药学学报

Group	AST/ng·mL^-1	CK/ng·mL^-1	LDH/ng·mL^-1
NC	8.89 ± 1.2	35.35 ± 7.06	18.19 ± 2.05
OGD/R	16.41 ± 2.82^##	66.28 ± 2.71^##	28.82 ± 2.14^##
ICA-L	13.52 ± 1.89^**	56.91 ± 3.4^**	25.76 ± 1.54^**
ICA-M	10.68 ± 1.24^**	39.11 ± 6.57^**	21.61 ± 1.73^**
ICA-H	13.66 ± 1.74^**	49.09 ± 8.19^**	24.61 ± 1.94^**

Group

AST/ng·mL^-1

CK/ng·mL^-1

LDH/ng·mL^-1

8.89 ± 1.2

35.35 ± 7.06

18.19 ± 2.05

OGD/R

16.41 ± 2.82^##

66.28 ± 2.71^##

28.82 ± 2.14^##

ICA-L

13.52 ± 1.89^**

56.91 ± 3.4^**

25.76 ± 1.54^**

ICA-M

10.68 ± 1.24^**

39.11 ± 6.57^**

21.61 ± 1.73^**

ICA-H

13.66 ± 1.74^**

49.09 ± 8.19^**

24.61 ± 1.94^**

Group	AST/ng·mL^-1	CK/ng·mL^-1	LDH/ng·mL^-1
NC	8.89 ± 1.2	35.35 ± 7.06	18.19 ± 2.05
OGD/R	16.41 ± 2.82^##	66.28 ± 2.71^##	28.82 ± 2.14^##
ICA-L	13.52 ± 1.89^**	56.91 ± 3.4^**	25.76 ± 1.54^**
ICA-M	10.68 ± 1.24^**	39.11 ± 6.57^**	21.61 ± 1.73^**
ICA-H	13.66 ± 1.74^**	49.09 ± 8.19^**	24.61 ± 1.94^**

Group

AST/ng·mL^-1

CK/ng·mL^-1

LDH/ng·mL^-1

8.89 ± 1.2

35.35 ± 7.06

18.19 ± 2.05

OGD/R

16.41 ± 2.82^##

66.28 ± 2.71^##

28.82 ± 2.14^##

ICA-L

13.52 ± 1.89^**

56.91 ± 3.4^**

25.76 ± 1.54^**

ICA-M

10.68 ± 1.24^**

39.11 ± 6.57^**

21.61 ± 1.73^**

ICA-H

13.66 ± 1.74^**

49.09 ± 8.19^**

24.61 ± 1.94^**

Ingredient	PubChem CID	Target	Uniprot ID	AlphaFold ID	Affinity/kcal·mol^-1
ICA	123133824	FLNB	O75369	AF-O75369-F1	-8.5
ACTB	P60709	AF-P60709-F1	-6.8
CCND1	Q6FI00	AF-Q6FI00-F1	-7.9

Ingredient

PubChem CID

Target

Uniprot ID

AlphaFold ID

Affinity/kcal·mol^-1

ICA

123133824

FLNB

O75369

AF-O75369-F1

-8.5

ACTB

P60709

AF-P60709-F1

-6.8

CCND1

Q6FI00

AF-Q6FI00-F1

-7.9

Ingredient	PubChem CID	Target	Uniprot ID	AlphaFold ID	Affinity/kcal·mol^-1
ICA	123133824	FLNB	O75369	AF-O75369-F1	-8.5
ACTB	P60709	AF-P60709-F1	-6.8
CCND1	Q6FI00	AF-Q6FI00-F1	-7.9

Ingredient

PubChem CID

Target

Uniprot ID

AlphaFold ID

Affinity/kcal·mol^-1

ICA

123133824

FLNB

O75369

AF-O75369-F1

-8.5

ACTB

P60709

AF-P60709-F1

-6.8

CCND1

Q6FI00

AF-Q6FI00-F1

-7.9

淫羊藿苷调节FLNB/ACTB/CCND1信号通路减轻H9C2心肌细胞OGD/R损伤

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曹策 , 宋鉴书 , 杨丽丽 , 刘子馨 , 周青梅 , 李磊 , 付建华 ^* , 刘建勋 ^*

