药学学报

Item	miRNA	Key miRNA	Signal pathway	Ref.
Myocardial damage		miRNA-449	CXCR4	[3, 4]
miR-1227-3p, miR-5010-5p, miR-1976, miR-23b-5p, miR-1843, miR-33a-5p, miR-3127-3p, let-7i-5p, miR-143-3p, miR-1180-3p, miR-3615, miR-144-5p, miR-3186-5p, miR-203a-3p, miR-1273h-3p, miR-106b-5p, miR-17-5p and miR-629-3p	miR-1227-3p, miR-5010-5p, miR-1976, miR-23b-5p, miR-1843, miR-33a-5p, let-7i-5p, miR-143-3p, miR-1180-3p, miR-3615, miR-3186-5p, miR-106b-5p, miR-17-5p and miR-629-3p		[5]
miR-6718-5p, miR-4329, miR-1207-3p, miR-34b-3p and miR-296-5p	miR-6718-5p and miR-4329	MAPK signal pathway and PI3K signal pathway	[6]
miR-4507, miR-3656, miR-6803-5p, miR-7108-5p, miR-6850-5p, miR-4486, miR-6741-5p, miR-1227-5p, miR-3195, miR-4634, miR-7975, miR-6798-3p and miR-1915-3p	miR-1915-3p, miR-4507 and miR-3656	NGF signal pathway and FGFRs signal pathway	[7]
Lipid homeostasis regulation		miR-4516 and miR-203	Wnt/β-catenin signal pathway	[8]
	miR-21-3p and miR-21-5p		[9]
Inflammatory reaction		About 175		[10]

Item	miRNA	Key miRNA	Signal pathway	Ref.
Myocardial damage		miRNA-449	CXCR4	[3, 4]
miR-1227-3p, miR-5010-5p, miR-1976, miR-23b-5p, miR-1843, miR-33a-5p, miR-3127-3p, let-7i-5p, miR-143-3p, miR-1180-3p, miR-3615, miR-144-5p, miR-3186-5p, miR-203a-3p, miR-1273h-3p, miR-106b-5p, miR-17-5p and miR-629-3p	miR-1227-3p, miR-5010-5p, miR-1976, miR-23b-5p, miR-1843, miR-33a-5p, let-7i-5p, miR-143-3p, miR-1180-3p, miR-3615, miR-3186-5p, miR-106b-5p, miR-17-5p and miR-629-3p		[5]
miR-6718-5p, miR-4329, miR-1207-3p, miR-34b-3p and miR-296-5p	miR-6718-5p and miR-4329	MAPK signal pathway and PI3K signal pathway	[6]
miR-4507, miR-3656, miR-6803-5p, miR-7108-5p, miR-6850-5p, miR-4486, miR-6741-5p, miR-1227-5p, miR-3195, miR-4634, miR-7975, miR-6798-3p and miR-1915-3p	miR-1915-3p, miR-4507 and miR-3656	NGF signal pathway and FGFRs signal pathway	[7]
Lipid homeostasis regulation		miR-4516 and miR-203	Wnt/β-catenin signal pathway	[8]
	miR-21-3p and miR-21-5p		[9]
Inflammatory reaction		About 175		[10]

Source	miRNA	Target gene and/or signal pathway	Effect	Ref.
BMSCs	miR-21a-5p	PDCD4, PTEN, Peli1, Fasl	Slow down apoptosis of cardiomyocytes	[11, 12]
miR-30e	LOX1; NF-κB p65/caspase-9	Slow down apoptosis and the degree of fibrosis of cardiomyocytes	[14]
miR-153-3p	ANGPT1; VEGF/VEGFR2/PI3K/Akt/eNOS	Slow down apoptosis of cardiomyocytes and vascular endothelial cells	[15]
miR-210	AIFM3	Slow down apoptosis	[17, 18]
miR-125b-5p	p53, Bnip3	Inhibit autophagy	[24]
miR-301	p62	Inhibit autophagy	[27]
miR-143-3p	CHK2, p-Beclin 1, LC3; CHK2-Beclin 2	Inhibit autophagy	[26]
miR-29b-3p	VEGF, ADAMTS16	Promote neovascularization	[36]
miR-210-3p	EFNA3	Promote neovascularization	[38]
miR-205	HIF-1α	Promote neovascularization	[39]
miR-25-3p	FASL, PTEN, E2H2	Reduce inflammation	[44]
miR-146-5p	TRAF6	Promote the polarization of M1 macrophages into M2	[52]
miR-182	TLR4	Promote the polarization of M1 macrophages into M2	[51]
miR-205	HIF-1α	Promote neovascularization	[38]
miR-25-3p	FASL, PTEN, E2H2	Reduce inflammation	[43]
BMSCs	miR-146-5p	TRAF6	Promote the polarization of M1 macrophages into M2	[51]
miR-182	TLR4	Promote the polarization of M1 macrophages into M2	[50]
miR-182-5p	GSDMD, caspase-1; TLR4, p65-TLR4/NF-κB	Slow down apoptosis of cardiomyocytes and reduce inflammation	[27, 30, 44]
Plasma	miR-16-5p	p53, caspase-3	Slow down apoptosis of cardiomyocyte	[21]
miR-328-3p	Caspase	Slow down apoptosis of cardiomyocytes	[22]
miR-342-5p	Caspase-9, Jnk2, P-Akt	Slow down apoptosis of cardiomyocytes	[20]
miR-342-3p	SOX6, EBB	Inhibit autophagy	[28]
miR-26b-5p	SLC7A11	Inhibit ferroptosis	[33]
miR-143	IGF-IR	Promote neovascularization	[41]
ADSCs	miR-671	TGFBR2, Smad2	Reduce inflammation	[46]
miR-146a	EGR1; TLR4/NF-κB	Reduce inflammation	[45]
miR-126	MAP and PI3 signal pathway	Reduce inflammation	[48]
miR-196a-5p, miR-425-5p	IFN-γ, activin A	Promote the polarization of M1 macrophages into M2	[52]
Macrophages	miR-1271-5p	SOX6	Slow down apoptosis of cardiomyocytes	[19]
Dendritic cells	miR-494-3p	VEGF	Promote neovascularization	[39]
Cardiac fibroblasts	miR-133a	ELAVL1, NLRP3, caspase-1	Inhibition scorched cell death of cardiomyocytes	[31]
Myocardial cells	miR-21-5p	cdip1, caspase-3	Promote neovascularization	[40]
hucMSCs	miR-100-5p	FOXO3, NLPR3, caspase-1	Inhibit scorched cell death of cardiomyocytes	[32]
miR-23a-3p	DMT1	Inhibit ferroptosis	[34]

