Androgen-Sensitive Hypertension Associates with Upregulated Vascular CYP4A12–20-HETE Synthase
| Autor: | Shaojun Mei, Cheng-Chia Wu, Katherine H. Gotlinger, Jennifer Cheng, Victor Garcia, John R. Falck, Vijaya L. Manthati, Fan Zhang, Michal L. Schwartzman, Yan Ding, Adam Weidenhammer, Jorge H. Capdevila |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Male
medicine.medical_specialty medicine.drug_class Blood Pressure Vasodilation Biology Kidney Mice Cytochrome P-450 Enzyme System Internal medicine Hydroxyeicosatetraenoic Acids medicine Animals Cytochrome P450 Family 4 Antagonist Kidney metabolism Dihydrotestosterone hemic and immune systems General Medicine Androgen medicine.disease Up-Regulation Basic Research Endocrinology Eicosanoid Nephrology Pathophysiology of hypertension Hypertension Androgens cardiovascular system lipids (amino acids peptides and proteins) medicine.symptom Vasoconstriction circulatory and respiratory physiology medicine.drug |
| Zdroj: | Journal of the American Society of Nephrology. 24:1288-1296 |
| ISSN: | 1046-6673 |
| DOI: | 10.1681/asn.2012070714 |
| Popis: | Although the mechanism underlying the effect of androgen on BP and cardiovascular disease is not well understood, recent studies suggest that 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE), a primary cytochrome P450 4 (Cyp4)-derived eicosanoid, may mediate androgen-induced hypertension. Here, treatment of normotensive mice with 5α-dihydrotestosterone increased BP and induced both Cyp4a12 expression and 20-HETE levels in preglomerular microvessels. Administration of a 20-HETE antagonist prevented and reversed the effects of dihydrotestosterone on BP. Cyp4a14(-/-) mice, which exhibit androgen-sensitive hypertension in the male mice, produced increased levels of vascular 20-HETE; furthermore, administration of a 20-HETE antagonist normalized BP. To examine whether androgen-independent increases in 20-HETE are sufficient to cause hypertension, we studied Cyp4a12-transgenic mice, which express the CYP4A12-20-HETE synthase under the control of a doxycycline-sensitive promoter. Administration of doxycycline increased BP by 40%, and administration of a 20-HETE antagonist prevented this increase. Levels of CYP4A12 and 20-HETE in preglomerular microvessels of doxycycline-treated transgenic mice approximately doubled, correlating with increased 20-HETE-dependent sensitivity to phenylephrine-mediated vasoconstriction and with decreased acetylcholine-mediated vasodilation in the renal microvasculature. We observed a similar contribution of 20-HETE to myogenic tone in the mesenteric microvasculature. Taken together, these results suggest that 20-HETE both mediates androgen-induced hypertension and can cause hypertension independent of androgen. |
| Databáze: | OpenAIRE |
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