Li Linyi, Yang Yunyun, Zhang Huina, Du Yunhui, Jiao Xiaolu, Yu Huahui, Wang Yu, Lv Qianwen, Li Fan, Sun Qiuju, Qin Yanwen
The Key Laboratory of Upper Airway Dysfunction-Related Cardiovascular Diseases, Beijing Anzhen Hospital, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Capital Medical University, Beijing, China.
The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Anzhen Hospital, Ministry of Education, Capital Medical University, Beijing, China.
Front Pharmacol. 2021 Aug 24;12:723922. doi: 10.3389/fphar.2021.723922. eCollection 2021.
Endothelial barrier dysfunction plays a key role in atherosclerosis progression. The primary pathology of obstructive sleep apnea-hypopnea syndrome is chronic intermittent hypoxia (IH), which induces reactive oxygen species (ROS) overproduction, endothelial barrier injury, and atherosclerosis. Salidroside, a typical pharmacological constituent of Rhodiola genus, has documented antioxidative, and cardiovascular protective effects. However, whether salidroside can improve IH-aggravated endothelial barrier dysfunction and atherosclerosis has not been elucidated. In normal chow diet-fed ApoE mice, salidroside (100 mg/kg/d, p. o.) significantly ameliorated the formation of atherosclerotic lesions and barrier injury aggravated by 7-weeks IH (21%-5%-21%, 120 s/cycle). In human umbilical vein endothelial cells (HUVECs), exposure to IH (21%-5%-21%, 40 min/cycle, 72 cycles) decreased transendothelial electrical resistance and protein expression of vascular endothelial cadherin (VE-cadherin) and zonula occludens 1. In addition, IH promoted ROS production and activated ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway. All of these effects of IH were reversed by salidroside. Similar to salidroside, ROCK-selective inhibitors Y26732, and Fasudil protected HUVECs from IH-induced ROS overproduction and endothelial barrier disruption. Furthermore, salidroside increased intracellular cAMP levels, while the PKA-selective inhibitor H-89 attenuated the effects of salidroside on IH-induced RhoA/ROCK suppression, ROS scavenging, and barrier protection. Our findings demonstrate that salidroside effectively ameliorated IH-aggravated endothelial barrier injury and atherosclerosis, largely through the cAMP/PKA/RhoA signaling pathway.
内皮屏障功能障碍在动脉粥样硬化进展中起关键作用。阻塞性睡眠呼吸暂停低通气综合征的主要病理改变是慢性间歇性缺氧（IH），其可诱导活性氧（ROS）过度产生、内皮屏障损伤和动脉粥样硬化。红景天苷是红景天属的一种典型药理成分，已被证明具有抗氧化和心血管保护作用。然而，红景天苷是否能改善IH加重的内皮屏障功能障碍和动脉粥样硬化尚未阐明。在正常饮食喂养的载脂蛋白E（ApoE）小鼠中，红景天苷（100 mg/kg/d，口服）显著改善了由7周IH（21%-5%-21%，120秒/周期）加重的动脉粥样硬化病变形成和屏障损伤（21%-5%-21%）。在人脐静脉内皮细胞（HUVECs）中，暴露于IH（21%-5%-21%，40分钟/周期，72个周期）会降低跨内皮电阻以及血管内皮钙黏蛋白（VE-钙黏蛋白）和闭合蛋白1的蛋白表达。此外，IH促进ROS产生并激活Ras同源基因家族成员A（RhoA）/Rho相关蛋白激酶（ROCK）信号通路。IH的所有这些作用均被红景天苷逆转。与红景天苷类似，ROCK选择性抑制剂Y26732和法舒地尔可保护HUVECs免受IH诱导的ROS过度产生和内皮屏障破坏。此外，红景天苷增加细胞内cAMP水平，而PKA选择性抑制剂H-89减弱了红景天苷对IH诱导的RhoA/ROCK抑制、ROS清除和屏障保护的作用。我们的研究结果表明，红景天苷可有效改善IH加重的内皮屏障损伤和动脉粥样硬化，主要是通过cAMP/PKA/RhoA信号通路。