药学学报 | 研究论文 2026,61(4): 1258-1266

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药学学报 |研究论文 2026 , 61 (4) : 1258 -1266

淫羊藿苷调节FLNB/ACTB/CCND1信号通路减轻H9C2心肌细胞OGD/R损伤

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曹策, 宋鉴书, 杨丽丽, 刘子馨, 周青梅, 李磊, 付建华^*, 刘建勋^*

作者信息

中国中医科学院西苑医院基础医学研究所, 中药药理北京市重点实验室, 国家中医心血管疾病临床医学研究中心, 北京 100091

通讯作者:

付建华，Tel: 86-10-62835016, E-mail: jianhuaffcn@263.net

刘建勋，Tel: 86-10-62835601, E-mail: liujx0324@sina.com

作者简介:

作者贡献:

曹策负责实验操作和文章撰写; 刘建勋和付建华负责实验总体设计及稿件修改; 李磊、宋鉴书、杨丽丽、刘子馨和周青梅参与了部分实验操作与论文修改。

Icariin modulates FLNB/ACTB/CCND1 signaling pathway to mitigate OGD/R injury in H9C2 cardiomyocytes

Ce CAO, Jian-shu SONG, Li-li YANG, Zi-xin LIU, Qing-mei ZHOU, Lei LI, Jian-hua FU^*, Jian-xun LIU^*

Affiliations

Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing Key Laboratory of Chinese Materia Pharmacology, National Clinical Research Center of Traditional Chinese Medicine for Cardiovascular Diseases, Beijing 100091, China

出版时间: 2026-04-12 doi: 10.16438/j.0513-4870.2025-1324

文章导航

摘要

收起

观察淫羊藿苷(icariin, ICA) 对氧糖剥夺/再灌注(oxygen and glucose deprivation/reperfusion, OGD/R) 损伤的H9C2心肌细胞的增殖、细丝蛋白B (filamin B, FLNB)/β-肌动蛋白(β-actin, ACTB)/细胞周期素D1 (cyclin D1, CCND1) 信号通路的干预作用。选用H9C2心肌细胞作为研究对象, 采用细胞增殖与活性检测试剂盒检测H9C2细胞活性。将H9C2细胞分成对照组、OGD/R组和ICA组。对照组于正常条件下培养, 其余各组在处理后进行氧糖剥夺4 h/再灌注2 h。酶联免疫吸附法检测细胞上清液中天门冬氨酸氨基转移酶(aspartate transaminase, AST)、乳酸脱氢酶(lactate dehydrogenase, LDH)、肌酸激酶(creatine kinase, CK) 的含量; 通过转录组测序筛选ICA对H9C2的作用基因, 对差异表达基因进行基因本体(gene ontology, GO) 功能及京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes, KEGG) 通路富集分析; 采用分子对接和分子动力学模拟检测ICA与核心靶点的结合能力。与OGD/R组相比, ICA在1~10 μmol·L^-1具有保护作用, AST、LDH和CK的含量均降低。转录组测序结果显示ICA显著影响OGD/R后H9C2的436个共同差异基因, 主要影响解剖结构形态发生、蛋白质结合和细胞内解剖结构等生物功能和焦点黏附、癌症通路等信号通路。STRING筛选出FLNB/ACTB/CCND1等核心靶点; ICA显著逆转了OGD/R导致的FLNB/ACTB/CCND1表达量上调; 分子对接显示ICA和核心差异蛋白结合密切; 分子动力学模拟显示ICA显著维持了FLNB蛋白的稳定性。综上所述, ICA能降低OGD/R诱导的H9C2心肌细胞损伤, 降低AST、LDH、CK含量及FLNB/ACTB/CCND1的表达量, 这可能与其结合FLNB介导ACTB/CCND1信号通路密切相关。

