| CYP4A2-induced hypertension is 20-hydroxyeicosatetraenoic acid- and angiotensin II-dependent. | |
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MedLine Citation:
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PMID: 20837888 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have shown previously that increased vascular endothelial expression of CYP4A2 leads to 20-hydroxyeicosatetraenoic (20-HETE)-dependent hypertension. The renin-angiotensin system is a key regulator of blood pressure. In this study, we examined possible interactions between 20-HETE and the renin-angiotensin system. In normotensive (110±3 mm Hg) Sprague-Dawley rats transduced with a lentivirus expressing the CYP4A2 cDNA under the control of an endothelial-specific promoter (VECAD-4A2), systolic blood pressure increased rapidly, reaching 139±1, 145±3, and 150±2 mm Hg at 3, 5, and 10 days after transduction; blood pressure remained elevated, thereafter, with maximum levels of 163±3 mm Hg. Treatment with lisinopril, losartan, or the 20-HETE antagonist 20-hydroxyeicosa-6(Z), 15(Z)-dienoic acid decreased blood pressure to control values, but blood pressure returned to its high levels after cessation of treatment. Endothelial-specific overexpression of CYP4A2 resulted in increased expression of vascular angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor and increased levels of plasma and tissue angiotensin II; all were attenuated by treatment with HET0016, an inhibitor of 20-HETE synthesis, or with 20-hydroxyeicosa-6(Z), 15(Z)-dienoic acid. In cultured endothelial cells, 20-HETE specifically and potently induced ACE expression without altering the expression of ACE2, angiotensinogen, or angiotensin II receptors. This is the first study to demonstrate that 20-HETE, a key constrictor eicosanoid in the microcirculation, induces ACE and angiotensin II type 1 receptor expression and increases angiotensin II levels, suggesting that the mechanisms by which 20-HETE promotes hypertension include activation of the renin-angiotensin system that is likely initiated at the level of ACE induction. |
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Authors:
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Komal Sodhi; Cheng-Chia Wu; Jennifer Cheng; Katherine Gotlinger; Kazuyoshi Inoue; Mohan Goli; John R Falck; Nader G Abraham; Michal L Schwartzman |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-09-13 |
Journal Detail:
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Title: Hypertension Volume: 56 ISSN: 1524-4563 ISO Abbreviation: Hypertension Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-10-21 Completed Date: 2010-11-10 Revised Date: 2012-03-30 |
Medline Journal Info:
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Nlm Unique ID: 7906255 Medline TA: Hypertension Country: United States |
Other Details:
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Languages: eng Pagination: 871-8 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amidines
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pharmacology Analysis of Variance Angiotensin II / metabolism* Angiotensin II Type 1 Receptor Blockers / pharmacology, therapeutic use Angiotensin-Converting Enzyme Inhibitors / pharmacology, therapeutic use Animals Blood Pressure / genetics Blotting, Western Cells, Cultured Cytochrome P-450 Enzyme System / genetics* Endothelium, Vascular / cytology, drug effects, metabolism Hydroxyeicosatetraenoic Acids / metabolism*, pharmacology, therapeutic use Hypertension / genetics*, metabolism* Lentivirus Lisinopril / pharmacology, therapeutic use Losartan / pharmacology, therapeutic use Mass Spectrometry Oligonucleotide Array Sequence Analysis Peptidyl-Dipeptidase A / genetics, metabolism Rats Rats, Sprague-Dawley Receptor, Angiotensin, Type 1 / genetics, metabolism Renin-Angiotensin System / drug effects Reverse Transcriptase Polymerase Chain Reaction Time Factors |
| Grant Support | |
ID/Acronym/Agency:
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DK068134/DK/NIDDK NIH HHS; F30 HL097402/HL/NHLBI NIH HHS; GM31278/GM/NIGMS NIH HHS; HL34300/HL/NHLBI NIH HHS; HL55601/HL/NHLBI NIH HHS; R01 DK056601-11/DK/NIDDK NIH HHS; R01 DK056601-12/DK/NIDDK NIH HHS; R01 GM031278-27/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/20-hydroxyeicosa-6(Z),15(Z)-dienoic acid; 0/Amidines; 0/Angiotensin II Type 1 Receptor Blockers; 0/Angiotensin-Converting Enzyme Inhibitors; 0/Hydroxyeicosatetraenoic Acids; 0/N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine; 0/Receptor, Angiotensin, Type 1; 11128-99-7/Angiotensin II; 114798-26-4/Losartan; 79551-86-3/20-hydroxy-5,8,11,14-eicosatetraenoic acid; 83915-83-7/Lisinopril; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.15.3/cytochrome P-450 CYP4A2 (rat); EC 3.4.15.1/Peptidyl-Dipeptidase A |
| Comments/Corrections | |
Comment In:
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Hypertension. 2010 Nov;56(5):822-3
[PMID:
20837886
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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