ABSTRACT
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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.
Subject(s)
Aldosterone/metabolism , Blood Pressure/genetics , Cytochrome P-450 CYP11B2/genetics , Sodium Chloride, Dietary/metabolism , Animals , Biomarkers , Cytochrome P-450 CYP11B2/antagonists & inhibitors , Cytochrome P-450 CYP11B2/metabolism , Electrolytes/blood , Fadrozole/pharmacology , Gene Expression , Genotype , Hematocrit , Humans , Hypertension/etiology , Hypertension/metabolism , Hypertension/physiopathology , Kidney/metabolism , Mice , Mice, Transgenic , Phenotype , Renin/blood , Renin/metabolism , Sodium Chloride, Dietary/blood , Steroid 11-beta-Hydroxylase/genetics , Steroid 11-beta-Hydroxylase/metabolismABSTRACT
Previous studies suggest that the delivery of neurotrophic factors secreted from adipose stromal cells (ASC) protect the brain from 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. However, it remains unclear which secreted neurotrophic factor has an important role in protecting 6-OHDA-treated neurons. Through the use of antibodies in this study, we demonstrated that specific neutralization of IGF-1 activity in ASC conditioned media (ASC-CM) significantly blocks ASC-CM-induced neuroprotection against 6-OHDA neurotoxicity. Consistently, this neuroprotection was mostly attributed to the activation of the AKT-mediated signaling pathway. In contrast, brain derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in ASC-CM did not play a role in ASC-CM-induced neuroprotection against 6-OHDA.
