沙库巴曲缬沙坦钠片预防多柔比星所致心脏毒性的机制

doi:10.3969/j.issn.1006-5725.2024.02.011

Abstract

Abstract:

Objective To explore the efficacy of a new anti?heart failure drug， Entresto， in the prevention of cardiotoxicity caused by doxorubicin （DOX）. Methods Male adult ICR mice were randomly divided into three groups （n = 8）： control group， DOX group and DOX plus Entresto group. Cardiac function of mice was measured by echocardiography. H9c2 cells were pretreated with Entresto （0 - 48 μmol/L） for 24 hours in the presence or absence of DOX （1 mmol/L）， and then cell viability， oxidative stress， apoptosis and mitochondrial function were evaluated. Results As compared with the control group， leakage of CK， CK?MB and LDH increased significantly in the DOX group （P < 0.01）， and left ventricular systolic dysfunction occurred. Entresto administration reversed these changes in the DOX group. The level of ROS and the number of apoptotic cells in cardiomyocytes in the DOX plus Entresto group were lower than those in the DOX group （P < 0.05）. As compared with the DOX group， the level of ROS and the number of apoptotic cells in H9c2 cells decreased significantly in the Entresto plus DOX group （P < 0.05）， and mitochondrial membrane potential increased significantly （P < 0.05）. Entresto reversed the inhibitory effect of DOX on SIRT1/PGC?1α/MFN2 signaling pathway. Conclusions Entresto improves DOX?induced cardiotoxicity by inhibiting ROS?mediated oxidative stress and apoptosis， and its mechanism may be related to SIRT1/PGC?1α/MFN2 signal transduction pathway.

Key words: entresto, doxorubicin, cardiotoxicity, oxidative stress, mitochondria

CLC Number:

R542.2

Jieqiong LIU,Yali YAO,Qian SUI,Ke LI,Fang HUANG,Yongqing. CAO. Based on the novel anti-heart failure drug ARNI， the mechanism of prevention of cardiotoxicity caused by anthracycline antitumor drugs was discussed[J]. The Journal of Practical Medicine, 2024, 40(2): 188-194.

