Identification of securinine as vascular protective agent targeting atherosclerosis in vascular endothelial cells,smooth muscle cells,and apolipoprotein E deficient mice |
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| Affiliation: | 1. Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Republic of Korea;2. College of Korean Medicine and Professional Graduate School of Korean Medicine, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Republic of Korea;3. Clinical Medicine Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34504, Republic of Korea;1. Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, 16 Nanxiaojie, Inner Dongzhimen, Beijing 100700, China;2. XiYuan Hospital, China Academy of Chinese Medical Sciences, No.1 Xiyuan playground Road, Haidian District, Beijing 100091, China;3. Guang''anmen Hospital, China Academy of Chinese Medical Sciences, No.5, North Line Pavilion, Xicheng District, Beijing 100053, China;4. Guangdong Provincial Hospital of Traditional Chinese Medicine, No.111 Dade Road, Yuexiu District, Guangzhou 510120, China;5. General Hospital of Beijing PLA Military Region, No.5, Nan men Cang, Dongsishitiao, Dongcheng District, Beijing 100700, China;6. Department of Epidemiology, University of California-Los Angeles, 405 Hilgard Avenue, California 90095, USA;1. State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China;2. School of Pharmacy, Lanzhou University, Lanzhou, Gansu 730000, China |
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| Abstract: | BackgroundAtherosclerosis is a chronic vascular disease and characterized by accumulation within the intima of inflammatory cells, smooth muscle cells, lipid, and connective tissue.PurposeThe purpose of the present study was to identify natural agents that commonly reverse advanced atherosclerotic plaque to early atherosclerotic plaque.MethodsDifferentially expressed genes (DEGs) were analyzed in silico. The differentially expressed genes from 9 intimal thickening and 8 fibrous cap atheroma tissue which were collected from GEO data were assessed by the connectivity map. Natural candidate securinine, a main compound from Securinega suffruticosa, was selected and administrated 1, 5 mg/kg/day in apolipoprotein-E-deficient (ApoE KO) mice for 18 weeks.ResultsSecurinine significantly showed lowered blood pressure and improvement of metabolic parameters with hyperlipidemia. The impairment in vasorelaxation was remarkably decreased by treatment with securinine. H&E staining revealed that treatment with securinine reduced atherosclerotic lesions. Securinine suppressed the expression of adhesion molecules and matrix metalloproteinase-2/-9 in both ApoE KO and vascular endothelial cells (HUVEC). In HUVEC pretreatment with securinine significantly inhibited ROS generation and NF-κB activation. Growth curve assays using the real-time cell analyzer showed that securinine significantly decreased TNF-α-induced aortic smooth muscle cell proliferation and migration in a dose-dependent manner.ConclusionSecurinine may be a potential natural candidate for the treatment of atherosclerosis because it attenuates vascular inflammation and dysfunction as well as vascular lesion. |
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