外泌体miRNA差异表达可作为诊断慢性心力衰竭合并高尿酸血症患者新型分子标志物及靶基因功能分析

doi:10.12122/j.issn.1673-4254.2025.01.06

南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (1): 43-51.doi: 10.12122/j.issn.1673-4254.2025.01.06

外泌体miRNA差异表达可作为诊断慢性心力衰竭合并高尿酸血症患者新型分子标志物及靶基因功能分析

陈志亮¹(), 杨永刚², 黄霞¹, 成彦³, 瞿媛⁴, 衡琪琪⁵, 符羽佳⁵, 李可薇⁵, 顾宁¹()

^1.南京中医药大学附属南京中医院，心血管病科，江苏南京 210022
^2.南京中医药大学附属南京中医院，检验科，江苏南京 210022
^3.南京中医药大学附属南京中医院，药学部，江苏南京 210022
^4.南京中医药大学附属南京中医院，急诊科，江苏南京 210022
^5.南京中医药大学，江苏南京 210023

收稿日期:2024-03-23 出版日期:2025-01-20 发布日期:2025-01-20
通讯作者: 顾宁 E-mail:czhilt@126.com;guning@njucm.edu.cn
作者简介:陈志亮，博士，副主任中医师，E-mail: czhilt@126.com
基金资助:
南京市中医药青年人才培养计划(ZYQ20027);南京市中医药科技专项项目(ZYQN202203);南京中医药大学自然科学基金项目(XZR2021052);南京市医疗机构中药传统制剂研究项目(NJCC-ZJ-202315);第六批南京市老中医药专家学术经验继承项目(宁卫中医[2024]6号)

Differential expressions of exosomal miRNAs in patients with chronic heart failure and hyperuricemia: diagnostic values of miR-27a-5p and miR-139-3p

Zhiliang CHEN¹(), Yonggang YANG², Xia HUANG¹, Yan CHENG³, Yuan QU⁴, Qiqi HENG⁵, Yujia FU⁵, Kewei LI⁵, Ning GU¹()

^1.Department of Cardiology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, China
^2.Clinical Laboratory, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, China
^3.Department of Pharmacy, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, China
^4.Department of Emergency Medicine, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, China
^5.Nanjing University of Chinese Medicine, Nanjing 210023, China

Received:2024-03-23 Online:2025-01-20 Published:2025-01-20
Contact: Ning GU E-mail:czhilt@126.com;guning@njucm.edu.cn

摘要/Abstract

摘要：

目的分析慢性心力衰竭（CHF）合并高尿酸血症（HUA）患者血清外泌体miRNA的差异表达，探讨其作为CHF合并HUA新型诊断分子标志物的可能性，并对差异miRNA进行靶基因功能分析，分析作用靶点。方法以2020年9月~2023年9月南京中医药大学附属南京中医院心血管病科收治的CHF合并HUA患者为观察组（n=30），选择同期健康志愿者为对照组（n=30）。两组各选取6例样本，采用高通量测序分析血清外泌体中的差异表达miRNA，采用RT-PCR检测对未作高通量测序的观察组和对照组样本（n=24）进行验证，使用R软件进行GO、KEGG富集分析，预测差异表达miRNA的作用靶点，并通过动物实验验证临床筛查的差异miRNA。结果高通量测序分析显示，观察组患者共检测到42个差异表达的miRNA（18个上调，24个下调），其中miR-27a-5p上调（P<0.001），miR-139-3p下调（P<0.001）。RT-PCR检测显示，观察组患者血清外泌体中miR-27a-5p表达量上调（P=0.004）、miR-139-3p表达量下调（P=0.005）；ROC曲线下面积（AUC）分析发现，miR-27a-5p、miR-139-3p预测CHF合并HUA发病的AUC分别是0.708（95% CI：0.562-0.855）和0.734（95% CI：0.593-0.876），两者联合预测CHF与HUA发病的AUC为0.899（95% CI：0.812-0.987）。对差异基因进行GO富集分析发现，细胞自噬是富集程度最高的靶点；KEGG功能注释显示，激活AMPK-mTOR信号通路可能是差异表达的miR-27a-5p和miR-139-3p作用靶点之一。进一步动物实验得到了相同的验证。结论血清外泌体中miR-27a-5p上调和miR-139-3p下调可作为精准诊断CHF合并HUA的新型分子标志物，激活AMPK-mTOR信号通路后促进心肌细胞的自噬反应可能是差异表达的miR-27a-5p、miR-139-3p的作用靶点之一。