Figures/Tables 12

Tab.1

Fig.1

Fig.2

Tab.2

Tab.3

Fig. 3

Tab.4

Fig.4

Tab.5

Fig. 5

Tab.6

Tab.7

References 20

1	邱佳，丁波泥，钱立元，等. 紫衫烷类与蒽环类药物用药顺序不同对乳腺癌新辅助化疗疗效影响的meta分析［J］. 重庆医学， 2021， 50（21）： 3720-3725. doi:10.3969/j.issn.1671-8348.2021.21.025 doi: 10.3969/j.issn.1671-8348.2021.21.025
2	SYAHPUTRA R A， HARAHAP U， DALIMUNTHE A， et al. The role of flavonoids as a cardioprotective strategy against doxorubicin-induced cardiotoxicity： a review［J］. Molecules， 2022， 27（4）： 1320. doi:10.3390/molecules27041320 doi: 10.3390/molecules27041320
3	CHRISTIDI E， BRUNHAM L R. Regulated cell death pathways in doxorubicin-induced cardiotoxicity［J］. Cell Death Dis， 2021， 12（4）： 339. doi:10.1038/s41419-021-03614-x doi: 10.1038/s41419-021-03614-x
4	吴勤研，王楠，冷静，等. 右雷佐生在预防表柔比星心脏毒性时使用的合理性分析［J］. 安徽医药， 2019， 23（11）： 2296-2298. doi:10.3969/j.issn.1009-6469.2019.11.047 doi: 10.3969/j.issn.1009-6469.2019.11.047
5	向长铁，刘佳丽，张爱民，等. 沙库巴曲缬沙坦钠片通过NF2/Mst1信号通路抑制细胞凋亡改善心肌梗死大鼠心肌纤维化［J］. 中国老年学杂志， 2022， 42（8）： 1927-1931. doi:10.3969/j.issn.1005-9202.2022.08.043 doi: 10.3969/j.issn.1005-9202.2022.08.043
6	DINDAŞ F， GÜNGÖR H， EKICI M， et al. Angiotensin receptor-neprilysin inhibition by sacubitril/valsartan attenuates doxorubicin-induced cardiotoxicity in a pretreatment mice model by interfering with oxidative stress， inflammation， and Caspase 3 apoptotic pathway［J］. Anatol J Cardiol， 2021， 25（11）： 821-828. doi:10.5152/anatoljcardiol.2021.356 doi: 10.5152/anatoljcardiol.2021.356
7	DING M， SHI R， CHENG S， et al. Mfn2-mediated mitochondrial fusion alleviates doxorubicin-induced cardiotoxicity with enhancing its antEntrestoncer activity through metabolic switch［J］. Redox Biol， 2022， 52： 102311. doi:10.1016/j.redox.2022.102311 doi: 10.1016/j.redox.2022.102311
8	YEH J N， YUE Y， CHU Y C， et al. Entresto protected the cardiomyocytes and preserved heart function in cardiorenal syndrome rat fed with high-protein diet through regulating the oxidative stress and Mfn2-mediated mitochondrial functional integrity［J］. Biomed Pharmacother， 2021， 144： 112244. doi:10.1016/j.biopha.2021.112244 doi: 10.1016/j.biopha.2021.112244
9	SUO Y， YUAN M， LI H， et al. Sacubitril/valsarEntrestomproves left atrial and left atrial appendage function in patients with atrial fibrillation and in pressure overload-induced mice［J］. Front Pharmacol， 2019， 10： 1285. doi:10.3389/fphar.2019.01285 doi: 10.3389/fphar.2019.01285
10	SUN X， SUN P， ZHEN D， et al. Melatonin alleviates doxorubicin-induced mitochondrial oxidative damage and ferroptosis in cardiomyocytes by regulating YAP expression［J］. Toxicol Appl Pharmacol， 2022， 437： 115902. doi:10.1016/j.taap.2022.115902 doi: 10.1016/j.taap.2022.115902
11	RAJ P， SAYFEE K， PARIKH M， et al. Comparative and combinatorial effects of resveratrol and sacubitril/valsartan alongside valsartan on cardiac remodeling and dysfunction in MI-induced rats［J］. Molecules， 2021， 26（16）： 5006. doi:10.3390/molecules26165006 doi: 10.3390/molecules26165006
12	JEREMIC J， GOVORUSKINA N， BRADIC J， et al. Sacubitril/valsartan reverses cardiac structure and function in experimental model of hypertension-induced hypertrophic cardiomyopathy［J］. Mol Cell Biochem， 2023，478（12）：2645-2656. doi:10.1007/s11010-023-04690-7 doi: 10.1007/s11010-023-04690-7
13	RAWAT P S， JAISWAL A， KHURANA A， et al. Doxorubicin-induced cardiotoxicity： An update on the molecular mechanism and novel therapeutic strategies for effective management［J］. Biomed Pharmacother， 2021， 139： 111708. doi:10.1016/j.biopha.2021.111708 doi: 10.1016/j.biopha.2021.111708
14	SONGBO M， LANG H， XINYONG C， et al. Oxidative stress injury in doxorubicin-induced cardiotoxicity［J］. Toxicol Lett， 2019， 307： 41-48. doi:10.1016/j.toxlet.2019.02.013 doi: 10.1016/j.toxlet.2019.02.013
15	HAFEZ H M， HASSANEIN H. Montelukast ameliorates doxorubicin-induced cardiotoxicity via modulation of p-glycoprotein and inhibition of ROS-mediated TNF-α/NF-κB pathways［J］. Drug Chem Toxicol， 2022， 45（2）： 548-559. doi:10.1080/01480545.2020.1730885 doi: 10.1080/01480545.2020.1730885
16	HU B， ZHEN D， BAI M， et al. Ethanol extracts of Rhaponticum uniflorum （L.） DC flowers attenuate doxorubicin-induced cardiotoxicity via alleviating apoptosis and regulating mitochondrial dynamics in H9c2 cells［J］. J Ethnopharmacol， 2022， 288： 114936. doi:10.1016/j.jep.2021.114936 doi: 10.1016/j.jep.2021.114936
17	ZHANG Q， ZHANG Y， XIE B， et al. Resveratrol activation of SIRT1/MFN2 can improve mitochondria function， alleviating doxorubicin-induced myocardial injury［J］. Cancer Innovation， 2023， 2（4）： 253-264. doi:10.1002/cai2.64 doi: 10.1002/cai2.64
18	WANG J， ZHANG J， XIAO M， et al. Molecular mechanisms of doxorubicin-induced cardiotoxicity： novel roles of sirtuin 1-mediated signaling pathways［J］. Cell Mol Life Sci， 2021， 78（7）： 3105-3125. doi:10.1007/s00018-020-03729-y doi: 10.1007/s00018-020-03729-y
19	CUI W， WU X， SHI Y， et al. 20-HETE synthesis inhibition attenuates traumatic brain injury-induced mitochondrial dysfunction and neuronal apoptosis via the SIRT1/PGC-1α pathway： A translational study［J］. Cell Proliferation， 2021， 54（2）： e12964. doi:10.1111/cpr.12964 doi: 10.1111/cpr.12964
20	KUNO A， HOSODA R， TSUKAMOTO M， et al. SIRT1 in the cardiomyocyte counteracts doxorubicin-induced cardiotoxicity via regulating histone H2AX［J］. Cardiovasc Res， 2023， 118（17）： 3360-3373. doi:10.1093/cvr/cvac026 doi: 10.1093/cvr/cvac026