Source	miRNA	Target gene and/or signal pathway	Effect	Ref.
BMSCs	miR-21a-5p	PDCD4, PTEN, Peli1, Fasl	Slow down apoptosis of cardiomyocytes	[11, 12]
miR-30e	LOX1; NF-κB p65/caspase-9	Slow down apoptosis and the degree of fibrosis of cardiomyocytes	[14]
miR-153-3p	ANGPT1; VEGF/VEGFR2/PI3K/Akt/eNOS	Slow down apoptosis of cardiomyocytes and vascular endothelial cells	[15]
miR-210	AIFM3	Slow down apoptosis	[17, 18]
miR-125b-5p	p53, Bnip3	Inhibit autophagy	[24]
miR-301	p62	Inhibit autophagy	[27]
miR-143-3p	CHK2, p-Beclin 1, LC3; CHK2-Beclin 2	Inhibit autophagy	[26]
miR-29b-3p	VEGF, ADAMTS16	Promote neovascularization	[36]
miR-210-3p	EFNA3	Promote neovascularization	[38]
miR-205	HIF-1α	Promote neovascularization	[39]
miR-25-3p	FASL, PTEN, E2H2	Reduce inflammation	[44]
miR-146-5p	TRAF6	Promote the polarization of M1 macrophages into M2	[52]
miR-182	TLR4	Promote the polarization of M1 macrophages into M2	[51]
miR-205	HIF-1α	Promote neovascularization	[38]
miR-25-3p	FASL, PTEN, E2H2	Reduce inflammation	[43]
BMSCs	miR-146-5p	TRAF6	Promote the polarization of M1 macrophages into M2	[51]
miR-182	TLR4	Promote the polarization of M1 macrophages into M2	[50]
miR-182-5p	GSDMD, caspase-1; TLR4, p65-TLR4/NF-κB	Slow down apoptosis of cardiomyocytes and reduce inflammation	[27, 30, 44]
Plasma	miR-16-5p	p53, caspase-3	Slow down apoptosis of cardiomyocyte	[21]
miR-328-3p	Caspase	Slow down apoptosis of cardiomyocytes	[22]
miR-342-5p	Caspase-9, Jnk2, P-Akt	Slow down apoptosis of cardiomyocytes	[20]
miR-342-3p	SOX6, EBB	Inhibit autophagy	[28]
miR-26b-5p	SLC7A11	Inhibit ferroptosis	[33]
miR-143	IGF-IR	Promote neovascularization	[41]
ADSCs	miR-671	TGFBR2, Smad2	Reduce inflammation	[46]
miR-146a	EGR1; TLR4/NF-κB	Reduce inflammation	[45]
miR-126	MAP and PI3 signal pathway	Reduce inflammation	[48]
miR-196a-5p, miR-425-5p	IFN-γ, activin A	Promote the polarization of M1 macrophages into M2	[52]
Macrophages	miR-1271-5p	SOX6	Slow down apoptosis of cardiomyocytes	[19]
Dendritic cells	miR-494-3p	VEGF	Promote neovascularization	[39]
Cardiac fibroblasts	miR-133a	ELAVL1, NLRP3, caspase-1	Inhibition scorched cell death of cardiomyocytes	[31]
Myocardial cells	miR-21-5p	cdip1, caspase-3	Promote neovascularization	[40]
hucMSCs	miR-100-5p	FOXO3, NLPR3, caspase-1	Inhibit scorched cell death of cardiomyocytes	[32]
miR-23a-3p	DMT1	Inhibit ferroptosis	[34]

应用外泌体microRNA诊治心肌梗死的研究进展

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王晓童 ¹ , 董杨勇 ¹ , 王冉 ¹ , 张毓萱 ¹ , 陈静宜 ¹ , 王同尧 ¹ , 邱小燕 ² , 肖雄 ¹^,^*

药学学报 | 综述 2025,60(5): 1285-1296

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药学学报 | 综述 2025, 60(5): 1285-1296

应用外泌体microRNA诊治心肌梗死的研究进展

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王晓童¹, 董杨勇¹, 王冉¹, 张毓萱¹, 陈静宜¹, 王同尧¹, 邱小燕², 肖雄¹^,^*

作者信息

1.西南大学动物医学院, 重庆 400715

2.西南大学动物科学技术学院, 重庆 400715

通讯作者:

^*肖雄, Tel: 13996009270, E-mail: y1982@swu.edu.cn

Research progresses in diagnosis and treatment of myocardial infarction with exosomal microRNA

Xiao-tong WANG¹, Yang-yong DONG¹, Ran WANG¹, Yu-xuan ZHANG¹, Jing-yi CHEN¹, Tong-yao WANG¹, Xiao-yan QIU², Xiong XIAO¹^,^*

Affiliations

1. College of Veterinary Medicine, Southwest University, Chongqing 400715, China

2. College of Animal Science and Technology, Southwest University, Chongqing 400715, China

出版时间: 2025-05-12 doi: 10.16438/j.0513-4870.2024-1093

文章导航

摘要

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心肌梗死会严重危害人类和动物健康, 亟待提升其诊断速度和治疗效果。外泌体作为天然的细胞信息载体, 其包含的一些微小RNA (microRNA, miRNA) 能够反映或作用于心肌梗死所致病理变化, 进行有效诊治。本文就不同来源的外泌体miRNA作为心肌梗死诊断物(如miR-4516、miR-203和miR-1915-3p) 的可行性, 以及通过细胞凋亡(如miR-21a-5p、miR-30e和miR-210)、细胞自噬(如miR-125b-5p、miR-301和miR-143-3p)、细胞焦亡(如miR-182-5p、miR-133a和miR-100-5p) 和铁死亡(如miR-26b-5p和miR-23a-3p) 减缓细胞死亡, 促进新生血管的形成(如miR-29b-3p、miR-210-3p和miR-494-3p) 和抑制炎症反应(如miR-25-3p、miR-182-5p和miR-671) 等作用对心肌梗死进行干预治疗的研究进展进行了综述, 旨在为心肌梗死的诊断和治疗提供新策略。

关键词

外泌体 / microRNA / 心肌梗死 / 机制 / 诊治

Abstract

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Human and animal health will be seriously harmed by myocardial infarction, the diagnostic speed and the therapeutic effect of this disease need to be improved urgently. As the natural carrier for delivering cell information, some microRNAs (miRNAs) found in exosomes can reflect and act on the pathological changes caused by myocardial infarction for effective diagnosis and treatment. The feasibility of exosomal miRNAs (e.g. miR-4516, miR-203, and miR-1915-3p) from different sources as diagnostic agents for myocardial infarction, as well as the research progresses in relief of cell death via apoptosis (e.g. miR-21a-5p, miR-30e, and miR-210), autophagy (e.g. miR-125b-5p, miR-301, and miR-143-3p), pyroptosis (e.g. miR-182-5p, miR-133a, and miR-100-5p), and ferroptosis (e.g. miR-26b-5p and miR-23a-3p), promotion of forming new blood vessels (e.g. miR-29b-3p, miR-210-3p, and miR-494-3p), and inhibition of inflammatory response (e.g. miR-25-3p, miR-182-5p, and miR-671) for intervention therapy of myocardial infarction were reviewed here to provide new strategies for the diagnosis and treatment of myocardial infarction.

Key words

exosome / microRNA / myocardial infarction / mechanism / diagnosis and treatment

引用本文

王晓童, 董杨勇, 王冉, 张毓萱, 陈静宜, 王同尧, 邱小燕, 肖雄. 应用外泌体microRNA诊治心肌梗死的研究进展. 药学学报, 2025 , 60 (5) : 1285 -1296 . DOI: 10.16438/j.0513-4870.2024-1093

Xiao-tong WANG, Yang-yong DONG, Ran WANG, Yu-xuan ZHANG, Jing-yi CHEN, Tong-yao WANG, Xiao-yan QIU, Xiong XIAO. Research progresses in diagnosis and treatment of myocardial infarction with exosomal microRNA[J]. Acta Pharmaceutica Sinica, 2025 , 60 (5) : 1285 -1296 . DOI: 10.16438/j.0513-4870.2024-1093