关键词

淫羊藿苷 / 心肌细胞 / 增殖 / FLNB/ACTB/CCND1 / 氧糖剥夺/再灌注

Abstract

收起

To investigate the regulatory effects of icariin (ICA) on the proliferation of H9C2 cardiomyocytes injured by oxygen and glucose deprivation/reperfusion (OGD/R) and on filamin B (FLNB)/β-actin (ACTB)/cyclin D1 (CCND1) signaling pathway, H9C2 cardiomyocytes were used as the research model. Cell viability was determined using the cell counting kit-8 assay. The cells were divided into three groups, normal control group, OGD/R group, and ICA group. The normal control group was cultured under normal conditions, while the other two groups were subjected to 4 hours of OGD followed by 2 hours of reperfusion. Enzyme-linked immunosorbent assay was employed to measure the levels of aspartate transaminase (AST), lactate dehydrogenase (LDH), and creatine kinase (CK). Transcriptome sequencing was performed to identify the target genes of ICA in H9C2 cells; differentially expressed genes (DEGs) were analyzed via gene ontology (GO) functional annotation and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment. Molecular docking and molecular dynamics simulation were used to evaluate the binding affinity between ICA and core targets. Compared with the OGD/R group, ICA groups at concentrations of 1-10 μmol·L^-1 exerted a significant protective effect, and the levels of AST, LDH, and CK were notably decreased. Transcriptome sequencing results revealed that ICA significantly regulated 436 common DEGs in H9C2 cells after OGD/R, primarily affecting biological functions such as anatomical structure morphogenesis, protein binding, and intracellular anatomical structure, as well as signaling pathways including focal adhesion and pathways in cancer. STRING database analysis identified core targets including FLNB, ACTB, and CCND1. ICA significantly reversed the OGD/R-induced upregulation of FLNB, ACTB, and CCND1 expression. Molecular docking demonstrated strong binding between ICA and the core differential proteins, and molecular dynamics simulation confirmed that ICA significantly maintained the stability of FLNB protein. In conclusion, ICA can alleviate OGD/R-induced injury in H9C2, reduce the levels of AST, LDH, and CK, and downregulate the expression of FLNB, ACTB, and CCND1. This protective effect may be closely associated with ICA's binding to FLNB directly and subsequent mediation of the ACTB/CCND1 signaling pathway.

Key words

icariin / cardiomyocyte / proliferation / FLNB/ACTB/CCND1 / oxygen and glucose deprivation/reperfusion

引用本文

曹策, 宋鉴书, 杨丽丽, 刘子馨, 周青梅, 李磊, 付建华, 刘建勋. 淫羊藿苷调节FLNB/ACTB/CCND1信号通路减轻H9C2心肌细胞OGD/R损伤. 药学学报, 2026 , 61 (4) : 1258 -1266 . DOI: 10.16438/j.0513-4870.2025-1324

Ce CAO, Jian-shu SONG, Li-li YANG, Zi-xin LIU, Qing-mei ZHOU, Lei LI, Jian-hua FU, Jian-xun LIU. Icariin modulates FLNB/ACTB/CCND1 signaling pathway to mitigate OGD/R injury in H9C2 cardiomyocytes[J]. Acta Pharmaceutica Sinica, 2026 , 61 (4) : 1258 -1266 . DOI: 10.16438/j.0513-4870.2025-1324

正文

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全球疾病负担报告表明, 冠心病(coronary heart disease, CHD) 作为全球心血管疾病领域的首要致死病因, 其发病率在中老年人群中呈持续攀升趋势, 且近年来逐步向中青年群体蔓延, 已成为威胁人类健康与生命质量的重大公共卫生问题。CHD属于典型的缺血性心脏病(ischemic heart disease, IHD), 其核心病理基础是冠状动脉粥样硬化、长期脂质代谢异常、炎症反应及血管内皮损伤导致动脉壁脂质沉积、斑块形成, 当斑块破裂或继发血栓形成时, 会直接阻塞冠状动脉管腔, 引发冠脉循环动力学改变^{[1, 2]}。这种血流障碍会迅速导致心肌细胞血氧供应不足, 打破心肌能量代谢平衡(腺苷三磷酸合成锐减、乳酸堆积), 进而诱发心肌细胞功能紊乱甚至坏死, 最终表现为稳定性心绞痛、急性心肌梗死、心律失常、心力衰竭, 严重时可直接导致心源性休克, 对患者生命安全构成即刻威胁^{[1, 2]}。