项目	对照组（n = 8）	DOX组（n = 8）	DOX+Entresto组（n = 8）
CK（ng/mL）	42 ± 3	71 ± 5^*	48 ± 4^##
CK-MB（ng/mL）	1.24 ± 0.28	1.82 ± 0.18^*	1.33 ± 0.20^#
LDH（U/L）	422 ± 23	735 ± 38^**	531 ± 29^##
心脏指数	0.004 4 ± 0.000 3	0.003 6 ± 0.000 4^*	0.004 2 ± 0.000 6^#
心脏组织病理学评分	0.20 ± 0.01	3.21 ± 0.11^**	1.39 ± 0.14^##

项目	对照组（n = 8）	DOX组（n = 8）	DOX+Entresto组（n = 8）
E/A	1.71 ± 0.06	0.88 ± 0.18^*	1.42 ± 0.15^#
LVIDd（mm）	2.23 ± 0.43	2.95 ± 0.28^*	2.60 ± 0.22^#
LVIDs（mm）	2.62 ± 0.50	3.76 ± 0.47^*	3.42 ± 0.32^#
LVEF （%）	79.80 ± 2.03	52.65 ± 3.11^*	67.86 ± 2.14^#
LVFS （%）	52.21 ± 1.64	24.06 ± 2.08^*	43.39 ± 2.67^#

处理方法	剂量	细胞活力（%）
Entresto （μmol/L）	Ctrl	100 ± 2
	0.75	102 ± 2
	3	105 ± 3
	12	97 ± 3
	48	88 ± 3
	96	72 ± 2^*
DOX+Entresto （μmol/L）	Ctrl	100 ± 3
	0	70 ± 2^*
	0.75	72 ± 2^*
	3	84 ± 2^#
	12	90 ± 1^##
	48	82 ± 1^#