正文

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心血管疾病在我国已成为第一大致死性疾病, 被称为危害人类健康的“第一大杀手”。急性心肌梗死(acute myocardial infarction, AMI) 往往因冠状动脉持续缺氧、缺血而造成心肌的坏死, 一旦发病, 需立刻进行救治。因此, 提升AMI的诊断速度, 延缓其发病进程, 进行有效治疗是目前急需解决的问题。外泌体作为细胞外囊泡的一种类型, 可以进行细胞间信息的有效传递, 其包含的miRNA已被证明在心脏细胞的通讯中占有重要地位, 特定外泌体miRNA的含量会根据心脏的生理或病理过程而发生改变, 在多种心血管疾病中发挥重要作用。AMI的病理特征主要体现在心肌缺血后的细胞死亡、梗死区域的剧烈炎症和缺血再灌注后的损伤, 而外泌体中的miRNA可以参与并作用于这些病理变化通路(如NF-κB p65/caspase-9、VEGF/VEGFR2/PI3K/Akt/eNOS和TLR4/NF-κB) 的关键靶点, 发挥调节功能^[1]。本文综述了不同来源外泌体miRNA作为AMI诊断标志物的价值以及治疗AMI的作用机制, 为研发诊治该病的新策略提供参考。

1 外泌体miRNA作为AMI的诊断标志物

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当前AMI的诊断主要依赖于血清中的心肌肌钙蛋白I (cardiac troponin I, cTnI)、肌钙蛋白T (cardiac troponin T, cTnT) 和肌酸激酶(creatine kinase, CK) 等。肌钙蛋白的水平在AMI发生后的1~2 h内尚未升高, 2~4 h后开始上升。其中, cTnI可以在症状出现后的90 min内被检测到。12 h后, AMI患者的肌钙蛋白水平均会明显升高。此外, 肌钙蛋白的高水平会在AMI发生后持续保持1~2周, 其中cTnT可能在10天内仍处于高水平, 而cTnI会在4~5天内保持高水平。因此, 在发病早期可能无法检测到可测量的肌钙蛋白水平, 临床上通常采用在入院后3~6 h内多次测量, 以提高检测率。CK在AMI发生后大约3~6 h开始释放入血, 并在9~30 h内达到峰值, 这一高峰期为其临床检测提供了关键参考。在24~48 h后, CK水平逐渐下降, 并在3~4天内恢复到正常水平, 这一恢复期可以有效评估AMI的严重性和患者的恢复情况。

AMI后, 心肌缺血的持续时间越长, 心肌细胞损伤就越严重, 及时对患者进行抢救可以有效保留其较多的心肌功能, 减少并发症的发生, 有效降低死亡率, 但以往的数据显示大量的AMI患者在到达医院之前就已经死亡^[2]。因此, 需要能够更早、更迅速地预警AMI发作的诊断标志物。

此外, 由于AMI患者病情的复杂性, 其并发的急性心包炎、心肌炎、心力衰竭和血压亢进等疾病也会导致目前已有传统标志物的水平升高。外泌体作为细胞间通讯的一种重要介质, 其内包含的miRNA参与调节各种细胞功能, 与传统标志物相比, 不同疾病产生外泌体中的miRNA具有特异性和及时性等优势, 有望成为AMI的新型生物标志物。目前已有的研究显示, 在AMI发生后, 不同来源的外泌体miRNA会在心肌损伤、心脏脂质稳态调节和炎性反应3个方面产生差异性的表达, 可为AMI的诊断提供一定的帮助。

1.1 心肌损伤

心脏特异性miR-499的水平与心肌损伤相关指标呈线性相关, 且能在AMI发生后的4 h内检测到。Gensini评分是用来评估冠状动脉狭窄程度的指标之一, miR-499与该评分呈正相关(r = 0.52, P < 0.01); 此外, AMI患者的血浆miR-499水平与cTnI (r = 0.384, P < 0.01) 和肌酸激酶同工酶MB (creatine kinase-MB, CK-MB)(r = 0.402, P < 0.01) 呈正相关^[3]。后续研究发现缺血心肌释放的miR-499可以通过靶向CXCR4, 促进骨髓祖细胞的修复作用, 从而进一步修复受损的心脏组织^[4]。

Guo等^[5]通过小RNA高通量测序对健康人群、冠心病(coronary artery disease, CAD) 患者和AMI患者进行分析, 研究发现与健康人群相比, AMI患者存在18个差异性表达的miRNA (miR-1227-3p、miR-5010-5p、miR-1976、miR-23b-5p、miR-1843、miR-33a-5p、miR-3127-3p、let-7i-5p、miR-143-3p、miR-1180-3p、miR-3615、miR-144-5p、miR-3186-5p、miR-203a-3p、miR-1273h-3p、miR-106b-5p、miR-17-5p和miR-629-3p), 其中14个中高丰度的miRNA (miR-1227-3p、miR-5010-5p、miR-1976、miR-23b-5p、miR-1843、miR-33a-5p、let-7i-5p、miR-143-3p、miR-1180-3p、miR-3615、miR-3186-5p、miR-106b-5p、miR-17-5p和miR-629-3p) 能够以77%的特异性和84%的敏感性诊断AMI。曲线下面积(area under the curve, AUC) 可以有效评估某一指标预测的准确性。在该实验中, 健康组的AUC为0.93, AMI组为0.87, 表明这18个miRNA能够准确预测AMI的发生。这些差异表达的miRNA靶向蛋白的表达与心脏的发育和收缩能力相关, 提示其参与了心血管系统功能的调节。

同样采用高通量测序方法检测健康人群、术前AMI患者、术后1天AMI患者和术后3天AMI患者的差异性外泌体miRNA, 发现5种与AMI相关的miRNA: miR-6718-5p、miR-4329、miR-1207-3p、miR-34b-3p和miR-296-5p。其中, miR-6718-5p和miR-4329的水平在术前显著低于对照组(P < 0.05), 术后显著高于对照组(P < 0.05), 表明了两种miRNA的特异性, 进一步研究发现这两种miRNA可能作用于丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK) 信号通路和磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase, PI3K) 信号通路调控心肌细胞的分化和凋亡等过程^[6]。Su等^[7]进一步分析了AMI和CAD患者的外泌体miRNA谱, 发现在AMI患者有13个miRNAs (miR-4507、miR-3656、miR-6803-5p、miR-7108-5p、miR-6850-5p、miR-4486、miR-6741-5p、miR-1227-5p、miR-3195、miR-4634、miR-7975、miR-6798-3p和miR-1915-3p) 的表达显著下调, 其中miR-1915-3p、miR-4507和miR-3656的表达量能较为准确地预测AMI, 其AUC分别为0.772 (P < 0.01)、0.68 (P = 0.02) 和0.771 (P < 0.01), 三者分别对应心肌收缩能力、细胞凋亡和炎性反应的损伤指标, 其靶基因主要参与心脏的康复和重构, 调节NGF信号通路和激活下游FGFRs信号通路等。