在临床治疗中, 快速恢复缺血心肌区域的血流灌注是逆转心肌损伤、改善患者预后的核心策略, 目前临床常用的干预手段包括经皮冠状动脉介入治疗、冠状动脉旁路移植术及静脉溶栓治疗等^[3-5]。然而, 临床实践发现, 血流再灌注虽能终止缺血损伤, 但部分患者会出现再灌注后损伤, 即表现为梗死心肌面积进一步扩大、心肌细胞坏死数量增加, 甚至诱发恶性心律失常、微血管堵塞, 最终导致心功能不全或心力衰竭加重, 这一现象被称为心肌缺血再灌注损伤(myocardial ischemia-reperfusion injury, MIRI), 已成为制约CHD治疗效果的关键瓶颈^{[6, 7]}。为深入解析MIRI的分子机制并筛选潜在治疗药物, 体外细胞模型构建至关重要。氧糖剥夺/再灌注(oxygen and glucose deprivation/reperfusion, OGD/R) 模型因能高度模拟临床MIRI的病理过程, 被广泛应用于心肌细胞损伤机制研究^{[8, 9]}。

淫羊藿苷(icariin, ICA) 为中药淫羊藿(Epimedium brevicornu Maxim.) 的主要生物活性化合物, 分子结构式如图1所示。既往研究显示其具有良好的心、脑血管疾病治疗作用, 有相关研究表明ICA可激活核因子E2相关因子-2 (nuclear factor E2-related factor 2, Nrf2) 和线粒体减轻糖尿病心肌病、结合人抗原R (human antigen R, HuR) 抑制人主动脉平滑肌增殖、刺激血管内皮生长因子(vascular endothelial growth factor, VEGF) 介导的血管生成等作用^[10-12], 但ICA对心肌细胞的保护作用尚未有相关深入研究。本研究旨在通过建立体外OGD/R模型, 结合转录组测序、分子对接和分子动力学模拟, 探究ICA对于OGD/R模型诱导损伤的H9C2心肌细胞的影响, 为IHD的干预治疗提供新的途径和药物。

材料与方法

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材料大鼠H9C2心肌细胞购于中国医学科学院基础医学研究所细胞资源中心。ICA (约20 mg, 110737-202017, 2~8 ℃保存, 中国食品药品检定研究院); DMEM高糖培养基(8117283)、DMEM无糖培养基(1897256)、胎牛血清(fetal bovine serum, FBS) (10099-141), 美国Invitrogen公司; DMSO (3483C285, 美国Amresco公司); cell counting kit-8 (CCK-8, TR689, 日本Dojindo公司); 乳酸脱氢酶(lactate dehydrogenase, LDH) 试剂盒(JL13677-96T)、肌酸激酶(creatine kinase, CK) 试剂盒(JL46377-96T)、天门冬氨酸氨基转移酶(aspartate transaminase, AST) 试剂盒(JL21297-96T), 上海江莱生物科技有限公司; 细丝蛋白B (filamin B, FLNB, 20685-1-AP)、细胞周期素D1 (cyclin D1, CCND1) 抗体(26969-1-AP), 武汉三鹰生物技术有限公司; β-肌动蛋白(β-actin, ACTB) 抗体(GB15003, 武汉赛维尔生物科技有限公司)。

细胞培养 取冻存于液氮中的H9C2细胞, 置37 ℃水浴中解冻, 将细胞转移至离心管, 加入含10% FBS高糖DMEM的培养基4 mL, 充分混合后1 000 r·min^-1离心5 min, 使用完全培养基5 mL重悬沉淀, 将其置于37 ℃、5% CO₂条件下静置培养24 h后, 待细胞达到80%融合时, 使用0.25%胰蛋白酶消化传代、重悬。调节每毫升细胞数至0.5×10⁵~1×10⁵个, 接种于细胞培养瓶或96孔板内。复苏细胞稳定3代后, 用于实验。