[1]	Lulu CHEN,Meng LUO,Kaiqi SU,Jing GAO,Xiaodong. FENG. Research progress of the endoplasmic reticulum⁃mitochondrial interactions in post⁃stroke cognitive impairment [J]. The Journal of Practical Medicine, 2024, 40(7): 1023-1028.
[2]	Jiadong WANG,Fangzhou HUANG,Yan HUANG,Guanxiong CHEN,Jun LIU,Peiqi. HUANG. Role of eupatilin in protection of mitochondrial function through Sesn2⁃Nrf2 in septic brain injury [J]. The Journal of Practical Medicine, 2024, 40(5): 601-607.
[3]	Kanglin CAI,Jinkai ZHANG,Liangdi RAN,Dajun HU,Zhitao FENG,Huilian. HUANG. Research progress on antidepressant pharmacological effects and mechanisms of Bupleuri Radix⁃Paeoniae Radix Alba herb⁃pair [J]. The Journal of Practical Medicine, 2024, 40(4): 447-452.
[4]	Tianyue YU,Qian GUO,Hao HU,Yujing SU,Jianhua CHEN. Advances in oxidative stress⁃related pathways with diagnostic and predictive value in schizophrenia [J]. The Journal of Practical Medicine, 2024, 40(20): 2935-2940.
[5]	Yingjun TAO,Tengzhu REN,Feng WEI,Xintong. LIU. Effects of agatroban combined with mitochondrial transplantation on endothelial function and hemorheology in mice with cerebral ischemia⁃reperfusion injury [J]. The Journal of Practical Medicine, 2024, 40(19): 2665-2671.
[6]	Ganggang LU,Shenglong LI,Yongqiang ZHAO,Yunpeng JIA,Yonglin LIANG,Yuanbo. ZHAO. Research progress on the correlation between oxidative stress and ferroptosis in diabetic impotence [J]. The Journal of Practical Medicine, 2024, 40(16): 2229-2235.
[7]	Yunlong SUN,Zhe MENG,Xijia WANG,Lu. GAO. Liraglutide ameliorates high glucose⁃induced endothelial cell injuryvia Nrf2 [J]. The Journal of Practical Medicine, 2024, 40(15): 2051-2055.
[8]	Zhu LI,Yan WANG,Wenjing ZHOU,Haiying. WANG. Advances in the role of mitochondrial respiratory chain enzyme complexes in myocardial ischemia-reperfusion injury [J]. The Journal of Practical Medicine, 2024, 40(15): 2172-2176.
[9]	Chun LONG,Hongying BI,Changzhen YANG,Jiakai WANG,Yan TANG,Xu. LIU. Emodin upregulates the Sirt2 to attenuate LPS-induced oxidative stress response in RAW264.7 cells [J]. The Journal of Practical Medicine, 2024, 40(13): 1785-1790.
[10]	Limin WEN,Ran LI,Yanlei HAO,Qingxia KONG,Min. XIA. Mitochondrial gene heterogeneity related to MELAS syndrome： A review of literature [J]. The Journal of Practical Medicine, 2024, 40(13): 1885-1888.
[11]	Juan LIU,Yanjie LI,Hewei QIN,Luyao MA,Nannan ZHAO,Huimin. DING. Mechanism of action of dysregulated mitochondrial quality control system mediating Parkinson′s disease [J]. The Journal of Practical Medicine, 2024, 40(11): 1479-1482.
[12]	Ruyue XUE,Yuexian LI,Defeng. SUN. Research progress on stellate ganglion block improving postoperative cognitive dysfunction [J]. The Journal of Practical Medicine, 2024, 40(11): 1500-1504.
[13]	Xuan LIANG,Jingran MU,Yan LUO,Tao XU,Junwei. ZENG. Research progress on the mechanism of CRMP2 phosphorylation in Alzheimer′s disease [J]. The Journal of Practical Medicine, 2024, 40(10): 1467-1472.
[14]	LI Ruonan, YANG Jun, ZHANG Jing, YANG Jian, XIANG Zujin.. Research progress of mitochondrial quality control system in cardiac aging [J]. The Journal of Practical Medicine, 2023, 39(8): 1052-1057.
[15]	CHEN Lu, LIU Yuan.. Alpinetin targets Nrf2 to inhibit oxidative stress in H9C2 cells [J]. The Journal of Practical Medicine, 2023, 39(7): 813-818.

Based on the novel anti-heart failure drug ARNI， the mechanism of prevention of cardiotoxicity caused by anthracycline antitumor drugs was discussed

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 12

References 20

Related Articles 15

Recommended Articles

Metrics

Comments