1.2 心脏脂质稳态调节

低密度脂蛋白(low-density lipoprotein, LDL) 和高密度脂蛋白胆固醇(high-density lipoprotein cholesterol, HDL-C) 等脂类物质指标是动脉粥样硬化形成和发展的主要推动因素, 与动脉硬化程度密切相关, 动脉硬化严重时即可能发生AMI。在一项对AMI患者血浆外泌体的研究中发现, AMI患者组血浆外泌体中miR-4516和miR-203的水平分别极显著(P < 0.001) 和显著(P < 0.05) 高于对照组, 且二者靶蛋白分泌性卷曲相关蛋白1 (secretory frizzled-related protein 1, SFRP1) 的表达水平显著升高。外泌体miR-4516和miR-203的AUC分别为0.980 9 (P < 0.000 1) 和0.682 3 (P = 0.006), AMI组血浆SFRP1的AUC为0.960 3 (P < 0.000 1)。miR-4516与SYNTAX评分(冠状动脉评分) 呈正相关, SFRP1与cTnI、LDL的水平呈正相关, 表明三者可能是AMI的候选诊断生物标志物, 暗示了三者在AMI后脂质稳态调节的功能, 且SFRP1作为Wnt/β‑catenin信号通路的抑制因子, 提示了该通路在AMI过程中的可能作用^[8]。通过收集135例CAD患者和150例健康受试者的数据样本发现, miR-21-3p与CAD患者的生化因子超敏C反应蛋白(high-sensitivity C-reactive protein, hs-CRP)、LDL-C呈正相关, 与HDL-C呈负相关, miR-21-5p与生化因子的相关性结果与miR-21-3p相反, 但效果并不显著。此外, 通过AMI造模的小鼠进行动物实验, 验证发现miR-21-3p/5p在AMI组的表达与对照组相比显著上调, AUC评分分别为0.82 (P = 0.000 2) 和0.92 (P = 0.004), 提示这两种miRNA对于AMI的显著预测能力^[9]。

1.3 炎性反应

由于免疫细胞大量参与心脏疾病的各阶段修复, 中性粒细胞已成为传统的生物标志物, 同时中性粒细胞引起的急性炎症反应是AMI的核心病理过程。因此, 评估中性粒细胞炎症反应的生物标志物可以有效预测AMI的发生。通过生物信息学方法测序比较AMI患者、CAD患者和健康人员的外泌体miRNA和免疫细胞富集图谱, 发现在AMI患者体内中性粒细胞和单核细胞显著富集, 证实了AMI的急性炎症反应生物学过程。此外, 结果显示外泌体miRNA、ALPL和CXCR2与免疫细胞富集图存在大量重叠, 约有175个外泌体miRNA参与了中性粒细胞介导的急性炎症反应, 可作为诊断AMI的潜在生物标志物^[10]。

综上所述，外泌体miRNA可以从心肌损伤、心脏脂质稳态和炎性反应3个方面预测心肌梗死的发生(表 1)^[3-10]。然而, 目前有关外泌体miRNA诊断AMI方面的研究较少, 其确切的诊断机制尚不明确, 而已有的研究中临床试验样本数量较少, 仍需大量的研究对外泌体miRNA诊断的准确性进行更为深入的探讨。

2 外泌体miRNA对AMI的治疗机制

收起

本课题组前期开展了应用nanoLC-ESI-MS-MS质谱检测分析3D培养的心脏祖细胞中外泌体的蛋白质组, 分离外泌体中的miRNA, 挖掘了外泌体治疗AMI的相关机制。结合本课题组的前期工作, 从细胞死亡、促进血管生成和炎症反应3个方面对外泌体miRNA治疗AMI的机制进行比较和总结。

2.1 细胞死亡

2.1.1 细胞凋亡

细胞凋亡是指为了维持内环境的稳定从而进行的由基因控制的细胞程序性死亡。AMI发生后, 缺血、缺氧和其后的再灌注过程均会引起心肌细胞的凋亡。心肌细胞的凋亡在心室重构和心功能调控中起到了关键作用, 同时心肌细胞作为难以再生的细胞, 其受损后的修复较为困难。因此, 通过减缓心肌细胞的凋亡过程, 可以有效控制AMI的病情发展, 其调节信号通路主要聚焦在Akt和caspase相关通路(图 1)。

外泌体携带的miRNA可以进入心肌细胞内, 参与并调控心肌细胞凋亡的过程。人子宫内膜来源间充质干细胞(endometrial-derived mesenchymal stem cells, EnMSCs) 的外泌体可选择性地增强miR-21的表达, 增强心肌细胞抗凋亡和促进血管生成的作用; 同时, 阻断miR-21会使PTEN和Akt磷酸化失活, 降低受体细胞中VEGF和Bcl-2的表达, 提示了miR-21可通过PTEN/Akt信号通路提高心肌细胞的存活率, 成为心血管疾病细胞疗法的优先选择^[11]。此外, 通过进行深度的miRNA测序, 发现miR-21a-5p是心脏中含量最丰富的且具有心脏保护性的miRNA。在氧-葡萄糖剥夺(oxygen and glucose deprivation, OGD) 模型中, 骨髓间充质干细胞(bone marrow mesenchymal stem cells, BMSCs) 中的外泌体可以有效传递miR-21a-5p进入心脏组织, 下调心肌组织中促凋亡基因PDCD4、磷酸酶和紧张蛋白同源物(phosphatase and tensin homolog, PTEN)、Peli1和FasL的表达。经300 μg外泌体蛋白处理后, H9c2细胞的死亡率降低了60.5% ± 4.4%, 有效减少了AMI后细胞的凋亡情况^[12]。miR-21a-5p的前体miR-21已被证明在缺血再灌注(ischemia reperfusion, I/R) 和缺氧/再氧(hypoxia/reoxygenation, H/R) 时期存在相同的心肌细胞保护机制, 其可以通过抑制PTEN的表达来上调Akt的信号活性, 增加Bcl-2蛋白的表达量, 进一步抑制凋亡基因caspase-3的表达, 实现对心肌细胞凋亡的保护^[13]。源自BMSCs的外泌体作用于AMI大鼠的心肌细胞后, 有效提高了miR-30e的表达, 后者显著抑制LOX1的表达, 从而下调大鼠NF-κB p65/caspase-9信号通路的活性, 改善AMI后的细胞凋亡和纤维化程度^[14]。低表达的间充质干细胞(mesenchymal stem cells, MSCs) 外泌体miR-153-3p靶向作用于ANGPT1基因, 进一步促进VEGF/VEGFR2/PI3K/Akt/eNOS通路, 有效减轻了OGD模型中心肌细胞和血管内皮细胞的凋亡, 提高了细胞活力, 而VEGFR2抑制剂的干预显著逆转了miR-153-3p对血管内皮细胞和心肌细胞的保护作用^[15]。

AIFM3是一种线粒体相关蛋白, 与凋亡诱导因子(apoptosis inducing factor, AIF) 的序列相似性为35%, 广泛存在于各种类型的细胞或组织中, 通过caspase依赖方式诱导细胞凋亡^[16]。过表达miR-210能减少活性氧(reactive oxygen species, ROS) 的产生, 减轻氧化应激作用下的心肌细胞死亡, 降低凋亡诱导因子线粒体相关3 (apoptosis-inducing factor, mitochondrion-associated 3, AIFM3) 的水平, 但在miR-210过表达的情况下, AIFM3的过表达不会降低细胞活力^[17]。而在后续的实验中发现, 通过向大鼠AMI模型中直接注射MSC外泌体发现, 中介物质miR-210有效增加了心肌细胞的存活率, 激活了下游靶点AIFM3, 随后抑制了磷酸化p53、Akt和PI3k的表达。此外, 随着AIFM3的上调, Bcl2表达水平上升, caspase-3、BAD和BAX等凋亡因子的水平显著降低, 抑制了心肌细胞的凋亡, 减少了AMI的面积^[18]。

其他细胞来源的外泌体miRNA也有效发挥了对AMI后心脏的保护作用。来源于巨噬细胞外泌体的miR-1271-5p直接作用于下游靶点SOX6, 下调其表达, 降低了缺氧诱导梗死后心肌细胞的凋亡^[19]。一项有趣的运动试验显示, 通过比较接受了4周游泳训练和久坐不动的大鼠血浆循环中外泌体的情况, 运动大鼠血浆循环外泌体中的miR-342-5p能够降低caspase-9和Jnk2的表达水平, 抑制H/R诱导的心肌细胞凋亡, 其还靶向作用于磷酸酶基因Ppm1f, 增强生存信号通路p-Akt, 表明长期的运动可以有效增强机体对心脏的保护作用^[20]。

