沙库巴曲缬沙坦对心肌梗死后心力衰竭大鼠的心脏保护机制探讨

doi:10.11958/20220298

天津医药 ›› 2022, Vol. 50 ›› Issue (11): 1171-1176.doi: 10.11958/20220298

沙库巴曲缬沙坦对心肌梗死后心力衰竭大鼠的心脏保护机制探讨

庞志华¹(), 赵伟², 田留洋¹, 任颖¹, 李栋¹, 姚朱华¹^,^△()

1 天津市人民医院心内一科（邮编300121）
2 天津市红桥区妇幼保健计划生育服务中心

收稿日期:2022-02-28 修回日期:2022-05-10 出版日期:2022-11-15 发布日期:2022-11-11
通讯作者: 姚朱华 E-mail:hz1126@126.com;yaozhuhua021@126.com
作者简介:庞志华（1979），男，副主任医师，主要从事心脏介入和心力衰竭研究。E-mail：hz1126@126.com

Study on the cardioprotective mechanism of sacubitril and valsartan in post-myocardial infarction heart failure of rats

PANG Zhihua¹(), ZHAO Wei², TIAN Liuyang¹, REN Ying¹, LI Dong¹, YAO Zhuhua¹^,^△()

1 Department of Cardiology, Tianjin Union Medical Center, Tianjin 300121, China
2 Maternal and Child Health Care and Family Planning Service Center of Tianjin Hongqiao District

Received:2022-02-28 Revised:2022-05-10 Published:2022-11-15 Online:2022-11-11
Contact: YAO Zhuhua E-mail:hz1126@126.com;yaozhuhua021@126.com

庞志华, 赵伟, 田留洋, 任颖, 李栋, 姚朱华. 沙库巴曲缬沙坦对心肌梗死后心力衰竭大鼠的心脏保护机制探讨[J]. 天津医药, 2022, 50(11): 1171-1176.

PANG Zhihua, ZHAO Wei, TIAN Liuyang, REN Ying, LI Dong, YAO Zhuhua. Study on the cardioprotective mechanism of sacubitril and valsartan in post-myocardial infarction heart failure of rats[J]. Tianjin Medical Journal, 2022, 50(11): 1171-1176.

摘要/Abstract

摘要：

目的探究沙库巴曲缬沙坦对心肌梗死后心力衰竭大鼠的心脏保护作用机制。方法成年雄性SD大鼠60只按随机数字表法均分为对照（Control）组、模型组、沙库巴曲缬沙坦（ARNI）组。通过结扎左冠状动脉前降支构建心力衰竭模型，其中Control组仅穿线但不结扎，其余2组结扎后分别给予生理盐水、沙库巴曲缬沙坦（68 mg/kg）进行灌胃。3个月后超声心动图检查左心室舒张末期内径（LVEDD）、左心室收缩末期内径（LVESD）、左心室舒张末期容积（LVEDV）、左心室短轴缩短分数（LVFS）和左心室射血分数（LVEF）。苏木精-伊红（HE）染色、Masson染色和天狼猩红染色明确心肌结构、纤维化以及胶原分布情况，酶标仪检测血浆炎症氧化应激相关指标，Western blot检测B淋巴细胞瘤-2基因（Bcl-2）、Bcl-2相关的X蛋白（Bax）、半胱氨酸蛋白酶-3（Caspase-3）、凋亡相关因子（Fas）和凋亡相关因子配体（FasL）蛋白表达情况。结果与Control组相比，模型组LVEDV、LVEDD、LVESD、IL-2、IL-6、TNF-α、Bax、Caspase-3、Fas和FasL表达水平增加，LVEF、LVFS、SOD、GST、IL-10和Bcl-2表达水平降低，心肌细胞坏死增加，胶原生成和纤维化加剧。ARNI组相较于模型组，左心室重构明显减轻，LVEF和LVFS上升，心肌细胞坏死减少，纤维化减轻，IL-2、IL-6、TNF-α、Fas和FasL表达减少，GST、IL-4、IL-10和Bcl-2表达增加（P<0.05）。结论沙库巴曲缬沙坦通过下调Bax、Fas和FasL蛋白，减少心肌细胞凋亡，减轻氧化应激、炎症反应和心肌纤维化，减轻左心室重构。

