动脉粥样硬化中的IL-33/ST2通路：IL-33悖论

吐尔孙阿依·依斯米提; 阿里米江·阿布里米提; 麦合甫热提·乌甫尔; 袁玉娟; 帕提古丽·喀迪尔江; 穆叶赛·尼加提

doi:10.16766/j.cnki.issn.1674-4152.002802

动脉粥样硬化中的IL-33/ST2通路：IL-33悖论

doi: 10.16766/j.cnki.issn.1674-4152.002802

1.
新疆维吾尔自治区人民医院急救中心, 新疆乌鲁木齐 830000
2.
新疆维吾尔自治区维吾尔医医院心病科, 新疆乌鲁木齐 830000
3.
新疆维吾尔自治区人民医院心内科

基金项目:

国家自然科学基金地区科学基金项目 81760068

详细信息

通讯作者:
穆叶赛·尼加提，E-mail：muyassar11@aliyun.com

中图分类号: R543.5
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- 被引次数: 0
出版历程
- 收稿日期: 2022-07-21
- 网络出版日期: 2023-04-07

IL-33/ST2 pathway in atherosclerosis: the IL-33 paradox

1.
Emergency Department, Xinjiang Uygur Autonomous Region People ' s Hospital, Urumqi, Xinjiang 830000, China

摘要

摘要: 目的探讨人和动物实验模型中IL-33/可溶性生长刺激表达基因2蛋白(sST2)通路与冠状动脉硬化之间的关系。方法纳入2019年1—12月就诊于新疆维吾尔自治区人民医院心内科明确诊断为急性心肌梗死的患者(AMI组，50例)和稳定型冠心病患者(CAD组，50例)。收集研究对象冠状动脉血标本，用ELISA法检测IL-33水平。动物实验模型中，收集ApoE基因敲除小鼠的下腔静脉血液，检测TG、总胆固醇(CHOL) 浓度，用ELISA法计算样品的凝血酶-抗凝血酶复合物(TAT)水平。结果 AMI组患者的IL-33、Gensini评分显著高于CAD组(均P＜0.05)。Pearson相关性分析显示, Gensini评分与IL-33表达水平呈正相关关系(P＜0.05)。多元线性回归分析显示，IL-33(β=0.295，P=0.001)水平是Gensini评分的独立影响因素。ROC曲线分析可知，IL-33、Gensini评分及其联合预测的AUC分别为0.716、0.820、0.864。动物实验模型中，不同浓度IL-33干预后ApoE基因敲除的小鼠TAT浓度、TG、CHOL浓度随着干预时间的延长而降低(均P＜0.05)。结论 AMI患者冠脉血IL-33通过IL-33/ST2依赖性途径促进动脉硬化的进展，并诱导血栓形成。IL-33可降低动脉粥样硬化的ApoE小鼠的血脂来抑制动脉粥样硬化的进展。
- 白细胞介素-33 /
- 可溶性生长刺激表达基因2蛋白 /
- 动脉硬化
Abstract: Objective This study aimed to investigate the relationship between the IL-33/soluble growth stimulation expressed gene 2 (ST2) pathway and coronary arteriosclerosis in human and animal models. Methods The clinical trial included patients with a clear diagnosis of acute myocardial infarction (AMI group, n=50) and stable coronary artery disease (CAD group, n=50) who visited the Department of Cardiology, People ' s Hospital of Xinjiang Uygur Autonomous Region from January 2019 to December 2019. Coronary blood specimens were collected from the study subjects, and IL-33 levels were detected by ELISA. In the animal experimental model, blood was collected from inferior vena cava of ApoE knockout mice, TG and cholesterol (CHOL) concentrations were measured. In addition, the thrombin-antithrombin complex (TAT) levels of the samples were calculated by ELISA. Results IL-33 and Gensini scores in AMI group were significantly higher than those in CAD group (all P < 0.05). Pearson correlation analysis showed a positive correlation between Gensini score and IL-33 level expression (P < 0.05). Multiple linear regression analysis showed that Gensini score levels were independently correlated with IL-33 (β=0.295, P=0.001) levels. The area under the curve (AUC) of the Gensini score, the AUC for IL-33, Gensini score and joint predictors were 0.716, 0.820 and 0.864, respectively. In the animal experimental model, the TAT concentration, TG and CHOL concentrations in ApoE knockout mice decreased with the increase of intervention time after different concentrations of IL-33 intervention (all P < 0.05). Conclusion Coronary blood IL-33 in patients with AMI accelerates the progression of atherosclerosis through the IL-33/ST2 pathway and induces thrombosis. IL-33 reduces lipids in atherosclerotic ApoE mice to inhibit the progression of atherosclerosis.
- Interleukin-33 /
- Soluble growth stimulation expressed gene 2 /
- Atherosclerosis

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图 1 ROC曲线分析

Figure 1. ROC curve analysis

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表 1 AMI组和CAD组患者一般临床资料比较

Table 1. Comparison of general clinical data between patients in AMI group and CAD group

