Lund Amie K, Goens M Beth, Nuñez Bethany A, Walker Mary K
College of Pharmacy, School of Medicine, Department of Pediatrics, University Hospital, University of New Mexico, Albuquerque, New Mexico 87131, USA.
Toxicol Appl Pharmacol. 2006 Apr 15;212(2):127-35. doi: 10.1016/j.taap.2005.07.005. Epub 2005 Aug 15.
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor characterized to play a role in detection and adaptation to environmental stimuli. Genetic deletion of AhR results in hypertension, and cardiac hypertrophy and fibrosis, associated with elevated plasma angiotensin II (Ang II) and endothelin-1 (ET-1), thus AhR appears to contribute to cardiovascular homeostasis. In these studies, we tested the hypothesis that ET-1 mediates cardiovascular pathology in AhR null mice via ETA receptor activation. First, we determine the time courses of cardiac hypertrophy, and of plasma and tissue ET-1 expression in AhR wildtype and null mice. AhR null mice exhibited increases in heart-to-body weight ratio and age-related expression of cardiac hypertrophy markers, beta-myosin heavy chain (beta-MHC), and atrial natriuretic factor (ANF), which were significant at 2 months. Similarly, plasma and tissue ET-1 expression was significantly elevated at 2 months and increased further with age. Second, AhR null mice were treated with ETA receptor antagonist, BQ-123 (100 nmol/kg/day), for 7, 28, or 58 days and blood pressure, cardiac fibrosis, and cardiac hypertrophy assessed, respectively. BQ-123 for 7 days significantly reduced mean arterial pressure in conscious, catheterized mice. BQ-123 for 28 days significantly reduced the histological appearance of cardiac fibrosis. Treatment for 58 days significantly reduced cardiac mass, assessed by heart weight, echocardiography, and beta-MHC and ANF expression; and reduced cardiac fibrosis as determined by osteopontin and collagen I mRNA expression. These findings establish ET-1 and the ETA receptor as primary determinants of hypertension and cardiac pathology in AhR null mice.
芳烃受体（AhR）是一种配体激活的转录因子，其作用是检测和适应环境刺激。AhR基因缺失会导致高血压、心脏肥大和纤维化，这与血浆血管紧张素II（Ang II）和内皮素-1（ET-1）升高有关，因此AhR似乎有助于心血管稳态。在这些研究中，我们测试了以下假设：ET-1通过ETA受体激活介导AhR基因敲除小鼠的心血管病理变化。首先，我们确定了AhR野生型和基因敲除小鼠心脏肥大以及血浆和组织ET-1表达的时间进程。AhR基因敲除小鼠的心脏与体重比增加，心脏肥大标志物β-肌球蛋白重链（β-MHC）和心钠素（ANF）的年龄相关表达增加，在2个月时显著。同样，血浆和组织ET-1表达在2个月时显著升高，并随年龄进一步增加。其次，用ETA受体拮抗剂BQ-123（100 nmol/kg/天）治疗AhR基因敲除小鼠7、28或58天，分别评估血压、心脏纤维化和心脏肥大。BQ-123治疗7天可显著降低清醒插管小鼠的平均动脉压。BQ-123治疗28天可显著减轻心脏纤维化的组织学表现。治疗58天可显著减轻心脏重量、超声心动图以及β-MHC和ANF表达所评估的心脏质量；并通过骨桥蛋白和I型胶原mRNA表达确定减轻心脏纤维化。这些发现确定ET-1和ETA受体是AhR基因敲除小鼠高血压和心脏病理的主要决定因素。
