Effect of verbascoside on endothelial dysfunction in atherosclerotic rats by regulating HMGB1/RAGE signal pathway

doi:10.11958/20230325

Abstract

Abstract:

Objective To investigate the effect of verbascoside (VB) on endothelial dysfunction in atherosclerotic (AS) rats by regulating high-mobility group protein B1 (HMGB1)/receptor for advanced glycation endproducts (RAGE)/nuclear factor κB (NF-κB) signal pathway. Methods The rat model of AS was established by high fat feeding combined with vitamin D3 solution intraperitoneal injection. Rats were divided into the control group (n=10), the model group (n=12), the low (VB-L), medium (VB-M) and high dose (VB-H) VB groups (2, 5 and 10 mg/kg, n=10), and the positive control group (simvastatin, 5 mg/kg, n=10). The serum level of blood lipids was detected by automatic biochemical analyzer. Pathological changes of aorta were observed by HE staining. Serum levels of inflammatory factors and vascular endothelial cytokines were detected by enzyme-linked immunosorbent assay (ELISA). The level of oxidative stress in rats was detected by micro-method kit. The expression of HMGB1/RAGE signal pathway protein in aorta was detected by Western blot assay. Results Compared with the control group, the intima of aorta in the model group was thickened, plaque appeared in blood vessels, accompanied by lipid deposition and inflammatory cell infiltration. Serum levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), C-reactive protein (CRP), matrix metalloproteinase-9 (MMP-9), endothelin-1 (ET-1), visfatin, intercellular adhesion molecule-1 (ICAM-1) and malondialdehyde (MDA), and HMGB1, RAGE and phosphorylation levels of NF-κB in aorta were obviously increased. Serum levels of high-density lipoprotein cholesterol (HDL-C), nitric oxide (NO), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were obviously decreased (P<0.05). Compared with the model group, pathological changes of rats were obviously improved in the VB-L, VB-M and VB-H groups and the simvastatin group. Serum levels of TC, TG, LDL-C, TNF-α, IL-1β, CRP, MMP-9, ET-1, visfatin, ICAM-1, MDA, and HMGB1, RAGE, phosphorylation levels of NF-κB in aorta were obviously decreased, and serum levels of HDL-C, NO, SOD and GSH-Px were obviously increased (P<0.05). Conclusion VB can down-regulate the expression of HMGB1/RAGE/NF-κB signal pathway protein, inhibit inflammation and oxidative stress in AS rats, and improve lipid metabolism and vascular endothelial function.

Key words: acteoside, atherosclerosis, HMGB1 protein, receptor for advanced glycation end products, endothelial dysfunction, verbascoside

CLC Number:

