Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, USA.
Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, USA.
Am J Hypertens. 2017 Dec 8;31(1):108-114. doi: 10.1093/ajh/hpx144.
Besides environmental risk factors, genetic factors play a crucial role in the pathogenesis of primary hypertension. The current study is to unravel whether hypertensive phenotypes vary in mice with different genetic background.
Hypertension was induced in C57BL/6J (B6), DBA/2J (D2), and 25 BXD strains by administrating angiotensin (Ang)II (2.5 mg/kg/day infused by osmotic minipump) for 4 weeks. Systolic blood pressure was monitored before (baseline) and after 4 weeks of AngII treatment by tail cuff. Cardiac and renal fibrosis was evaluated by picrosirius red staining and collagen volume fraction (CVF) was quantitated using imaging analyzing system; cardiac transforming growth factor (TGF)-β gene expression was monitored by RT-PCR, and inflammatory response was detected by immunohistochemical ED-1 staining.
AngII infusion caused hypertension in all strains. However, blood pressure elevation was more evident in the D2 strain than the B6 group, while it was widely variable among BXD strains. Furthermore, chronic AngII treatment lead to development of hypertensive cardiac and renal diseases. Cardiac and renal CVF levels in the D2 strain was significantly higher than the B6 cohort, whereas these varied vastly across BXD strains. Moreover, cardiac TGF-β mRNA levels were markedly diverse among various mouse strains.
Our study unequivocally demonstrates that in response to AngII, BXDs with different genetic background expressed hypertension phenotypes with varied degree in severity. It implicates that genomics contribute to pathogenesis of primary hypertension. Building upon the genotype and hypertensive phenotypes, the BXD cohort can be further exploited experimentally to identify genes that influence blood pressure.
除了环境风险因素外，遗传因素在原发性高血压的发病机制中也起着至关重要的作用。本研究旨在揭示具有不同遗传背景的小鼠是否存在不同的高血压表型。
通过给予血管紧张素（Ang）II（通过渗透微型泵每天 2.5mg/kg 输注）4 周，在 C57BL/6J（B6）、DBA/2J（D2）和 25 个 BXD 品系中诱导高血压。在 AngII 治疗前（基线）和 4 周后通过尾套监测收缩压。通过苦味酸红染色评估心脏和肾脏纤维化，并使用成像分析系统定量胶原容积分数（CVF）；通过 RT-PCR 监测心脏转化生长因子（TGF）-β基因表达，并通过免疫组织化学 ED-1 染色检测炎症反应。
AngII 输注在所有品系中均引起高血压。然而，D2 品系的血压升高比 B6 组更为明显，而 BXD 品系之间的血压变化则非常广泛。此外，慢性 AngII 治疗导致高血压性心脏和肾脏疾病的发展。D2 品系的心脏和肾脏 CVF 水平明显高于 B6 组，而 BXD 品系之间的差异则非常大。此外，不同小鼠品系的心脏 TGF-β mRNA 水平差异显著。
我们的研究明确表明，在 AngII 刺激下，具有不同遗传背景的 BXD 表现出不同严重程度的高血压表型。这表明基因组学参与了原发性高血压的发病机制。基于基因型和高血压表型，BXD 群体可以进一步在实验中被利用来鉴定影响血压的基因。