然而, 并不是所有的外泌体miRNA都能对心脏有保护作用。在一种由骨骼肌减少症诱导的AMI模型中, 研究发现其心脏的循环外泌体miR-16-5p的分泌水平显著升高, 体外培养的心肌细胞在miR-16-5p模拟物的作用下, p53和caspase-3基因表达上调, 增加了细胞凋亡, 证明了心脏修复紊乱伴随骨骼肌减少症的作用机制^[21]。通过分析正常心肌细胞、AMI细胞和邻近的正常心肌细胞中外泌体miRNA的表达差异, miR-328-3p在邻近的正常心肌细胞中显著升高, 在后续实验中证实了miR-328-3p在梗死后细胞的外泌体中增加并进入正常心肌细胞中。通过过表达miR-328-3p的慢病毒载体处理心肌细胞, 发现其增加了肌纤维之间的空间, 心肌细胞凋亡水平增加, caspase-3表达升高, 说明miR-328-3p激活caspase通路是心肌细胞凋亡和AMI的重要机制^[22]。

2.1.2 细胞自噬

细胞自噬是真核生物将细胞内一些损坏的蛋白质、细胞器等进行降解再循环的一种重要代谢过程。基本的细胞自噬对于维持正常的心脏功能发挥了作用, 甚至可以在AMI发生后产生一定的保护效果, 但是, 自噬的过度激活会对心肌细胞造成损伤^[23]。

研究显示, 大量的外泌体miRNA可以抑制细胞的过度自噬, 实现对心脏的保护作用。将BMSCs外泌体miR‐125b-5p注射到小鼠AMI模型后, 结果显示由巴菲霉素A1 (bafilomycin A1, BafA 1) 诱导的LC3-Ⅱ自噬通量的积累显著降低, 抑制了细胞死亡, 而注射了miR-125b-5p抗体处理组的小鼠并未显示出对心脏的保护作用。p53作为miR-125b-5p的下游靶点可以负调控Bnip3的表达水平, 在经过miR-125b-5p处理后, p53和Bnip3的蛋白水平均降低, 表明外泌体中的miR-125b-5p通过p53和Bnip3信号通路对自噬进行调控^[24]。p53作为传统的促凋亡蛋白, 却能够在缺氧的情况下抑制细胞的死亡。定位于线粒体的p53会以一种依赖于Bcl-2、Bnip3蛋白的方式引发线粒体的自噬, Bnip3作为p53可能的下游基因, 其功能的丧失可以完全抵消p53诱导的自噬, 二者相互依赖, 在高度缺氧或缺血条件下, 对心肌细胞的自噬和死亡起到双重调控作用^[25]。

在体外实验中, 通过将MSCs与H/R模型的H9c2细胞的共培养, 发现MSCs外泌体中miR-143-3p显著抑制了自噬相关蛋白CHK2、p-Beclin 1和LC3的表达, 通过介导CHK2-Beclin 2通路, 抑制细胞自噬, 减轻细胞凋亡, 有效保护AMI对心肌细胞的损伤^[26]。此外, 对注射了经miR-301转染后的BMSCs外泌体的大鼠进行观察发现, 大鼠心功能参数中左心室射血分数和左心室缩短分数明显升高, 左心室收缩末期直径和左心室舒张末期直径明显降低, 有效改善了心肌功能。免疫组织化学结果显示, 外泌体miR-301处理组的LC3-Ⅱ/LC3-Ⅰ比值明显降低, p62蛋白的相对表达量明显升高, 自噬囊泡数量明显降低, 表明miR-301能够抑制AMI中的细胞自噬^[27]。

在一项对比健康志愿者和AMI恢复患者血浆外泌体功能情况的调查显示, 恢复期患者的血浆外泌体miR-342-3p含量显著下降, 而miR-342-3p通过分别靶向SOX6和TEBB基因, 减轻细胞的缺氧损伤, 降低自噬通量LC3-Ⅱ的表达, 增加p62的表达水平, 减少细胞凋亡和自噬, 从而导致AMI患者后期心脏自然修复功能上调^[28]。

外泌体对AMI后细胞自噬的调控主要通过自噬通量LC3-Ⅱ的变化进行检测。自噬过程中脂溶性LC3-Ⅱ作为微管相关蛋白轻链3 (microtubule-associated protein light chain 3, LC3) 的一种, 在自噬过程中由Atg 4降解形成, 会与自噬体膜表面结合, 同时p62作为一种选择性自噬受体, 通过形成蛋白聚集物促进泛素化蛋白的组装和去除, 最终与自噬体一起降解^[29]。因此, p62蛋白的表达下降也被认定为自噬增强的标志(图 2)。

2.1.3 细胞焦亡

细胞焦亡是机体中一种重要的天然免疫反应, 细胞会不断涨大直至破裂, 导致内容物的释放进而激活强烈的炎症反应。相较于细胞凋亡, 细胞焦亡的发生速度更快, 伴随的反应更加剧烈。细胞焦亡的主要发生机制为caspase-1的激活会裂解gasdermin D (GSDMD), 导致细胞膜上产生N端片段聚合物, 形成较大的孔隙, 导致细胞焦亡。心肌I/R会导致NOD样受体热蛋白结构域相关蛋白3 (nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3, NLRP3) 炎症小体的激活, 并通过caspase-1依赖性焦亡过程增加炎症和心肌细胞死亡(图 3)。

GSDMD是参与NLRP3炎症诱导的细胞焦亡配体蛋白, 也是BMSCs外泌体miR-182-5p的下游靶基因, miR-182-5p通过抑制GSDMD的表达, 降低了心肌细胞中caspase-1前体和caspase-1蛋白的水平, 进而抑制心肌细胞的焦亡和损伤^[30]。心肌成纤维细胞(cardiac fibroblasts, CFs) 作为心肌细胞中最大的细胞群, 已被证实能够有效保护心肌I/R后的损伤。在CFs分泌的外泌体中, miR-133a的水平较高, 其传送至心肌细胞后, 靶向作用于ELAVL1 (一种促炎的miRNA结合蛋白), 下调了包括其本身在内和NLRP3、caspase-1等细胞焦亡标志蛋白的表达, 降低了心肌细胞死亡率, 从而抑制心肌细胞的焦亡^[31]。同样, 在人脐带间充质干细胞(human umbilical cord MSCs, hucMSCs) 的外泌体中富含miR-100-5p, 抑制了H/R损伤导致的NLRP3表达, 激活caspase-1、GSDMD-N、IL-1β和IL-18的释放。其参与调控的主要机制为miR-100-5p靶向抑制NLRP3上游因子FOXO3的表达, 实现对心肌细胞焦亡的保护作用^[32]。

2.1.4 抑制铁死亡

铁死亡作为一种调节铁依赖的死亡形式, 其特征是由于脂质ROS的积累, 引起细胞膜的过氧化损伤以及铁代谢稳态的破坏。AMI会造成谷胱甘肽(glutathione, GSH) 依赖性抗氧化应激系统失活, 引起ROS的积累, 同时缺血会导致心肌中铁的积累, 铁作为一种自由基也会引起氧化应激, 进而引起心肌细胞的铁死亡。