指标	AMI组(n=50)	CAD组(n=50)	统计量	P值
基线资料
年龄(x±s，岁)	57.6±12.3	60.9±7.9	1.617^a	0.109
性别(男/女，例)	38/12	34/16	0.794^b	0.373
BMI(x±s)	26.6±6.9	24.7±3.8	1.613^a	0.110
吸烟[例(%)]	24(48.0)	28(56.0)	0.641^b	0.423
收缩压(x±s，mm Hg)	129.4±23.1	136.9±20.2	1.754^a	0.083
舒张压(x±s，mm Hg)	76.9±13.8	78.4±11.8	0.583^a	0.561
既往病史
高血压[例(%)]	29(58.0)	23(46.0)	1.442^b	0.230
糖尿病[例(%)]	33(66.0)	37(74.0)	0.762^b	0.383
高脂血症[例(%)]	43(86.0)	41(82.0)	0.298^b	0.585
生化指标
TG(x±s，mmol/L)	1.5±0.8	1.7±1.4	0.772^a	0.442
CHOL(x±s，mmol/L)	4.4±1.2	4.2±1.3	0.614^a	0.054
HDL-C(x±s，mmol/L)	1.0±0.3	0.9±0.2	2.005^a	0.061
LDL-C(x±s，mmol/L)	3.0±1.0	2.3±0.9	3.603^a	0.001
LPa[M(P₂₅, P₇₅)，mmol/L]	186.7(117.7, 380.0)	228.8(134.0, 349.0)	0.411^c	0.682
C-反应蛋白[M(P₂₅, P₇₅), μg/L]	3.8(2.5, 12.3)	2.5(1.7, 3.5)	-1.781^c	0.079
血肌酐[M(P₂₅, P₇₅)，μg/L]	69.5(57.9, 78.5)	62.5(55.5, 72.6)	-1.557^c	0.123
NT-proBNP[M(P₂₅, P₇₅), pmol/L]	238.6(97.1, 573.5)	29.0(15.7, 64.0)	0.062^c	0.066
注：1 mm Hg =0.133 kPa，^a为t值，^b为χ²值，^c为Z值。

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表 2 AMI组和CAD组患者IL-33水平和Gensini评分比较(x ±s)

Table 2. The levels of IL-33 and Gensini score in patients with AMI andCAD(x ±s)

组别	例数	IL-33(pg/mL)	Gensini评分(分)
AMI	50	139.1±43.9	70.6±36.9
CAD	77	111.9±28.9	32.2±15.7
t值		3.656	6.040
P值		＜0.001	＜0.001

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表 3 临床指标与Gensini评分的相关性分析

Table 3. Correlation between Gensini score and clinical index

项目	r值	P值
IL-33(pg/mL)	0.314	0.001
LDL-C(mmol/L)	0.113	0.270

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表 4 相关临床指标与Gensini评分的多元线性回归分析

Table 4. Multiple linear regression analysis of Gensini score and clinical indexes

变量	β	SE	B	t值	P值
IL-33(pg/mL)	0.295	0.090	0.314	3.270	0.001
LDL-C(mmol/L)	4.003	3.606	0.113	1.110	0.270
注：R²=0.607，调整R²=0.565，F=1.736，P=0.004。连续变量均以实际值赋值。

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表 5 不同浓度的IL-33干预时的CHOL浓度随时间变化(x ±s)

Table 5. Changes in CHOL concentration over time during intervention with different concentrations of IL-33 (x ±s)

组别	例数	4周	6周	8周	F值	P值
对照组		7.25±1.14	6.90±0.96	7.02±1.04	0.144	0.867
IL-33(1.0×10⁶ pg/mL)		5.96±0.98	6.02±0.81	5.37±0.85^a	0.841	0.455
IL-33(2.5×10⁶ pg/mL)		5.45±0.99^a	4.88±1.14^a	4.59±0.99^a	0.882	0.439
IL-33(5.0×10⁶ pg/mL)		5.70±0.75^a	5.44±0.88^a	4.69±0.66^a	2.382	0.135
F值		3.384	4.088	7.895
P值		0.044	0.025	0.002
注：与同一时间对照组比较，^aP＜0.05。

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表 6 不同浓度的IL-33干预时的TG浓度随时间变化(x ±s)

Table 6. Changes in TG concentration over time during intervention with different concentrations of IL-33 (x ±s)

组别	例数	4周	6周	8周	F值	P值
对照组		4.34±0.62	4.45±0.56	4.30±0.64	0.085	0.919
IL-33(1.0×10⁶ pg/mL)		3.99±0.44	3.63±0.41	3.88±0.38^a	1.054	0.379
IL-33(2.5×10⁶ pg/mL)		3.93±0.57	3.37±0.66^a	3.27±0.41^a	2.094	0.166
IL-33(5.0×10⁶ pg/mL)		3.82±0.74	3.63±0.46	3.31±0.35^a	2.382	0.358
F值		0.694	3.962	5.883
P值		0.569	0.027	0.007
注：与同一时间对照组比较，^aP＜0.05。

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表 7 不同浓度的IL-33干预时的TAT浓度随时间变化(x ±s)

Table 7. Changes in TAT concentration over time during intervention with different concentrations of IL-33 (x ±s)

组别	4周	6周	8周	F值	P值
对照组	0.95±0.08	0.95±0.06	0.92±0.07	0.165	0.850
IL-33(1.0×10⁶ pg/mL)	0.85±0.10	0.74±0.06^a	0.73±0.10^ac	2.961	0.900
IL-33(2.5×10⁶ pg/mL)	0.79±0.07^a	0.70±0.07^a	0.62±0.10^ac	4.886	0.028
IL-33(5.0×10⁶ pg/mL)	0.77±0.08^a	0.65±0.05^ab	0.60±0.08^ac	7.287	0.008
F值	4.630	21.431	12.940
P值	0.016	＜0.001	＜0.001
注：与同一时间对照组比较，^aP＜0.05；与同一浓度4周和6周比较，^bP＜0.05；与同一浓度4周和8周比较，^cP＜0.05；与同一浓度6周和8周比较，^dP＜0.05。

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