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

doi:10.11958/20220298

Abstract

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

CLC Number:

R542.22

Figures/Tables 6

References 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^＊＊