Familtseva Anastasia, Chaturvedi Pankaj, Kalani Anuradha, Jeremic Nevena, Metreveli Naira, Kunkel George H, Tyagi Suresh C
Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.
Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky
Am J Physiol Cell Physiol. 2016 Oct 1;311(4):C596-C606. doi: 10.1152/ajpcell.00088.2016. Epub 2016 Aug 3.
Hyperhomocysteinemia (HHcy) has been observed to promote hypertension, but the mechanisms are unclear. Toll-like receptor 4 (TLR-4) is a cellular membrane protein that is ubiquitously expressed in all cell types of the vasculature. TLR-4 activation has been known to promote inflammation that has been associated with the pathogenesis of hypertension. In this study we hypothesize that HHcy induces hypertension by TLR-4 activation, which promotes inflammatory cytokine (IL-1β, IL-6, and TNF-α) upregulation and initiation of mitochondria-dependent apoptosis, leading to cell death and chronic vascular inflammation. To test this hypothesis, we used C57BL/6J (WT) mice, cystathionine β-synthase (CBS)-deficient (CBS) mice with genetic mild HHcy, C3H/HeJ (C3H) mice with TLR-4 mutation, and mice with combined genetic HHcy and TLR-4 mutation (CBS/C3H). Ultrasonography of the superior mesenteric artery (SMA) detected an increase in wall-to-lumen ratio, resistive index (RI), and pulsatility index (PI). Tail cuff blood pressure (BP) measurement revealed elevated BP in CBS mice. RI, PI, and wall-to-lumen ratio of the SMA in CBS/C3H mice were similar to the control group, and BP was significantly alleviated. TLR-4, IL-1β, IL-6, and TNF-α expression were upregulated in the SMA of CBS mice and reduced in the SMA of CBS/C3H mice. Molecules involved in the mitochondria-mediated cell death pathway (BAX, caspase-9, and caspase-3) were upregulated in CBS mice and attenuated in CBS/C3H mice. We conclude that HHcy promotes TLR-4-driven chronic vascular inflammation and mitochondria-mediated cell death, inducing hypertension. TLR-4 mutation attenuates vascular inflammation and cell death, which suppress hypertension.
高同型半胱氨酸血症（HHcy）已被观察到会促进高血压，但其机制尚不清楚。Toll样受体4（TLR-4）是一种细胞膜蛋白，在脉管系统的所有细胞类型中普遍表达。已知TLR-4激活会促进与高血压发病机制相关的炎症。在本研究中，我们假设HHcy通过激活TLR-4诱导高血压，这会促进炎性细胞因子（IL-1β、IL-6和TNF-α）上调以及线粒体依赖性凋亡的启动，导致细胞死亡和慢性血管炎症。为了验证这一假设，我们使用了C57BL/6J（野生型，WT）小鼠、具有遗传性轻度HHcy的胱硫醚β-合酶（CBS）缺陷（CBS）小鼠、具有TLR-4突变的C3H/HeJ（C3H）小鼠以及具有遗传性HHcy和TLR-4突变的联合小鼠（CBS/C3H）。肠系膜上动脉（SMA）的超声检查发现壁腔比、阻力指数（RI）和搏动指数（PI）增加。尾袖带血压（BP）测量显示CBS小鼠的血压升高。CBS/C3H小鼠的SMA的RI、PI和壁腔比与对照组相似，并且血压显著减轻。CBS小鼠的SMA中TLR-4、IL-1β、IL-6和TNF-α表达上调，而CBS/C3H小鼠的SMA中这些表达降低。参与线粒体介导的细胞死亡途径的分子（BAX、caspase-9和caspase-3）在CBS小鼠中上调，而在CBS/C3H小鼠中减弱。我们得出结论，HHcy促进TLR-4驱动的慢性血管炎症和线粒体介导的细胞死亡，从而诱发高血压。TLR-4突变减弱血管炎症和细胞死亡，进而抑制高血压。
