Salidroside Ameliorated Intermittent Hypoxia-Aggravated Endothelial Barrier Disruption and Atherosclerosis via the cAMP/PKA/RhoA Signaling Pathway
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 atheroscle...
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.723922/full |
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| author | Linyi Li Linyi Li Linyi Li Yunyun Yang Yunyun Yang Yunyun Yang Huina Zhang Huina Zhang Huina Zhang Yunhui Du Yunhui Du Yunhui Du Xiaolu Jiao Xiaolu Jiao Xiaolu Jiao Huahui Yu Huahui Yu Huahui Yu Yu Wang Yu Wang Yu Wang Qianwen Lv Qianwen Lv Qianwen Lv Fan Li Fan Li Fan Li Qiuju Sun Qiuju Sun Qiuju Sun Yanwen Qin Yanwen Qin Yanwen Qin |
| author_facet | Linyi Li Linyi Li Linyi Li Yunyun Yang Yunyun Yang Yunyun Yang Huina Zhang Huina Zhang Huina Zhang Yunhui Du Yunhui Du Yunhui Du Xiaolu Jiao Xiaolu Jiao Xiaolu Jiao Huahui Yu Huahui Yu Huahui Yu Yu Wang Yu Wang Yu Wang Qianwen Lv Qianwen Lv Qianwen Lv Fan Li Fan Li Fan Li Qiuju Sun Qiuju Sun Qiuju Sun Yanwen Qin Yanwen Qin Yanwen Qin |
| author_sort | Linyi Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T20:05:52Z |
| format | Article |
| id | doaj.art-0a408d262bd64639af52313ecdf10206 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-13T20:05:52Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-0a408d262bd64639af52313ecdf102062022-12-21T23:33:01ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-08-011210.3389/fphar.2021.723922723922Salidroside Ameliorated Intermittent Hypoxia-Aggravated Endothelial Barrier Disruption and Atherosclerosis via the cAMP/PKA/RhoA Signaling PathwayLinyi Li0Linyi Li1Linyi Li2Yunyun Yang3Yunyun Yang4Yunyun Yang5Huina Zhang6Huina Zhang7Huina Zhang8Yunhui Du9Yunhui Du10Yunhui Du11Xiaolu Jiao12Xiaolu Jiao13Xiaolu Jiao14Huahui Yu15Huahui Yu16Huahui Yu17Yu Wang18Yu Wang19Yu Wang20Qianwen Lv21Qianwen Lv22Qianwen Lv23Fan Li24Fan Li25Fan Li26Qiuju Sun27Qiuju Sun28Qiuju Sun29Yanwen Qin30Yanwen Qin31Yanwen Qin32The 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, ChinaThe Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Anzhen Hospital, Ministry of Education, Capital Medical University, Beijing, ChinaBeijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, ChinaThe 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, ChinaThe Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Anzhen Hospital, Ministry of Education, Capital Medical University, Beijing, ChinaBeijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, ChinaThe 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, ChinaThe Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Anzhen Hospital, Ministry of Education, Capital Medical University, Beijing, ChinaBeijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, ChinaThe 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, ChinaThe Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Anzhen Hospital, Ministry of Education, Capital Medical University, Beijing, ChinaBeijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, ChinaThe 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, ChinaThe Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Anzhen Hospital, Ministry of Education, Capital Medical University, Beijing, ChinaBeijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, ChinaThe 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, ChinaThe Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Anzhen Hospital, Ministry of Education, Capital Medical University, Beijing, ChinaBeijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, ChinaThe 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, ChinaThe Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Anzhen Hospital, Ministry of Education, Capital Medical University, Beijing, ChinaBeijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, ChinaThe 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, ChinaThe Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Anzhen Hospital, Ministry of Education, Capital Medical University, Beijing, ChinaBeijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, ChinaThe 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, ChinaThe Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Anzhen Hospital, Ministry of Education, Capital Medical University, Beijing, ChinaBeijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, ChinaThe 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, ChinaThe Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Anzhen Hospital, Ministry of Education, Capital Medical University, Beijing, ChinaBeijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, ChinaThe 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, ChinaThe Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Anzhen Hospital, Ministry of Education, Capital Medical University, Beijing, ChinaBeijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, ChinaBackground: 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.https://www.frontiersin.org/articles/10.3389/fphar.2021.723922/fullatherosclerosisobstructive sleep apnea-hypopnea syndromeintermittent hypoxiasalidrosideendothelial barrier |
| spellingShingle | Linyi Li Linyi Li Linyi Li Yunyun Yang Yunyun Yang Yunyun Yang Huina Zhang Huina Zhang Huina Zhang Yunhui Du Yunhui Du Yunhui Du Xiaolu Jiao Xiaolu Jiao Xiaolu Jiao Huahui Yu Huahui Yu Huahui Yu Yu Wang Yu Wang Yu Wang Qianwen Lv Qianwen Lv Qianwen Lv Fan Li Fan Li Fan Li Qiuju Sun Qiuju Sun Qiuju Sun Yanwen Qin Yanwen Qin Yanwen Qin Salidroside Ameliorated Intermittent Hypoxia-Aggravated Endothelial Barrier Disruption and Atherosclerosis via the cAMP/PKA/RhoA Signaling Pathway Frontiers in Pharmacology atherosclerosis obstructive sleep apnea-hypopnea syndrome intermittent hypoxia salidroside endothelial barrier |
| title | Salidroside Ameliorated Intermittent Hypoxia-Aggravated Endothelial Barrier Disruption and Atherosclerosis via the cAMP/PKA/RhoA Signaling Pathway |
| title_full | Salidroside Ameliorated Intermittent Hypoxia-Aggravated Endothelial Barrier Disruption and Atherosclerosis via the cAMP/PKA/RhoA Signaling Pathway |
| title_fullStr | Salidroside Ameliorated Intermittent Hypoxia-Aggravated Endothelial Barrier Disruption and Atherosclerosis via the cAMP/PKA/RhoA Signaling Pathway |
| title_full_unstemmed | Salidroside Ameliorated Intermittent Hypoxia-Aggravated Endothelial Barrier Disruption and Atherosclerosis via the cAMP/PKA/RhoA Signaling Pathway |
| title_short | Salidroside Ameliorated Intermittent Hypoxia-Aggravated Endothelial Barrier Disruption and Atherosclerosis via the cAMP/PKA/RhoA Signaling Pathway |
| title_sort | salidroside ameliorated intermittent hypoxia aggravated endothelial barrier disruption and atherosclerosis via the camp pka rhoa signaling pathway |
| topic | atherosclerosis obstructive sleep apnea-hypopnea syndrome intermittent hypoxia salidroside endothelial barrier |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.723922/full |
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