Department of Cardiology, The First Affiliated Hospital, Harbin Medical University, Harbin, China.
Key Laboratory of Cardiac Diseases and Heart Failure, Harbin Medical University, Harbin, China.
J Cardiovasc Pharmacol. 2019 Aug;74(2):143-151. doi: 10.1097/FJC.0000000000000690.
Chronic exposure to cold causes arterial hypertension [cold-induce hypertension (CIH)]. Emerging data have indicated that gut barrier dysfunction is involved in the pathogenesis of hypertension. In this study, we explored the effect of gut barrier dysfunction on vascular inflammation induced by cold exposure and the therapeutic effect of atorvastatin in a CIH rat model. The CIH was established by cold exposure for 2 weeks. Two groups of Sprague Dawley rats were exposed to moderate cold (4 ± 1°C), whereas the control group was maintained at room temperature (23 ± 1°C) (10 rats/group). The 2 groups received atorvastatin or vehicle at the beginning of cold exposure, respectively, for 2 weeks. Cold exposure increased mean arterial pressure compared with room temperature group, indicating that animals developed arterial hypertension. Cold exposure induced vascular dysfunction due to decreasing phosphorylated endothelial nitric oxide synthase protein expression in aorta, and these were blunted by atorvastatin. Cold exposure increased the levels of gut-derived inflammatory cytokines, tumor necrosis factor-α, and interleukin-6 production in aorta and resulted in vascular inflammation, whereas atorvastatin prevented these effects. Cold exposure also increased gut permeability, inhibited tight junction protein expression in proximal colon, and resulted in gut barrier dysfunction. Interestingly, atorvastatin eliminated increasing gut permeability, decreasing tight junction protein expression, and gut pathology and reversed gut barrier dysfunction. Atorvastatin attenuated CIH and improved gut barrier function; the beneficial effects might be via inhibiting gut-derived inflammatory cytokines and reversing cold-induced vascular inflammation, suggesting that gut barrier dysfunction may be involved in the pathogenesis of CIH.
慢性冷暴露会导致动脉高血压（冷诱导高血压，CIH）。新出现的数据表明，肠道屏障功能障碍与高血压的发病机制有关。在这项研究中，我们探讨了肠道屏障功能障碍对冷暴露诱导的血管炎症的影响，以及阿托伐他汀在 CIH 大鼠模型中的治疗效果。通过 2 周的冷暴露建立 CIH。两组 Sprague Dawley 大鼠分别暴露于中度寒冷（4±1°C），而对照组保持室温（23±1°C）（每组 10 只大鼠）。两组大鼠在冷暴露开始时分别接受阿托伐他汀或载体，持续 2 周。冷暴露导致平均动脉压升高，与室温组相比，表明动物发生了动脉高血压。冷暴露导致血管功能障碍，原因是主动脉中磷酸化内皮型一氧化氮合酶蛋白表达减少，而阿托伐他汀可减轻这种作用。冷暴露增加了肠道来源的炎症细胞因子肿瘤坏死因子-α和白细胞介素-6 在主动脉中的产生，导致血管炎症，而阿托伐他汀则阻止了这些作用。冷暴露还增加了肠道通透性，抑制了近端结肠中紧密连接蛋白的表达，导致肠道屏障功能障碍。有趣的是，阿托伐他汀消除了肠道通透性的增加、紧密连接蛋白表达的减少以及肠道病理学改变，逆转了肠道屏障功能障碍。阿托伐他汀减轻了 CIH 并改善了肠道屏障功能；这些有益作用可能是通过抑制肠道来源的炎症细胞因子和逆转冷诱导的血管炎症来实现的，这表明肠道屏障功能障碍可能与 CIH 的发病机制有关。