R285.5

Figures/Tables 7

References 21

[1]	VALLEJO J, COCHAIN C, ZERNECKE A, et al. Heterogeneity of immune cells in human atherosclerosis revealed by scRNA-Seq[J]. Cardiovasc Res, 2021, 117(13):2537-2543. doi:10.1093/cvr/cvab260.
[2]	XU S, ILYAS I, LITTLE P J, et al. Endothelial dysfunction in atherosclerotic cardiovascular diseases and beyond:from mechanism to pharmacotherapies[J]. Pharmacol Rev, 2021, 73(3):924-967. doi:10.1124/pharmrev.120.000096.
[3]	SOEHNLEIN O, LIBBY P. Targeting inflammation in atherosclerosis - from experimental insights to the clinic[J]. Nat Rev Drug Discov, 2021, 20(8):589-610. doi:10.1038/s41573-021-00198-1.
[4]	MA S, LU G, ZHANG Q, et al. Extracellular-superoxide dismutase DNA methylation promotes oxidative stress in homocysteine-induced atherosclerosis[J]. Acta Biochim Biophys Sin (Shanghai), 2022, 54(9):1222-1233. doi:10.3724/abbs.2022093.
[5]	FAN J, WATANABE T. Atherosclerosis:Known and unknown[J]. Pathol Int, 2022, 72(3):151-160. doi:10.1111/pin.13202.
[6]	ZHANG G, YU F, DONG R, et al. Verbascoside alleviates renal fibrosis in unilateral ureteral obstruction rats by inhibiting macrophage infiltration[J]. Iran J Basic Med Sci, 2021, 24(6):752-759. doi:10.22038/ijbms.2021.52759.11903.
[7]	FAN Y, ZHANG K. Verbascoside inhibits the progression of atherosclerosis in high fat diet induced atherosclerosis rat model[J]. J Physiol Pharmacol, 2021, 72(3):329-337. doi:10.26402/jpp.2021.3.03.
[8]	WANG J, LI R, PENG Z, et al. HMGB1 participates in LPS-induced acute lung injury by activating the AIM2 inflammasome in macrophages and inducing polarization of M1 macrophages via TLR2,TLR4,and RAGE/NF-κB signaling pathways[J]. Int J Mol Med, 2020, 45(1):61-80. doi:10.3892/ijmm.2020.4530.
[9]	ZHANG X, FERNÁNDEZ-HERNANDO C. Endothelial HMGB1(high-mobility group box 1)regulation of LDL(low-density lipoprotein)transcytosis:a novel mechanism of intracellular HMGB1 in atherosclerosis[J]. Arterioscler Thromb Vasc Biol, 2021, 41(1):217-219. doi:10.1161/ATVBAHA.120.315517.
[10]	焦艳, 谢世静, 李喆. 沙棘黄酮对大鼠动脉粥样硬化斑块的影响及作用机制[J]. 中国老年学杂志, 2022, 42(6):1472-1475.
	JIAO Y, XIE S J, LI Z. Effect of sea-buckthorn flavone on atherosclerotic plaque in rats and its mechanism of action[J]. Chinese Journal of Gerontology, 2022, 42(6):1472-1475. doi:10.3969/j.issn.1005-9202.2022.06.055.
[11]	白荣钰, 易欢, 陈丰连, 等. 毛冬青三萜皂苷对动脉粥样硬化大鼠肠道菌群的影响[J]. 中草药, 2021, 52(20):6245-6253.
	BAI R Y, YI H, CHEN F L, et al. Effect of triterpenoid saponins from llex pubescens on intestinal flora in atherosclerotic rats[J]. Chinese Traditional and Herbal Drugs, 2021, 52(20):6245-6253. doi:10.7501/j.issn.0253-2670.2021.20.014.
[12]	MAN J J, BECKMAN J A, JAFFE I Z. Sex as a biological variable in atherosclerosis[J]. Circ Res, 2020, 126(9):1297-1319. doi:10.1161/CIRCRESAHA.120.315930.
[13]	WU M, GAO Y, CHEN B. Mechanism of acteoside-activated let-7g-5P attenuating Aβ-induced increased permeability and apoptosis of brain microvascular endothelial cells based on experimental and network pharmacology[J]. Neuroreport, 2022, 33(16):714-722. doi:10.1097/WNR.0000000000001837.
[14]	ZHANG S, HONG F, MA C, et al. Hepatic lipid metabolism disorder and atherosclerosis[J]. Endocr Metab Immune Disord Drug Targets, 2022, 22(6):590-600. doi:10.2174/1871530322666211220110810.
[15]	SHRAMKO V S, STRYUKOVA E V, KASHTANOVA E V, et al. Adipokines and adipocytokines in men with coronary atherosclerosis and overweight[J]. Kardiologiia, 2022, 62(11):49-55. doi:10.18087/cardio.2022.11.n2237.
[16]	JEON S, KIM T K, JEONG S J, et al. Anti-inflammatory actions of soluble ninjurin-1 ameliorate atherosclerosis[J]. Circulation, 2020, 142(18):1736-1751. doi:10.1161/CIRCULATIONAHA.120.046907.
[17]	LIU P, WANG S, WANG G, et al. Macrophage-derived exosomal miR-4532 promotes endothelial cells injury by targeting SP1 and NF-κB P65 signalling activation[J]. J Cell Mol Med, 2022, 26(20):5165-5180. doi:10.1111/jcmm.17541.
[18]	DORAN A C. Inflammation resolution:implications for atherosclerosis[J]. Circ Res, 2022, 130(1):130-148. doi:10.1161/CIRCRESAHA.121.319822.
[19]	KAKE S, KAWAGUCHI H, NAGASATO T, et al. Association between HMGB1 and thrombogenesis in a hyperlipaemia-induced microminipig model of atherosclerosis[J]. In Vivo, 2020, 34(4):1871-1874. doi:10.21873/invivo.11982.
[20]	JEONG J, LEE J, LIM J, et al. Soluble RAGE attenuates AngII-induced endothelial hyperpermeability by disrupting HMGB1-mediated crosstalk between AT1R and RAGE[J]. Exp Mol Med, 2019, 51(9):1-15. doi:10.1038/s12276-019-0312-5.
[21]	OLEJARZ W, GŁUSZKO A, CYRAN A, et al. TLRs and RAGE are elevated in carotid plaques from patients with moderate-to-severe obstructive sleep apnea syndrome[J]. Sleep Breath, 2020, 24(4):1573-1580. doi:10.1007/s11325-020-02029-w.