分组及OGD/R模型建立 实验分为空白对照(normal control, NC) 组, OGD/R组, 给药组分ICA低、中、高浓度组(L、M、H, 1、5、10 μmol·L^-1)。取接种于细胞板或细胞瓶中的细胞, 弃旧培养基, PBS洗板/孔2次之后, NC组更换成10% FBS高糖DMEM完全培养基后, 放回37 ℃、5% CO₂培养箱中培养6 h。模型组更换成低氧处理过的无糖DMEM培养基, 给药组换成低氧处理过的含药无糖DMEM培养基后, 将细胞放进充入氮气的缺氧盒中密闭培养4 h, 缺氧结束后, 每瓶/孔加入葡萄糖, 使葡萄糖终浓度为4.5 g·L^-1, 随后置于37 ℃、5% CO₂培养箱中培养2 h。给药组在氧糖剥夺时加入不同浓度的受试药物, 其余操作同模型组。实验结束后, 收集细胞或细胞上清进行检测。

CCK-8法测定细胞活力取对数生长期的H9C2心肌细胞, 以每孔4 000个细胞的密度接种于96孔板中。待细胞经OGD/R处理不同时间后, 每孔加入CCK-8溶液10 μL, 同时设置无细胞但含有相应量细胞培养基和CCK-8溶液的孔作为NC, 随后将培养板放置于37 ℃细胞培养箱中孵育2 h, 后用酶标仪检测。以上步骤重复3次, 每次每组设置6个复孔。用酶标仪在450 nm处测定A值。细胞活力(%) = [(A_实验组 - A_空白对照)/(A_对照组 - A_空白对照)] × 100%。

细胞上清液AST、CK、LDH检测 取对数生长期的H9C2细胞, 按上述方法进行分组和处置。待细胞经OGD/R实验处理结束后, 收集细胞上清液, 按照试剂盒说明书分别检测CK、AST和LDH水平。

转录组测序 采用TRIzol法分别提取NC组、模型对照组及给药组细胞的总RNA。高通量测序仪生成的原始图像数据经CASAVA软件进行碱基识别, 转化为原始序列数据(FASTQ格式)。经数据质控过滤(去除带接头序列的reads、含未知碱基N的reads及低质量reads) 后, 对获得的清洁数据计算Q20、Q30及GC含量。两组间差异基因分析采用DESeq2软件(版本1.20.0), 以P_adj < 0.05为筛选标准; 差异基因的基因本体(gene ontology, GO) 功能及京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes, KEGG) 通路富集分析通过ClusterProfiler软件(版本3.8.1) 实现; 差异基因表达产物的蛋白互作关系及网络构建则借助STRING数据库完成。

蛋白质印迹检测 待造模完成后, 去除细胞上清液, 加入适量细胞裂解液, 14 000 ×g离心30 s获得蛋白。采用BCA蛋白定量法定量, 随后将定量变性后的蛋白进行电泳、转膜、封闭、抗体孵育和显影。图像分析采用ImageJ进行。

分子对接 从Protein Date Bank数据库中下载核心靶点的人源蛋白结构文件; 从PubChem数据库中下载ICA的小分子结构文件; 采用Autoduck vina 1.1.2软件进行分子对接, 稳定构象为每个对接结合能最低的构象; 使用PyMOL 2.2.0软件绘制图像。

分子动力学模拟 使用AlphaFold 3建模获取FLNB结构; 采用GROMACS进行化合物-靶标复合物的分子动力学模拟(molecular dynamics simulation, MDs)。蛋白质使用CHARMM36力场进行模拟, 并使用TIP3P水模型填充水分子。随机向模拟盒中添加氯离子和钠离子进而中和体系。使用最陡下降算法进行能量最小化, 然后在等温等容下进行500 ps平衡, 在等温等压状态下进行1 000 ps平衡。最后, 对复合物进行100 ns的模拟。使用GROMACS和PyMol进行结构和可视化分析。