铁死亡抗性基因SLC7A11可介导胱氨酸/谷氨酸逆向转运蛋白活性, 在胱氨酸摄取、GSH和谷胱甘肽过氧化物酶4 (glutathione peroxidase 4, GPX4) 合成和铁垂病抗性中发挥重要作用(图 4)。敲除AMI患者血浆外泌体中的miR-26b-5p可上调SLC7A11、GSH和GPX4的表达, 降低细胞内Fe²⁺和ROS的水平, 延缓心肌细胞的铁死亡进程, 证明了外泌体miR-26b-5p/SLC7A11轴可通过调控铁死亡对心肌细胞产生保护作用^[33]。二价金属转运体1 (divalent metal transporter 1, DMT1) 作为Fe²⁺的转运载体, 是铁代谢稳态的关键因子。来自hucMSCs的外泌体通过传递miR-23a-3p有效抑制DMT1的表达, 细胞内ROS、Fe²⁺和GSH的含量显著降低, 细胞活力提高, 但miR-23a-3p对GPX4的表达无明显作用。因此, 外泌体miR-23a-3p通过靶向DMT1抑制心肌细胞的铁死亡, 保护AMI后的心肌损伤^[34]。

2.2 促进血管生成

动脉粥样硬化和血栓等均会引起AMI, 其造成的冠状动脉闭塞会引起局部的微循环障碍, 进而导致梗死区的缺血和缺氧。因此, 促进梗死区的血管生成和建立侧支循环的供血是治疗AMI的关键措施^[35]。本课题组前期采用体外血管形成实验试剂盒评估了外泌体对血管形成的作用, 证实了外泌体促进血管生成的作用。

在BMSCs来源的外泌体中, 其传递的miR-29b-3p能够有效改善血流动力学, 增加毛细血管的密度, 并促进了血管内皮生长因子(vascular endothelial growth factor, VEGF) 的表达, 从而改善AMI的血管生成和心室重构。ADAMTS16作为miR-29b-3p的下游基因, 其过表达会加速AMI的病理进程, miR-29b-3p的存在起到了很好的保护作用^[36]。同样来自BMSCs外泌体的miR-153-3p却有相反的调节作用。当miR-153-3p的表达下调时, 会靶向作用于调节血管生成和心肌细胞凋亡的重要调控因子ANGPT1, 从而激活VEGF/VEGFR2/PI3K/Akt/eNOS通路, 促进血管的生成并恢复心肌细胞的功能, 减缓AMI^[15]。Pu等^[37]在体外利用烟酰胺单核苷酸对BMSCs的外泌体进行优化, 与未优化组相比, 优化组显著增进了人脐静脉内皮细胞(human umbilical vein endothelial cells, HUVECs) 的增殖、迁移和血管生成。测序结果表明miR-210-3p在优化的外泌体中含量丰富, 且靶向作用于EFNA3。因此, miR-210-3p对AMI具有治疗潜力。来源于脂肪间充质干细胞外泌体的miR-205能促进微血管内皮细胞的增殖和迁移, 活化血管生成蛋白缺氧诱导因子-1α (hypoxia-inducible factor 1α, HIF-1α) 和VEGF的表达, 显著改善左心室的射血分数, 缓解AMI引起的心脏衰竭^[38]。

除了干细胞的外泌体miRNA能够有效促进血管生成外, 其他来源的外泌体miRNA也能够发挥相应作用, 从而减轻AMI的损害。将提取的树突状细胞来源的外泌体注入AMI模型小鼠后, 与对照组相比, miR-494-3p的表达上调, VEGF表达上升, 增加了心脏微血管的形成, 提示了miR-494-3p在血管生成方面的作用^[39]。Liao等^[40]在研究心脏端粒细胞对AMI的作用时发现, 心脏端粒细胞外泌体miR-21-5p能靶向沉默细胞凋亡基因cdip1, 下调活化的caspase-3, 抑制心肌微血管内皮细胞的凋亡, 促进AMI后的血管生成。从AMI患者血清中分离提取外泌体, 与HUVECs共培养后发现, 过表达和敲除miR-143可以分别抑制和增强血管的生成, 而这种作用主要是由靶向基因胰岛素样生长因子1受体介导^[41]。

综上, 外泌体miRNA促进AMI后血管生成的主要作用靶点为VEGF (图 5)。缺氧是最经典的VEGF上游调节因素之一, HIF转录家族在缺氧条件下通过激活多种通路实现对生理功能的调控, 其中就包括VEGF、HIF-1α和HIF-2α会与VEGF基因上的一个高度保守的缺氧反应元件结合, 实现血管通透性的增加, 血管内皮细胞的增殖、迁移和黏附, 以及血管的生成^[42]。

2.3 减轻炎症反应

2.3.1 促炎因子和抑炎因子

AMI发生时, 在梗死区的边缘部分会出现大量的巨噬细胞和中性粒细胞等炎性细胞的浸润, 在这种情况下，通常以促炎因子和抑炎因子的变化为指标来确认炎症的发展情况(图 6)。因此, 可将减轻心肌的炎症反应作为AMI的治疗方向之一。

MSCs外泌体中的miR-25-3p直接靶向促凋亡基因FASL和PTEN, 并降低二者的表达水平, 减少细胞凋亡; miR-25-3p还可以降低EZH2的表达水平, 恢复心脏保护基因eNOS和抗炎基因SOCS3的表达, 从而减轻炎症反应^[43]。TLR4在心肌炎症中发挥着重要作用, 长期的AMI会导致TLR4的表达上升, 加剧炎症和病情。来自BMSCs外泌体的miR-182-5p能显著降低心脏组织中TLR4的表达, 促进磷酸化p65的下调, 抑制了TLR4/NF-κB通路的激活, 显著降低促炎因子IL-6、IL-1β、TNF-α和MCP-1的表达水平, 抑制AMI的炎症反应^[44]。来自脂肪间充质干细胞的外泌体miR-146a通过抑制早期生长因子1, 同样可以逆转AMI后TLR4/NF-κB信号通路的激活, 降低细胞的炎症反应^[45]。脂肪干细胞来源的外泌体miR-671作用于小鼠OGD模型后, 促炎因子IL-6和TNF-α的释放显著降低。主要的作用机制为miR-671降低了细胞中TGFBR2的蛋白水平和Smad2的磷酸化水平, 从而抑制了炎症因子的分泌^[46]。在AMI的大鼠模型中过表达脂肪干细胞外泌体miR-126, 可显著降低血清中IL-1β、IL-6和TNF-α的分泌, 表现出对AMI后炎性反应的保护作用^[47]。miR-126作为内皮细胞中一种高度富集的miRNA, 通过抑制其靶基因SPRED1、PIK3R2和VCAM1的表达, 响应VEGF因子的激活, 促进血管的生成, 减轻血管内皮炎症。此外, 经过后续的检测发现, VEGF激活了ERK和AKT的磷酸化, 推测可能激活了MAP和PI3通路的运行^[48]。目前, 已有研究通过构建免疫脂质体装载miR-126以减轻心血管疾病引发的血管内皮炎症, 其可以直接靶向产生炎症的血管内皮膜表面的血管细胞黏附因子-1 (vascular cell adhesion molecule-1, VCAM-1), 抑制其蛋白表达, 有效缓解炎症反应^[49]。