关键词: 心力衰竭, 炎症, 细胞凋亡, 氧化应激, 沙库巴曲缬沙坦

Abstract:

Objective To investigate the mechanism of cardioprotective effect of sacubitril/valsartan (ARNI) on heart failure rats after myocardial infarction. Methods A total of 60 adult male rats were randomly divided into the control group, the model group and the ARNI group. The model of heart failure was established by the ligation of of anterior descending branch of left coronary artery, while in the control group, threaded was inserted without ligation. The other two groups were given normal saline and ARNI (68 mg/kg) by gavage after ligation. After 3 months, echocardiography was completed to measure left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular end diastolic volume (LVEDV) and left ventricular ejection fraction (LVEF). Hematoxylin and eosin (HE) staining and Masson staining were used to determine the myocardial structure and fibrosis. Enzyme linked immunosorbent assay (ELISA) was used to detect related indicators of inflammation and oxidative stress. Western blot assay was used to detect the expression levels of Bcl-2, Bax, Caspase3, Fas and FasL proteins. Results Compared with the control group, values of LVEDD, LVESD, LVEDV, IL-2, IL-6, TNF-α, Bax, Caspase-3, Fas and FasL were increased, but LVEF, LVFS, SOD, GST, IL-10 and Bcl-2 were decreased in the model group. Myocardial cell necrosis obviously increased, collagen production and fibrosis intensified in the model group. The application of ARNI reduced left ventricular remodeling and increased LVEF and LVFS, decreased inflammation and fibrosis, and decreased expression levels of IL-2, IL-6, TNF-α, Fas and FasL, and increased the expression levels of GST, IL-4, IL-10 and Bcl-2 (P<0.05). Conclusion Sacubitril/valsartan can reduce myocardial cell apoptosis, reduce oxidative stress, inflammatory response and fibrosis by down-regulating Bax, Fas and FasL proteins, and reducing left ventricular remodeling to preserve LVEF.

Key words: heart failure, inflammation, apoptosis, oxidative stress, sacubitril-valsartan

中图分类号:

R542.22

图/表 6

参考文献 24

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组别	LVEF						LVFS（%）						LV mass（mg）
组别	术前		术后		t		术前		术后		t		术前		术后			t
Control组	0.79±0.04		0.77±0.01		1.263		49.16±3.95		47.19±0.72		1.101		640.84±132.95		797.28±117.85			1.969
模型组	0.77±0.03		0.43±0.05^a		14.230^＊＊		47.06±2.56		20.59±2.89^a		15.319^＊＊		607.80±76.64		1 001.42±257.98			3.270^＊
ARNI组	0.77±0.02		0.58±0.02^ab		14.900^＊＊		47.32±2.32		33.91±2.40^ab		8.981^＊＊		614.92±72.82		812.41±165.47			2.443^＊
F	0.698		172.041^＊＊				0.716		181.427^＊＊				0.157		1.800
组别		LVEDV（μL）						LVEDD（mm）						LVESD（mm）
组别		术前		术后		t		术前		术后		t		术前		术后	t
Control组		236.88±48.37		266.41±48.40		0.965		6.50±0.69		7.09±0.56		1.505		3.36±0.42		3.91±0.41	2.107
模型组		214.15±25.88		348.00±41.52^a		6.117^＊＊		6.23±0.32		8.03±0.66^a		5.508^＊＊		3.20±0.25		6.20±0.26^a	18.511^＊＊
ARNI组		223.87±38.36		309.02±21.88^b		4.311^＊＊		6.30±0.62		7.75±0.24		4.868^＊＊		3.44±0.25		4.81±0.72^ab	4.034^＊＊
F		0.435		5.495^＊				0.300		4.357^＊				0.755		26.952^＊＊