统计学处理 用SPSS 26.00软件进行统计分析, 用GraphPad Prism 9软件进行做图。计量资料用x ± s表示, 先对数据进行正态性检验(Shapiro-Wilk检验) 和方差齐性检验(Levene检验), 满足正态性和方差齐性时, 多组数据比较用单因素方差分析, 组间两两比较用Bonferroni多重比较校正法; 若数据不满足正态性或方差齐性, 则采用非参数检验(Kruskal-Wallis H检验), 组间两两比较采用Dunn法多重比较校正。

结果

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1　ICA对OGD/R诱导H9C2细胞具有保护作用

按照图2A进行模型建立和ICA药物处理后, 细胞活力CCK-8检测结果显示, OGD/R损伤后H9C2细胞活力显著降低, 与NC组相比具有统计学差异(P < 0.01), 表明心肌细胞受损严重。给予ICA处理后各组细胞活力升高, 与模型组相比, 1~320 μmol·L^-1 ICA具有保护作用(P < 0.01), 且5 μmol·L^-1保护作用最为显著(P < 0.01) (图2B)。

2　ICA降低OGD/R诱导H9C2细胞CK、AST、LDH水平

根据化学发光试剂盒检测结果显示, 与NC组相比, OGD/R组CK、AST、LDH显著升高且具有显著差异(P < 0.01); 与OGD/R组相比, ICA各组CK、AST、LDH水平均有不同程度的降低, 具有统计学差异(P < 0.01)。该结果表明, ICA可降低心肌细胞中CK、LDH和AST含量(表1)。

3　ICA逆转OGD/R损伤后的H9C2基因表达

转录组结果表明, 相较于NC组, OGD/R显著上调差异基因3 272个, 下调2 879个(图2C); 相较于OGD/R组, ICA显著上调差异基因342个, 下调430个(图2D); 三者共有差异基因436个(图2E)。

4　ICA对OGD/R诱导H9C2细胞KEGG和GO的影响

将三者共同差异进行KEGG分析, 结果表明ICA显著影响焦点黏附(focal adhesion)、癌症通路(pathways in cancer) 和黏着连接(adherens junction) 等信号通路(图3)。GO显示, ICA可影响OGD/R后H9C2心肌细胞的解剖结构形态发生(anatomical structure morphogenesis)、蛋白质结合(protein binding) 和细胞内解剖结构(intracellular anatomical structure) 等生物功能(图4A)。课题组进一步将最为显著的焦点黏附信号通路中的基因进行PPI富集, 筛选出前3个核心靶点为FLNB、ACTB和CCND1 (图4B)。

5　核心基因的表达和分子对接

转录组测序结果表明, 相较于NC组, OGD/R显著增加FLNB、ACTB和CCND1的mRNA表达量(P < 0.01); 给予ICA处理后, 显著降低FLNB、ACTB和CCND1的mRNA表达量(P < 0.05, 图5A)。蛋白质印迹结果表明, ICA能显著逆转由OGD/R造成的FLNB和CCND1蛋白表达量增加(P < 0.05), 而并未显著影响ACTB的蛋白量表达(图5B)。进一步的分子对接结果表明, ICA与FLNB的结合能为-8.5 kcal·mol^-1; 与ACTB结合能为-6.8 kcal·mol^-1; 与CCND1结合能为-7.9 kcal·mol^-1 (表2)。此外, 可视化结果显示ICA可与FLNB蛋白的第139位GLN、第150位的GLN、第151位的ASN和第1 085位的ILE分别形成2.1、2.5、2.2和1.9 Å氢键; 与ACTB第18位LYS、第157位ASP和第215位LYS分别形成2.8、2.6和2.2 Å氢键; 与CCND1的第15位ARG、第74位GLU、第172位GLU、第176位GLN和第183位GLN分别形成2.4、2.2、2.9、2.2和2.1 Å氢键(图5C)。