组别	n	TC	TG	HDL-C	LDL-C
对照组	10	1.42±0.18	0.62±0.12	2.25±0.34	1.75±0.40
模型组	12	2.08±0.25^a	1.41±0.30^a	0.96±0.36^a	6.10±0.72^a
VB-L组	10	1.80±0.21^b	1.12±0.20^b	1.42±0.28^b	5.39±0.60^b
VB-M组	10	1.65±0.24^b	0.79±0.25^bc	1.69±0.45^b	4.66±0.45^bc
VB-H组	10	1.49±0.16^bc	0.74±0.22^bc	1.88±0.32^bc	3.85±0.51^bcd
辛伐他汀组	10	1.52±0.18^bc	0.70±0.20^bc	1.92±0.30^bc	3.48±0.45^bcd
F		15.589^＊＊	20.348^＊＊	18.493^＊＊	86.051^＊＊

组别	n	TC	TG	HDL-C	LDL-C
对照组	10	1.42±0.18	0.62±0.12	2.25±0.34	1.75±0.40
模型组	12	2.08±0.25^a	1.41±0.30^a	0.96±0.36^a	6.10±0.72^a
VB-L组	10	1.80±0.21^b	1.12±0.20^b	1.42±0.28^b	5.39±0.60^b
VB-M组	10	1.65±0.24^b	0.79±0.25^bc	1.69±0.45^b	4.66±0.45^bc
VB-H组	10	1.49±0.16^bc	0.74±0.22^bc	1.88±0.32^bc	3.85±0.51^bcd
辛伐他汀组	10	1.52±0.18^bc	0.70±0.20^bc	1.92±0.30^bc	3.48±0.45^bcd
F		15.589^＊＊	20.348^＊＊	18.493^＊＊	86.051^＊＊

组别	n	TNF-α/（ng/L）	IL-1β/（ng/L）	CRP/（mg/L）	MMP-9/（μg/L）
对照组	10	189.15±36.74	20.32±4.01	1.23±0.15	70.22±5.15
模型组	12	323.06±34.15^a	30.98±3.57^a	4.68±0.20^a	105.32±8.23^a
VB-L组	10	276.24±38.20^b	26.01±3.70^b	2.73±0.18^b	79.24±7.01^b
VB-M组	10	258.20±39.21^b	24.61±3.78^b	2.70±0.15^b	82.24±8.01^bc
VB-H组	10	223.78±36.22^bc	21.75±3.12^b	2.45±0.16^bcd	78.42±7.52^bc
辛伐他汀组	10	245.21±35.25^b	22.53±3.01^b	2.30±0.14^bcd	85.20±9.31^b
F		17.078^＊＊	12.941^＊＊	513.455^＊＊	27.992^＊＊

组别	n	TNF-α/（ng/L）	IL-1β/（ng/L）	CRP/（mg/L）	MMP-9/（μg/L）
对照组	10	189.15±36.74	20.32±4.01	1.23±0.15	70.22±5.15
模型组	12	323.06±34.15^a	30.98±3.57^a	4.68±0.20^a	105.32±8.23^a
VB-L组	10	276.24±38.20^b	26.01±3.70^b	2.73±0.18^b	79.24±7.01^b
VB-M组	10	258.20±39.21^b	24.61±3.78^b	2.70±0.15^b	82.24±8.01^bc
VB-H组	10	223.78±36.22^bc	21.75±3.12^b	2.45±0.16^bcd	78.42±7.52^bc
辛伐他汀组	10	245.21±35.25^b	22.53±3.01^b	2.30±0.14^bcd	85.20±9.31^b
F		17.078^＊＊	12.941^＊＊	513.455^＊＊	27.992^＊＊

组别	n	ET-1/（ng/L）	内脂素/（μg/L）	ICAM-1/（ng/L）	NO/（μmol/L）
对照组	10	106.30±22.12	18.32±3.10	14.02±2.65	31.02±3.74
模型组	12	158.36±25.52^a	45.15±5.23^a	57.21±6.78^a	18.81±3.23^a
VB-L组	10	130.02±18.04^b	39.21±4.60^b	50.10±4.52^b	23.90±2.61^b
VB-M组	10	125.74±22.47^b	28.15±5.12^bc	37.21±4.85^bc	25.17±3.02^b
VB-H组	10	112.80±23.52^b	22.45±2.98^bcd	24.72±4.12^bcd	28.49±3.42^bc
辛伐他汀组	10	115.63±20.13^b	22.04±3.01^bcd	28.32±4.74^bcd	29.33±3.14^bc
F		7.864^＊＊	71.208^＊＊	119.643^＊＊	21.224^＊＊