Division of Respiratory Disease, Renmin Hospital of Wuhan University, Wuhan, China.
Emergency Department, The Second Clinical College, Shenzhen People's Hospital, Jinan University, Shenzhen, China.
J Cell Physiol. 2019 Aug;234(8):13534-13543. doi: 10.1002/jcp.28031. Epub 2019 Jan 4.
Chronic intermittent hypoxia (CIH) is known to induce hypertension, but the mechanism is not well understood. We hypothesized that sensory plasticity of the carotid body (CB) and oxidative stress in the paraventricular nucleus (PVN) are involved in CIH-induced hypertension. In this study, rats were exposed to CIH for 28 days (intermittent hypoxia of 21% O for 60 s and 5% O for 30 s, cyclically repeated for 8 hr/day) and then randomly grouped for intracerebroventricular injection of 5-HT2 receptor antagonist ritanserin, Rho-associated protein kinase (ROCK) inhibitor Y-27632, and NADPH oxidase (NOX) inhibitor diphenyleneiodonium (DPI), respectively. We found that CIH increased blood pressure (BP), elevated carotid sinus nerve (CSN) and renal sympathetic nerve (RSN) activities, oxidative stress, and cell apoptosis in PVN. NOX-derived reactive oxygen species (ROS) production and cell apoptosis decreased when CIH-induced activation of 5-HT/5-HT2AR/PKC signaling was inhibited by ritanserin. In addition, RhoA expression was downregulated when oxidative stress was attenuated by DPI, while Y-27632 decreased the expression of endothelin-1, which is overexpressed in the vascular wall during hypertension. Moreover, treatment with ritanserin, DPI or Y-27632 attenuated the sensory plasticity and sympathetic hyperactivity as well as CIH-induced elevation of BP. In conclusion, CIH-induced activation of 5-HT/5-HT2AR/PKC signaling contributes to NOX-derived oxidative stress in PVN, which may cause sensory plasticity of CB, RSN hyperactivity, and elevated BP.
慢性间歇性低氧（CIH）已知可引起高血压，但机制尚不清楚。我们假设颈动脉体（CB）的感觉可塑性和室旁核（PVN）中的氧化应激参与了 CIH 引起的高血压。在这项研究中，大鼠暴露于 CIH 28 天（21% O 间歇性缺氧 60s 和 5% O 缺氧 30s，每天 8 小时周期性重复），然后随机分组进行脑室注射 5-HT2 受体拮抗剂利坦色林、Rho 相关蛋白激酶（ROCK）抑制剂 Y-27632 和 NADPH 氧化酶（NOX）抑制剂二苯乙烯碘（DPI）。我们发现，CIH 增加了血压（BP），升高了颈动脉窦神经（CSN）和肾交感神经（RSN）活动，PVN 中的氧化应激和细胞凋亡。当通过利坦色林抑制 CIH 诱导的 5-HT/5-HT2AR/蛋白激酶 C 信号激活时，NOX 衍生的活性氧（ROS）产生和细胞凋亡减少。此外，当通过 DPI 减轻氧化应激时，RhoA 表达下调，而 Y-27632 降低了高血压期间血管壁中过度表达的内皮素-1 的表达。此外，用利坦色林、DPI 或 Y-27632 治疗可减轻 CIH 引起的感觉可塑性和交感神经亢进以及血压升高。总之，CIH 诱导的 5-HT/5-HT2AR/蛋白激酶 C 信号的激活导致 PVN 中 NOX 衍生的氧化应激，这可能导致 CB 的感觉可塑性、RSN 活性亢进和血压升高。
