title: Salt-dependent Blood Pressure in Human Aldosterone Synthase-Transgenic Mice.
abstract: Hypertension is one of the most important, preventable causes of premature morbidity and mortality in the developed world. Aldosterone is a major mineralocorticoid hormone that plays a key role in the regulation of blood pressure and is implicated in the pathogenesis of hypertension and heart failure. Aldosterone synthase (AS, cytochrome P450 11B2, cyp11B2) is the sole enzyme responsible for the production of aldosterone in humans. To determine the effects of increased expression of human aldosterone synthase (hAS) on blood pressure (BP), we established transgenic mice carrying the hAS gene (cyp11B2). We showed that hAS overexpression increased levels of aldosterone in hAS+/-mice. On high salt diet (HS), BPs of hAS+/-mice were significantly increased compared with WT mice. Fadrozole (an inhibitor of aldosterone synthase) treatment significantly reduced BPs of hAS+/-mice on HS. This is the first time overexpression of AS in a transgenic mouse line has shown an ability to induce HP. Specifically inhibiting AS activity in these mice is a promising therapy for reducing hypertension. This hAS transgenic mouse model is therefore an ideal animal model for hypertension therapy studies.
authors.affiliation: Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Huiying
authors.initials: H
authors.lastname: Gu
authors.affiliation: Basic Medical School, Peking University, Beijing, China.
authors.forename: Zhizhong
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Du
authors.affiliation: Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Shatara
authors.affiliation: Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Yi
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Kowala
authors.affiliation: Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA. ydu@iupui.edu.
authors.forename: Yansheng
authors.initials: Y
authors.lastname: Du
mesh_terms: D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers; D001794:Blood Pressure / Q000235:genetics*; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004573:Electrolytes / Q000097:blood; D017316:Fadrozole / Q000494:pharmacology; D015870:Gene Expression; D005838:Genotype; D006400:Hematocrit; D006801:Humans; D006973:Hypertension / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D012083:Renin / Q000097:blood / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000097:blood / Q000378:metabolism*; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D004573:Electrolytes; D017673:Sodium Chloride, Dietary; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; D012083:Renin; D017316:Fadrozole