丹酚酸 B 通过 Nrf2/ARE 信号通路减轻心肌细胞的化疗损伤。

Salvianolic Acid B Ameliorated Chemotherapeutic Injury of Cardiac Myocytes through the Nrf2/ARE Signaling Pathway.

机构信息

Department of Pharmacy, Sanmen County People's Hospital, 317100 Taizhou, Zhejiang, China.

出版信息

Discov Med. 2024 Feb;36(181):415-423. doi: 10.24976/Discov.Med.202436181.39.

DOI:10.24976/Discov.Med.202436181.39

PMID:38409846

Abstract

BACKGROUND

Cardiotoxicity has been corroborated to be the toxic influence of cisplatin (CDDP). Oxidative stress and cardiomyocyte apoptosis play a vital part in cardiotoxicity induced by CDDP. Salvianolic acid Salvianolic acid B (SalB) is a monomeric component of Salvia miltiorrhiza, which has antioxidant and anti-inflammatory influences. In this research, we explored the mechanism of SalB in cardiotoxicity induced by CDDP.

METHOD

36 Wistar rats were separated into sham subgroup, CDDP (10 mg/kg) subgroup, CDDP (10 mg/kg) + SalB (1 μM) subgroup at random, CDDP (10 mg/kg) + SalB (5 μM) subgroup and CDDP (10 mg/kg) + SalB (10 μM) subgroup, Nicotinic Acid Riboside (NAR, 5 μM), with 6 rats in each subgroup. The cardiac function of rats in each subgroup was estimated by echocardiography, and hematoxylin-eosin (HE) staining and Masson staining corroborated the pathological changes of cardiac tissue. Biochemical kits were utilized for detecting the lactate dehydrogenase (LDH), creatine kinase (CK), interleukin-1β (IL-1β), IL-18, and caspase-1 concentrations in serum, superoxide dismutase (SOD), and malondialdehyde (MDA) in myocardial tissue, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and flow cytometry were utilized for estimating the apoptosis level in myocardial tissue, western blot was used for estimating caspase-3, Bcl2-Associated X (Bax) levels in myocardial tissue and proteins levels related to Nuclear factor E2 related factor 2 (Nrf2) signal pathway.

RESULTS

CDDP-induced cardiac dysfunction, myocardial injury, boosted LDH and CK levels in serum ( < 0.05), memorably increased oxidative stress level in myocardial tissue ( < 0.05), boosted inflammatory response ( < 0.05), boosted apoptosis rate of cardiomyocytes ( < 0.05), and declined the Nrf2, NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO-1) protein levels ( < 0.05). Interestingly, SalB remedy could alleviate the changes caused by CDDP in the above parameters, significantly decrease the level of myocardial oxidative stress and apoptosis ( < 0.05).

CONCLUSIONS

SalB ameliorates the injury of cardiomyocytes induced by chemotherapy through oxidative stress mediated by the Nrf2/antioxidant response element (ARE) signal pathway.

摘要

背景

顺铂（CDDP）的毒性已被证实会导致心脏毒性。氧化应激和心肌细胞凋亡在 CDDP 诱导的心脏毒性中起着至关重要的作用。丹参酸 B（SalB）是丹参的单体成分，具有抗氧化和抗炎作用。在这项研究中，我们探讨了 SalB 对 CDDP 诱导的心脏毒性的作用机制。

方法

将 36 只 Wistar 大鼠随机分为假手术亚组、CDDP（10mg/kg）亚组、CDDP（10mg/kg）+SalB（1μM）亚组、CDDP（10mg/kg）+SalB（5μM）亚组和 CDDP（10mg/kg）+SalB（10μM）亚组、烟酰胺核糖（NAR，5μM），每组 6 只大鼠。通过超声心动图评估各组大鼠的心脏功能，苏木精-伊红（HE）染色和 Masson 染色证实心脏组织的病理变化。利用生化试剂盒检测血清中乳酸脱氢酶（LDH）、肌酸激酶（CK）、白细胞介素-1β（IL-1β）、白细胞介素-18 和半胱天冬酶-1 的浓度，检测心肌组织中超氧化物歧化酶（SOD）和丙二醛（MDA），TUNEL 染色和流式细胞术检测心肌组织中的细胞凋亡水平，Western blot 检测心肌组织中半胱天冬酶-3、Bcl2 相关 X（Bax）的蛋白水平以及核因子 E2 相关因子 2（Nrf2）信号通路相关蛋白水平。

结果

CDDP 诱导的心脏功能障碍、心肌损伤、血清 LDH 和 CK 水平升高（<0.05），心肌组织氧化应激水平明显升高（<0.05），炎症反应增强（<0.05），心肌细胞凋亡率升高（<0.05），Nrf2、NAD（P）H 醌氧化还原酶 1（NQO1）、血红素加氧酶 1（HO-1）蛋白水平降低（<0.05）。有趣的是，SalB 治疗可以减轻 CDDP 引起的上述参数的变化，显著降低心肌氧化应激和凋亡水平（<0.05）。