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.
Highlights
Atherosclerotic cardio- or cerebrovascular diseases are common causes of morbidity and mortality worldwide (Gibbons et al, 2021)
Our findings demonstrate that salidroside effectively ameliorated IHaggravated endothelial barrier injury and atherosclerosis, largely through the cAMP/ protein kinase A (PKA)/ras homolog gene family member A (RhoA) signaling pathway
Analysis of Oil Red O staining revealed a significant increasein lipid accumulation (p < 0.01) in aortic sinus tissue of Chronic intermittent hypoxia (CIH) mice compared with control mice, as well as a significant decrease (p < 0.05) in CIH + Sali mice compared with CIH mice (Figures 1A,B)
Summary
Atherosclerotic cardio- or cerebrovascular diseases are common causes of morbidity and mortality worldwide (Gibbons et al, 2021). In addition to traditional risk factors such as hereditary susceptibility, aging, hypertension, obesity, diabetes, and smoking, obstructive sleep apnea-hypopnea syndrome (OSA) that affect up to 100 million people worldwide has emerged as a new significant and independent risk factor for atherosclerosis (Ali et al, 2014; Souza et al, 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. Whether salidroside can improve IHaggravated endothelial barrier dysfunction and atherosclerosis has not been elucidated
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