2.3.2 巨噬细胞的极化

巨噬细胞的极化通常是指当机体内环境稳态遭到破坏后, 巨噬细胞在不同的作用刺激下, 产生不同功能的表型, 以应对病原体的攻击和炎症反应等病理过程。外泌体miRNA可通过调控巨噬细胞的极化减轻AMI对心脏的损伤(图 7)。使用MSCs外泌体中的miR-182对AMI小鼠模型进行治疗时, 可减少心脏内M1表型巨噬细胞的数量, 促使其向M2表型的巨噬细胞转化, 通过转录调控抑制其靶基因TLR4的表达, 减少心脏中中性粒细胞的浸润, 降低促炎因子IL-6的表达, 增加抑炎因子IL-10的浓度, 减轻心肌缺血再灌注后的损伤^[50]。从新生小鼠心肌细胞收集富含miR-146-5p的外泌体处理巨噬细胞, 可促进M1巨噬细胞的极化, 抑制M2巨噬细胞的极化, 同时当miR-146-5p被激活时, 其靶向基因肿瘤坏死因子受体相关蛋白6的表达显著降低, 发挥抗炎作用^[51]。de Almeida Oliveira等^[52]运用高通量筛选平台验证了来自脂肪干细胞外泌体的miR-196a-5p和miR-425-5p对心肌细胞、CFs、内皮细胞和巨噬细胞的协同反应, 结果表明这两种miRNAs能够有效阻止AMI后线粒体的功能障碍和ROS的产生, 促进血管生成; 通过生物信息学的分析发现, miR-196a-5p可诱导IFN-γ基因的下调, 而IFN-γ基因相关通路往往与巨噬细胞M1的极化有关, miR-425-5p的过表达会抑制TGF-β家族的激活素A, 进而促进巨噬细胞向M1表型的转化, 抑制其向M2表型的转化, 实现抗炎作用。

目前, 部分药物治疗AMI时, 其主要的药理作用机制也是通过外泌体介导。如芪参益气滴丸中的皂苷Rh2成分对AMI有一定的治疗作用, 在使用该药物后, 通过HMGB1/NF-κB通路增强了外泌体对NLRP3炎症小体激活的抑制作用, 赋予心肌细胞保护作用^[53]。

3 小结与展望

收起

随着对外泌体研究的不断深入, 其对AMI的发生发展过程的重要调控作用已经得到了证实。外泌体以其传递信息的稳定性和其携带的miRNA可以发挥多种特异性生物学功能等优点, 为AMI的诊断提供了更加高效的方法。此外, BMSCs、脂肪干细胞等来源的外泌体miRNA可通过减缓细胞死亡、促进血管新生和减轻炎症反应等途径治疗AMI (表 2) ^{[11, 12, 14, 15, 17-22, 24, 26-28, 30-34, 36, 38-41, 43-46, 48, 50-52]}。但是, 采用细胞上清液提取外泌体的难度较大, 成本高, 提取含量往往难以满足实际应用, 且外泌体的提取和miRNA的检测方法尚未完全标准化, 可能影响结果的重复性和可靠性, 故有必要更为深入地优化外泌体的分离技术, 或使用人造外泌体替代物等。而且, 外泌体miRNA尽管在AMI中存在潜在的特异性, 但不同个体间的差异性问题会影响其作为诊断标志物的可靠性。另外, 应用外泌体miRNA进行治疗的靶向性和安全性仍有待进一步的评估, 其应用仍然缺乏相关的伦理和法规指导。后续应进一步探索外泌体miRNA发挥作用的相关机制, 集中在外泌体miRNA的标准化检测、机制探索及临床转化应用上, 开发出更为精准的诊断工具和治疗策略, 以提高心肌梗死的早期诊断率, 改善患者预后, 使外泌体miRNA在AMI的诊断和治疗中发挥更大作用。

作者贡献: 王晓童具体负责完成文章构思、文献检索、图片制作及综述撰写与修改; 董杨勇和王冉参与完成文献检索和综述撰写; 张毓萱和陈静宜参与图片制作; 王同尧参与表格制作与内容修改; 邱小燕参与图表制作指导和修改; 肖雄负责文章整体构思和修改, 并对文章撰写质量进行把关和审校。

利益冲突: 所有作者均声明不存在利益冲突。

基金

收起

重庆市教委科学技术研究项目(KJZD-K202200208)
西南大学研究生科研创新项目(SWUS24191)
西南大学研究生科研创新项目(SWUS23138)
重庆市研究生科研创新项目(CYS22246)

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2025年第60卷第5期

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doi: 10.16438/j.0513-4870.2024-1093

接收时间：2024-11-05
首发时间：2025-10-29
出版时间：2025-05-12

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收稿日期：2024-11-05
修回日期：2025-01-15

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重庆市教委科学技术研究项目(KJZD-K202200208)

西南大学研究生科研创新项目(SWUS24191)

西南大学研究生科研创新项目(SWUS23138)

重庆市研究生科研创新项目(CYS22246)

作者信息

1.西南大学动物医学院, 重庆 400715

2.西南大学动物科学技术学院, 重庆 400715

通讯作者:

^*肖雄, Tel: 13996009270, E-mail: y1982@swu.edu.cn

参考文献

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https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2024-1093

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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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Item	miRNA	Key miRNA	Signal pathway	Ref.
Myocardial damage		miRNA-449	CXCR4	[3, 4]
miR-1227-3p, miR-5010-5p, miR-1976, miR-23b-5p, miR-1843, miR-33a-5p, miR-3127-3p, let-7i-5p, miR-143-3p, miR-1180-3p, miR-3615, miR-144-5p, miR-3186-5p, miR-203a-3p, miR-1273h-3p, miR-106b-5p, miR-17-5p and miR-629-3p	miR-1227-3p, miR-5010-5p, miR-1976, miR-23b-5p, miR-1843, miR-33a-5p, let-7i-5p, miR-143-3p, miR-1180-3p, miR-3615, miR-3186-5p, miR-106b-5p, miR-17-5p and miR-629-3p		[5]
miR-6718-5p, miR-4329, miR-1207-3p, miR-34b-3p and miR-296-5p	miR-6718-5p and miR-4329	MAPK signal pathway and PI3K signal pathway	[6]
miR-4507, miR-3656, miR-6803-5p, miR-7108-5p, miR-6850-5p, miR-4486, miR-6741-5p, miR-1227-5p, miR-3195, miR-4634, miR-7975, miR-6798-3p and miR-1915-3p	miR-1915-3p, miR-4507 and miR-3656	NGF signal pathway and FGFRs signal pathway	[7]
Lipid homeostasis regulation		miR-4516 and miR-203	Wnt/β-catenin signal pathway	[8]
	miR-21-3p and miR-21-5p		[9]
Inflammatory reaction		About 175		[10]

Item

miRNA

Key miRNA

Signal pathway

Ref.

