin II-induced Hypertension In Male Mice
    Hypertension, 2014
    Co-Authors: Ajeeth K Pingili, Brett L Jennings, Anne M Estes, Mehmet Kara, K U Malik
    Abstract:

    Recently, we showed that 6β-hydroxytestosterone (6β-OHT), a Cytochrome P450 1B1 (CYP1B1)-derived metabolite of testosterone, contributes to the development of angiotensin II (Ang II)-induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of Ang II in renal homeostasis and end organ damage, we determined the contribution of 6β-OHT to Ang II actions on water consumption and renal function in male Cyp1B1 +/+ and Cyp1B1 -/- mice. Eight weeks old male Cyp1B1 +/+ and Cyp1B1 -/- intact or castrated mice were injected with 6β-OHT (15 μg/g, i.p. every 3 rd day) or vehicle (DMSO, 50 μl), and infused with Ang II (700 ng/kg/min) or vehicle for 2 weeks. Urine was collected for 24 hours on the final day of experiment. Castration attenuated Ang II-induced increase in water consumption and urine output, proteinuria and decrease in osmolality in both Cyp1B1 +/+ , and Cyp1B1 -/- mice (Table 1). 6β-OHT did not alter Ang II-induced increase in water intake, urine output, proteinuria and decrease in osmolality in Cyp1B1 +/+ mice, but restored these effects of Ang II in Cyp1B1 -/- or castrated mice (Table 1). Cyp1B1 gene disruption or castration prevented Ang II-induced renal fibrosis, inflammation, and oxidative stress. 6β-OHT did not alter Ang II-induced renal fibrosis, inflammation or oxidative stress in Cyp1B1 +/+ mice, however in Cyp1B1 -/- or castrated mice it restored these effects of Ang II. These data suggest that 6β-OHT, contributes to increased thirst, impairment of renal function and end organ damage associated with Ang II-induced hypertension in male mice, and that CYP1B1 could serve as a novel target for the treatment of renal disease and hypertension.

  • Cytochrome P450 1B1 gene disruption minimizes doca salt induced hypertension and associated cardiac dysfunction and renal damage in mice
    Hypertension, 2012
    Co-Authors: Brett L Jennings, Anne M Estes, Xiao R Fang, Frank J Gonzalez, Fariborz A Yaghini, William B Campbell, Larry J Anderson, K U Malik
    Abstract:

    Previously, we showed that the Cytochrome P450 1B1 inhibitor, 2,3´,4,5´-tetramethoxystilbene, reversed 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 Cyp1B1−/− mice; stroke volume was not altered in either genotype. DOCA-salt increased renal vascular resistance and caused vascular hypertrophy, renal fibrosis, increased renal infiltration of macrophages and T-lymphocytes, caused proteinuria, increased cardiac and renal NADPH oxidase activity, production of reactive oxygen species, and activities of ERK1/2, p38 MAPK and c-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 ERK1/2, p38 MAPK, and c-Src independent of eicosanoids.

  • Cytochrome P450 1B1 gene disruption minimizes deoxycorticosterone acetate salt induced hypertension and associated cardiac dysfunction and renal damage in mice
    Hypertension, 2012
    Co-Authors: Brett L Jennings, Anne M Estes, Xiao R Fang, Frank J Gonzalez, Fariborz A Yaghini, William B Campbell, Larry J Anderson, K U Malik
    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.

  • Cytochrome P450 1B1 Gene Disruption Minimizes Deoxycorticosterone Acetate-Salt–Induced Hypertension and Associated Cardiac Dysfunction and Renal Damage in MiceNovelty and Significance
    Hypertension, 2012
    Co-Authors: Brett L Jennings, Anne M Estes, Xiao R Fang, Frank J Gonzalez, Fariborz A Yaghini, William B Campbell, Larry J Anderson, K U Malik
    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.

  • Cytochrome P450 1B1 contributes to renal dysfunction and damage caused by angiotensin ii in mice
    Hypertension, 2012
    Co-Authors: Brett L Jennings, Anne M Estes, Xiao R Fang, Frank J Gonzalez, Fariborz A Yaghini, William B Campbell, Larry J Anderson, Jason Porter, K U Malik
    Abstract:

    Cytochrome P450 1B1 contributes to the development of angiotensin II–induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of angiotensin II in the kidney, as well as in salt and water homeostasis, and blood pressure regulation, we determined the contribution of Cytochrome P450 1B1 to renal dysfunction and injury associated with angiotensin II–induced hypertension in male Cyp1B1 +/+ and Cyp1B1 − / − mice. Angiotensin II infusion (700 ng/kg per minute) given by miniosmotic pumps for 13 and 28 days increased systolic blood pressure in Cyp1B1 +/+ mice; this increase was significantly reduced in Cyp1B1 − / − mice. Angiotensin II increased renal Cyp1B1 activity, vascular resistance, and reactivity to vasoconstrictor agents and caused endothelial dysfunction in Cyp1B1 +/+ but not Cyp1B1 − / − mice. Angiotensin II increased water consumption and urine output, decreased urine osmolality, increased urinary Na + and K + excretion, and caused proteinuria and albuminuria in Cyp1B1 +/+ mice that was diminished in Cyp1B1 − / − mice. Infusion of angiotensin II for 28 but not 13 days caused renal fibrosis, tubular damage, and inflammation in Cyp1B1 +/+ mice, which was minimized in Cyp1B1 − / − mice. Angiotensin II increased levels of 12- and 20-hydroxyeicosatetraenoic acids; reactive oxygen species; and activity of NADPH oxidase, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-Src in the kidneys of Cyp1B1 +/+ but not Cyp1B1 − / − mice. These data suggest that increased thirst, renal dysfunction, and injury and inflammation associated with angiotensin II–induced hypertension in mice depend on Cytochrome P450 1B1 activity, thus indicating that Cytochrome P450 1B1 could serve as a novel target for treating renal disease and hypertension.

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