6　ICA与FLNB结合并维持其结构稳定

为进一步评估FLNB及其与ICA形成的复合物(ICA-FLNB) 的结构动力学特征, 课题组通过分子动力学模拟分析均方根偏差(root mean square deviation, RMSD)、均方根波动(root mean square fluctuation, RMSF) 和回旋半径(radius of gyration, Rg)。在100 ns的模拟时间内监测ICA-FLNB和FLNB的RMSD曲线, 2个体系的RMSD均先出现上升, 反映构象调整过程, 随后进入相对稳定阶段。ICA-FLNB的RMSD维持在约1.7 nm, FLNB也呈现类似趋势, 但是其RMSD存在显著波动, 这表明ICA的结合可提高FLNB的整体结构稳定性(图6A)。通过RMSF分析评估残基水平的柔性, ICA-FLNB和FLNB的RMSF曲线呈现相似模式, 在相近的残基位置出现峰和谷, 结果提示, ICA的结合并未显著改变FLNB在残基水平的柔性, 保留了其固有的动力学特征(图6B)。Rg用于量化蛋白质结构的紧凑程度, 在整个模拟过程中, ICA-FLNB和FLNB的Rg值均在5.2~6.0 nm范围内波动, 表明两种体系均维持了相对紧凑的构象(图6C)。整个模拟时间内的典型图进一步呈现了上述结果(图6D)。综上所述, 分子动力学分析表明, ICA与FLNB结合时, 可显著改变其结构稳定性, 但不显著改变其残基水平柔性或整体紧凑性。

讨论

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CHD是全球范围内导致死亡和致残的主要心血管疾病类型之一, 其核心病理过程是冠状动脉粥样硬化导致的心肌缺血与缺氧。随着再灌注治疗(溶栓、介入或搭桥术) 的广泛应用, IHD的救治率显著提升, 但MIRI随之成为临床难题。再灌注虽然恢复了血流供应, 却可引发大量活性氧生成、钙超载、线粒体功能障碍及炎症因子风暴, 从而进一步加重心肌细胞坏死与凋亡, 导致心功能恶化甚至心衰^[13-17]。因此, 探索安全有效的分子干预手段以减轻MIRI损伤, 仍是当前心血管研究的重要方向。

近年来, 源自天然药物的活性成分因其多靶点、低毒性和良好组织选择性而受到关注。ICA作为黄酮类化合物, 具有抗炎、抗氧化、抗纤维化及细胞保护等多重作用, 已在心、脑及肾脏缺血模型中显示出潜在的保护效应^[18-24]。然而, ICA在MIRI中的分子靶点及其下游信号通路尚未完全阐明。

本研究从FLNB/ACTB/CCND1轴出发, 揭示ICA在H9C2细胞OGD/R损伤模型中的保护作用及其可能机制。细胞功能实验证实, ICA在1~10 μmol·L^-1内对OGD/R诱导的H9C2细胞损伤具有显著保护作用, 表现为细胞活力恢复、AST、LDH和CK水平下降, 这与已有研究中ICA抗MIRI、抑制细胞凋亡与氧化应激的作用一致^[25]。此外, 在神经细胞中, ICA可通过下调炎症因子缓解OGD/R诱导的损伤, 提示其具有较广谱的抗MIRI保护效应^[26]。