Myocardial damage

miRNA-449

CXCR4

[3, 4]

miR-1227-3p, miR-5010-5p, miR-1976, miR-23b-5p, miR-1843, miR-33a-5p, miR-3127-3p, let-7i-5p, miR-143-3p, miR-1180-3p, miR-3615, miR-144-5p, miR-3186-5p, miR-203a-3p, miR-1273h-3p, miR-106b-5p, miR-17-5p and miR-629-3p

miR-1227-3p, miR-5010-5p, miR-1976, miR-23b-5p, miR-1843, miR-33a-5p, let-7i-5p, miR-143-3p, miR-1180-3p, miR-3615, miR-3186-5p, miR-106b-5p, miR-17-5p and miR-629-3p

[5]

miR-6718-5p, miR-4329, miR-1207-3p, miR-34b-3p and miR-296-5p

miR-6718-5p and miR-4329

MAPK signal pathway and PI3K signal pathway

[6]

miR-4507, miR-3656, miR-6803-5p, miR-7108-5p, miR-6850-5p, miR-4486, miR-6741-5p, miR-1227-5p, miR-3195, miR-4634, miR-7975, miR-6798-3p and miR-1915-3p

miR-1915-3p, miR-4507 and miR-3656

NGF signal pathway and FGFRs signal pathway

[7]

Lipid homeostasis regulation

miR-4516 and miR-203

Wnt/β-catenin signal pathway

[8]

miR-21-3p and miR-21-5p

[9]

Inflammatory reaction

About 175

[10]

Source	miRNA	Target gene and/or signal pathway	Effect	Ref.
BMSCs	miR-21a-5p	PDCD4, PTEN, Peli1, Fasl	Slow down apoptosis of cardiomyocytes	[11, 12]
miR-30e	LOX1; NF-κB p65/caspase-9	Slow down apoptosis and the degree of fibrosis of cardiomyocytes	[14]
miR-153-3p	ANGPT1; VEGF/VEGFR2/PI3K/Akt/eNOS	Slow down apoptosis of cardiomyocytes and vascular endothelial cells	[15]
miR-210	AIFM3	Slow down apoptosis	[17, 18]
miR-125b-5p	p53, Bnip3	Inhibit autophagy	[24]
miR-301	p62	Inhibit autophagy	[27]
miR-143-3p	CHK2, p-Beclin 1, LC3; CHK2-Beclin 2	Inhibit autophagy	[26]
miR-29b-3p	VEGF, ADAMTS16	Promote neovascularization	[36]
miR-210-3p	EFNA3	Promote neovascularization	[38]
miR-205	HIF-1α	Promote neovascularization	[39]
miR-25-3p	FASL, PTEN, E2H2	Reduce inflammation	[44]
miR-146-5p	TRAF6	Promote the polarization of M1 macrophages into M2	[52]
miR-182	TLR4	Promote the polarization of M1 macrophages into M2	[51]
miR-205	HIF-1α	Promote neovascularization	[38]
miR-25-3p	FASL, PTEN, E2H2	Reduce inflammation	[43]
BMSCs	miR-146-5p	TRAF6	Promote the polarization of M1 macrophages into M2	[51]
miR-182	TLR4	Promote the polarization of M1 macrophages into M2	[50]
miR-182-5p	GSDMD, caspase-1; TLR4, p65-TLR4/NF-κB	Slow down apoptosis of cardiomyocytes and reduce inflammation	[27, 30, 44]
Plasma	miR-16-5p	p53, caspase-3	Slow down apoptosis of cardiomyocyte	[21]
miR-328-3p	Caspase	Slow down apoptosis of cardiomyocytes	[22]
miR-342-5p	Caspase-9, Jnk2, P-Akt	Slow down apoptosis of cardiomyocytes	[20]
miR-342-3p	SOX6, EBB	Inhibit autophagy	[28]
miR-26b-5p	SLC7A11	Inhibit ferroptosis	[33]
miR-143	IGF-IR	Promote neovascularization	[41]
ADSCs	miR-671	TGFBR2, Smad2	Reduce inflammation	[46]
miR-146a	EGR1; TLR4/NF-κB	Reduce inflammation	[45]
miR-126	MAP and PI3 signal pathway	Reduce inflammation	[48]
miR-196a-5p, miR-425-5p	IFN-γ, activin A	Promote the polarization of M1 macrophages into M2	[52]
Macrophages	miR-1271-5p	SOX6	Slow down apoptosis of cardiomyocytes	[19]
Dendritic cells	miR-494-3p	VEGF	Promote neovascularization	[39]
Cardiac fibroblasts	miR-133a	ELAVL1, NLRP3, caspase-1	Inhibition scorched cell death of cardiomyocytes	[31]
Myocardial cells	miR-21-5p	cdip1, caspase-3	Promote neovascularization	[40]
hucMSCs	miR-100-5p	FOXO3, NLPR3, caspase-1	Inhibit scorched cell death of cardiomyocytes	[32]
miR-23a-3p	DMT1	Inhibit ferroptosis	[34]

Source

miRNA

Target gene and/or signal pathway

Effect

Ref.

BMSCs

miR-21a-5p

PDCD4, PTEN, Peli1, Fasl

Slow down apoptosis of cardiomyocytes

[11, 12]

miR-30e

LOX1; NF-κB p65/caspase-9

Slow down apoptosis and the degree of fibrosis of cardiomyocytes

[14]

miR-153-3p

ANGPT1; VEGF/VEGFR2/PI3K/Akt/eNOS

Slow down apoptosis of cardiomyocytes and vascular endothelial cells

[15]

miR-210

AIFM3

Slow down apoptosis

[17, 18]

miR-125b-5p

p53, Bnip3

Inhibit autophagy

[24]

miR-301

p62

Inhibit autophagy

[27]

miR-143-3p

CHK2, p-Beclin 1, LC3; CHK2-Beclin 2

Inhibit autophagy

[26]

miR-29b-3p

VEGF, ADAMTS16

Promote neovascularization

[36]

miR-210-3p

EFNA3

Promote neovascularization

[38]

miR-205

HIF-1α

Promote neovascularization

[39]

miR-25-3p

FASL, PTEN, E2H2

Reduce inflammation

[44]

miR-146-5p

TRAF6

Promote the polarization of M1 macrophages into M2

[52]

miR-182

TLR4

Promote the polarization of M1 macrophages into M2

[51]

miR-205

HIF-1α

Promote neovascularization

[38]

miR-25-3p

FASL, PTEN, E2H2

Reduce inflammation

[43]

BMSCs

miR-146-5p

TRAF6

Promote the polarization of M1 macrophages into M2

[51]

miR-182

TLR4

Promote the polarization of M1 macrophages into M2

[50]

miR-182-5p

GSDMD, caspase-1; TLR4, p65-TLR4/NF-κB

Slow down apoptosis of cardiomyocytes and reduce inflammation

[27, 30, 44]

Plasma

miR-16-5p

p53, caspase-3

Slow down apoptosis of cardiomyocyte

[21]

miR-328-3p

Caspase

Slow down apoptosis of cardiomyocytes

[22]

miR-342-5p

Caspase-9, Jnk2, P-Akt

Slow down apoptosis of cardiomyocytes

[20]

miR-342-3p

SOX6, EBB

Inhibit autophagy

[28]

miR-26b-5p

SLC7A11

Inhibit ferroptosis

[33]

miR-143

IGF-IR

Promote neovascularization

[41]

ADSCs

miR-671

TGFBR2, Smad2

Reduce inflammation

[46]

miR-146a

EGR1; TLR4/NF-κB

Reduce inflammation

[45]

miR-126

MAP and PI3 signal pathway

Reduce inflammation

[48]

miR-196a-5p, miR-425-5p

IFN-γ, activin A

Promote the polarization of M1 macrophages into M2

[52]

Macrophages

miR-1271-5p

SOX6

Slow down apoptosis of cardiomyocytes

[19]

Dendritic cells

miR-494-3p

VEGF

Promote neovascularization

[39]

Cardiac fibroblasts

miR-133a

ELAVL1, NLRP3, caspase-1

Inhibition scorched cell death of cardiomyocytes

[31]

Myocardial cells

miR-21-5p

cdip1, caspase-3

Promote neovascularization

[40]

hucMSCs

miR-100-5p

FOXO3, NLPR3, caspase-1

Inhibit scorched cell death of cardiomyocytes

[32]

miR-23a-3p

DMT1

Inhibit ferroptosis

[34]