Salidroside Ameliorated Intermittent Hypoxia-Aggravated Endothelial Barrier Disruption and Atherosclerosis via the cAMP/PKA/RhoA Signaling Pathway

Linyi Li; Yunyun Yang; Huina Zhang; Yunhui Du; Xiaolu Jiao; Huahui Yu; Yu Wang; Qianwen Lv; Fan Li; Qiuju Sun; Yanwen Qin

doi:10.3389/fphar.2021.723922

Salidroside Ameliorated Intermittent Hypoxia-Aggravated Endothelial Barrier Disruption and Atherosclerosis via the cAMP/PKA/RhoA Signaling Pathway

Front Pharmacol. 2021 Aug 24:12:723922. doi: 10.3389/fphar.2021.723922. eCollection 2021.

Authors

Linyi Li^{1

2

3}, Yunyun Yang^{1

2

3}, Huina Zhang^{1

2

3}, Yunhui Du^{1

2

3}, Xiaolu Jiao^{1

2

3}, Huahui Yu^{1

2

3}, Yu Wang^{1

2

3}, Qianwen Lv^{1

2

3}, Fan Li^{1

2

3}, Qiuju Sun^{1

2

3}, Yanwen Qin^{1

2

3}

Affiliations

¹ 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.
² The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Anzhen Hospital, Ministry of Education, Capital Medical University, Beijing, China.
³ Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, China.

Abstract

Background: 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. Methods and results: 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. Conclusion: Our findings demonstrate that salidroside effectively ameliorated IH-aggravated endothelial barrier injury and atherosclerosis, largely through the cAMP/PKA/RhoA signaling pathway.

Keywords: atherosclerosis; endothelial barrier; intermittent hypoxia; obstructive sleep apnea-hypopnea syndrome; salidroside.