Department of Pathology, Basic Science Building, New York Medical College, Valhalla, New York, USA.
Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio, USA.
Am J Hypertens. 2018 Mar 10;31(4):495-503. doi: 10.1093/ajh/hpx176.
The transcriptional regulation of the human angiotensin receptor subtype 1 (AT1R) gene in pathophysiologies, like the metabolic syndrome, is poorly understood. The human AT1R gene has polymorphisms in its promoter that can be arranged in 2 haplotypes. Variants -810T, -713T, -214A, and -153A always occur together (Hap-I) and variants -810A, -713G, -214C, and -153G form Hap-II. We have hypothesized that high fat diet will alter cellular transcriptional milieu and increase hAT1R gene expression in a haplotype-dependent manner. This will set up an AT1R-mediated feed-forward loop promoting inflammation, oxidative stress, and hypertension in Hap-I mice.
Since Hap-I of the human AT1R gene is associated with hypertension in Caucasians, we generated transgenic (TG) mice with Hap-I and Hap-II and studied the physiological significance of high fat diet (HFD) on haplotype specific gene expression. Animals were fed with HFD for 20 weeks followed by blood pressure (BP) analysis and collection of their tissues for molecular and biochemical studies.
After HFD treatment, as compared to Hap-II, TG mice with Hap-I show increased expression of hAT1R gene and higher BP; suppression of antioxidant defenses (HO1, SOD1) and increased expression of IL-6, TNFα, IL-1β, NOX1. In vivo ChIP assay has shown that transcription factors CEBPβ, STAT3, and USF bind more strongly to the chromatin obtained from Hap-I TG mice.
Taken together, our results suggest, that after HFD treatment, as compared to Hap-II, the TG mice with Hap-I overexpress the AT1R gene due to the stronger transcriptional activity, thus resulting in an increase in their BP.
人类血管紧张素受体亚型 1（AT1R）基因在代谢综合征等病理生理状态下的转录调控机制尚不清楚。人类 AT1R 基因启动子存在多态性，可排列成 2 种单倍型。-810T、-713T、-214A 和-153A 变体总是一起出现（单倍型 I，Hap-I），而-810A、-713G、-214C 和-153G 形成单倍型 II（Hap-II）。我们假设高脂肪饮食会改变细胞转录环境，并以单倍型依赖的方式增加 hAT1R 基因表达。这将在 Hap-I 小鼠中建立一个 AT1R 介导的正反馈回路，促进炎症、氧化应激和高血压。
由于人类 AT1R 基因的 Hap-I 与白种人中的高血压有关，我们构建了携带 Hap-I 和 Hap-II 的转基因（TG）小鼠，并研究了高脂肪饮食（HFD）对单倍型特异性基因表达的生理意义。动物接受 HFD 喂养 20 周后，进行血压（BP）分析，并采集其组织进行分子和生化研究。
与 Hap-II 相比，接受 HFD 治疗后，携带 Hap-I 的 TG 小鼠 hAT1R 基因表达增加，BP 升高；抗氧化防御（HO1、SOD1）受到抑制，IL-6、TNFα、IL-1β、NOX1 表达增加。体内 ChIP 实验表明，转录因子 CEBPβ、STAT3 和 USF 与 Hap-I TG 小鼠染色质的结合更强。
综上所述，我们的结果表明，与 Hap-II 相比，接受 HFD 治疗后，携带 Hap-I 的 TG 小鼠由于转录活性增强，过度表达 AT1R 基因，导致 BP 升高。