组别	LVEF						LVFS（%）						LV mass（mg）
组别	术前		术后		t		术前		术后		t		术前		术后			t
Control组	0.79±0.04		0.77±0.01		1.263		49.16±3.95		47.19±0.72		1.101		640.84±132.95		797.28±117.85			1.969
模型组	0.77±0.03		0.43±0.05^a		14.230^＊＊		47.06±2.56		20.59±2.89^a		15.319^＊＊		607.80±76.64		1 001.42±257.98			3.270^＊
ARNI组	0.77±0.02		0.58±0.02^ab		14.900^＊＊		47.32±2.32		33.91±2.40^ab		8.981^＊＊		614.92±72.82		812.41±165.47			2.443^＊
F	0.698		172.041^＊＊				0.716		181.427^＊＊				0.157		1.800
组别		LVEDV（μL）						LVEDD（mm）						LVESD（mm）
组别		术前		术后		t		术前		术后		t		术前		术后	t
Control组		236.88±48.37		266.41±48.40		0.965		6.50±0.69		7.09±0.56		1.505		3.36±0.42		3.91±0.41	2.107
模型组		214.15±25.88		348.00±41.52^a		6.117^＊＊		6.23±0.32		8.03±0.66^a		5.508^＊＊		3.20±0.25		6.20±0.26^a	18.511^＊＊
ARNI组		223.87±38.36		309.02±21.88^b		4.311^＊＊		6.30±0.62		7.75±0.24		4.868^＊＊		3.44±0.25		4.81±0.72^ab	4.034^＊＊
F		0.435		5.495^＊				0.300		4.357^＊				0.755		26.952^＊＊

组别		SOD（U/mL）		GST（U/mL）		IL-2（ng/L）
Control组		38.72±10.26		0.06±0.02		39.80±8.32
模型组		26.74±1.98^a		0.02±0.01^a		56.40±5.83^a
ARNI组		36.18±6.50		0.06±0.02^b		25.29±2.48^ab
F		3.944^＊		6.522^＊		33.226^＊＊
组别	IL-6（ng/L）		TNF-α（ng/L）		IL-4（ng/L）		IL-10（ng/L）
Control组	39.33±9.23		115.47±4.93		19.74±1.82		20.28±4.15
模型组	104.41±4.53^a		147.80±2.04^a		18.63±1.51		12.17±2.76^a
ARNI组	46.03±5.06^b		117.18±2.72^b		33.48±2.29^ab		26.46±2.98^ab
F	146.362^＊＊		138.611^＊＊		94.680^＊＊		22.819^＊＊

组别		SOD（U/mL）		GST（U/mL）		IL-2（ng/L）
Control组		38.72±10.26		0.06±0.02		39.80±8.32
模型组		26.74±1.98^a		0.02±0.01^a		56.40±5.83^a
ARNI组		36.18±6.50		0.06±0.02^b		25.29±2.48^ab
F		3.944^＊		6.522^＊		33.226^＊＊
组别	IL-6（ng/L）		TNF-α（ng/L）		IL-4（ng/L）		IL-10（ng/L）
Control组	39.33±9.23		115.47±4.93		19.74±1.82		20.28±4.15
模型组	104.41±4.53^a		147.80±2.04^a		18.63±1.51		12.17±2.76^a
ARNI组	46.03±5.06^b		117.18±2.72^b		33.48±2.29^ab		26.46±2.98^ab
F	146.362^＊＊		138.611^＊＊		94.680^＊＊		22.819^＊＊

组别	Bax	Bcl-2	Caspase-3	Fas	FasL
Control组	1.00±0.10	1.00±0.11	1.00±0.14	1.00±0.08	1.00±0.04
模型组	1.48±0.13^a	0.77±0.11^a	1.85±0.21^a	1.76±0.23^a	1.47±0.08^a
ARNI组	1.30±0.15^a	1.13±0.12^b	1.52±0.35^a	1.19±0.17^b	0.85±0.08^ab
F	10.336^＊	7.618^＊	9.083^＊	15.503^＊	67.087^＊＊

沙库巴曲缬沙坦对心肌梗死后心力衰竭大鼠的心脏保护机制探讨

Study on the cardioprotective mechanism of sacubitril and valsartan in post-myocardial infarction heart failure of rats

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