本研究通过转录组、GO、KEGG富集分析及STRING筛选, 确立了FLNB、ACTB、CCND1为ICA可能的关键靶点。这三个基因在OGD/R条件下被上调, 而ICA给药可显著逆转其mRNA表达水平均上调的趋势, 提示ICA可能通过下调这一信号轴缓解损伤。转录组富集结果还显示ICA影响的通路包括焦点黏附、黏附连接等。蛋白质印迹结果表明, ICA逆转了由OGD/R导致的FLNB和CCND1表达增加, 而OGD/R模型和ICA给药并未显著影响ACTB的表达, 这主要与ACTB作为细胞骨架与黏附结构核心成分的角色一致, 其在众多细胞和模型中均表达稳定, 其功能调节主要与蛋白构象, 而非蛋白表达量改变有关^{[27, 28]}。FLNB蛋白是细胞骨架的重要组成部分, 不仅帮助维护细胞的形态和结构, 且在信号传导、细胞运动和物质运输中承担关键作用^[29-31]。CCND1作为高度保守的细胞周期家族蛋白成员, 在细胞周期的不同时期具有不同的表达和降解模式, 这有助于有丝分裂之间的时间协调, 且该蛋白的扩增和过表达常在癌症中发现^[32-34]。既往研究表明, ACTB可通过与β-连环蛋白(β-catenin) 结合促进其核转位, 进而增强CCND1的转录激活, 且在结肠癌细胞的临床样本中, β-catenin过表达与CCND1表达呈显著正相关^[35]。此外, 已有晶体结构研究证实, FLNB的N端肌动蛋白结合域可与肌动蛋白直接结合, 且其结合亲和力受自身结构修饰调控^[36]。因此, ICA可通过FLNB/ACTB/CCND1信号通路减轻OGD/R损伤。

OGD/R损伤会激活细胞应激反应(机械应力、细胞骨架重构、黏附受体信号), 导致FLNB作为细胞骨架交联蛋白被上调, 进而影响ACTB的构象或动态重组; ACTB的重构可能触发下游信号通路[黏着斑激酶(focal adhesion kinase, FAK)、Src或丝裂原活化蛋白激酶/细胞外调节蛋白激酶(mitogen-activated protein kinase/extracellular signal-regulated kinase, MAPK/ERK) 等] 激活细胞增殖/应激通路, 最终上调CCND1, 驱动细胞进入增殖或修复反应。然而, 在严重损伤状态下, 这种被动激活可能伴随细胞应激、代谢紊乱或凋亡。ICA介入后可通过与FLNB结合稳定其结构、抑制其异常激活, 从而阻断上述级联信号传导, 最终抑制ACTB重构及CCND1过度表达, 使细胞恢复平衡状态。此外, 这一机制为ICA改善心肌梗死患者再灌注治疗预后提供了支撑, 临床中再灌注治疗后30%~40%患者仍面临MIRI导致的心功能恶化, 现有干预手段存在局限, 而ICA靶向FLNB/ACTB/CCND1轴的多靶点作用, 恰好契合MIRI“细胞骨架紊乱-应激信号过度激活”的核心病理, 有望应用于术后治疗方案。

本研究还通过分子对接与分子动力学模拟展示了ICA与FLNB、ACTB、CCND1的结合能, 且ICA与FLNB复合物在模拟条件下结构稳定性较好。FLNB作为三者中结合能最强的靶点, 可能是ICA作用的关键枢纽。未来可以过表达实验验证ICA对FLNB的调控作用是否为其心肌细胞保护效果的必经环节。此外, 本实验受限于细胞系模型的局限性, H9C2虽为心肌样细胞, 但尚不能完全代表成体心肌细胞, 在后续实验中将采用成人心肌细胞、大鼠成熟心肌细胞或动物模型验证ICA对FLNB/ACTB/CCND1通路的调节作用, 进一步完善其在不同水平的机制作用。

总体而言, 本研究在细胞OGD/R模型中提出并验证了ICA通过FLNB/ACTB/CCND1通路发挥H9C2心肌细胞保护作用, 为进一步探讨中药活性成分在心肌细胞损伤修复中的分子靶点提供了新的视角与思路, 且为ICA或其衍生物在IHD中的潜在治疗价值奠定基础。

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2026年第61卷第4期

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doi: 10.16438/j.0513-4870.2025-1324

接收时间：2025-11-07
首发时间：2026-09-21
出版时间：2026-04-12

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收稿日期：2025-11-07
修回日期：2025-12-24

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中国中医科学院西苑医院基础医学研究所, 中药药理北京市重点实验室, 国家中医心血管疾病临床医学研究中心, 北京 100091

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付建华，Tel: 86-10-62835016, E-mail: jianhuaffcn@263.net

刘建勋，Tel: 86-10-62835601, E-mail: liujx0324@sina.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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