关键词: 慢性心力衰竭, 高尿酸血症, 外泌体, 微小RNA, AMPK, mTOR, 自噬

Abstract:

Objective To analyze the differentially expressed exosomal miRNAs in patients with chronic heart failure (CHF) complicated by hyperuricemia (HUA) and explore their potential as novel diagnostic molecular markers and their target genes. Methods This study was conducted among 30 CHF patients with HUA (observation group) and 30 healthy volunteers (control group) enrolled between September, 2020 and September, 2023. Peripheral blood samples were collected from 6 CHF patients with HUA for analyzing exosomal miRNAs by high-throughput sequencing, and the results were validated in the remaining 24 patients using qRT-PCR. GO and KEGG enrichment analyses were performed to predict the the target genes of the identified differential miRNAs. We also validated the differentially expressed miRNAs by animal experiment. Results A total of 42 differentially expressed exosomal miRNAs were detected in observation group by high-throughput sequencing; among them, miR-27a-5p was significantly upregulated (P=0.000179), and miR-139-3p was significantly downregulated (P=0.000058). In the 24 patients with both CHF and PUA, qRT-PCR validated significant upregulation of miR-27a-5p (P=0.004) and downregulation of miR-139-3p (P=0.005) in serum exosomes. When combined, miR-27a-5p and miR-139-3p had a maximum area under the curve (AUC) of 0.899 (95% CI: 0812-0.987) for predicting CHF complicated by HUA. GO and KEGG enrichment analyses suggested that the differential expressions of miR-27a-5p and miR-139-3p was associated with the activation of the AMPK-mTOR signaling pathway to activate the autophagic response. We obtained the same conclusion from animal experiment. Conclusion Upregulated exosomal miR-27a-5p combined with downregulated exosomal miR-139-3p expression can serve as a novel molecular marker for diagnosis of CHF complicated by HUA, and their differential expression may promote autophagy in cardiomyocytes by activating the AMPK-mTOR signaling pathway.

Key words: chronic heart failure, hyperuricemia, exosomes, microRNAs, AMP-activated protein kinases, TOR serine-threonine kinases, autophagy

陈志亮, 杨永刚, 黄霞, 成彦, 瞿媛, 衡琪琪, 符羽佳, 李可薇, 顾宁. 外泌体miRNA差异表达可作为诊断慢性心力衰竭合并高尿酸血症患者新型分子标志物及靶基因功能分析[J]. 南方医科大学学报, 2025, 45(1): 43-51.

Zhiliang CHEN, Yonggang YANG, Xia HUANG, Yan CHENG, Yuan QU, Qiqi HENG, Yujia FU, Kewei LI, Ning GU. Differential expressions of exosomal miRNAs in patients with chronic heart failure and hyperuricemia: diagnostic values of miR-27a-5p and miR-139-3p[J]. Journal of Southern Medical University, 2025, 45(1): 43-51.

图/表 13

表1 引物信息

Tab.1 Primer sequences for qRT-PCR for miR-27a-5p, miR-139-3p and U6

Target genes	Primer	Sequences	Annealing temp (℃)	Product size (bp)	Notes
hsa-miR-27a-5p	hsa-miR-27a-5p-RT	GTCGTATCCAGTGCAGGGTCCGAGGTATTCGCACTGGATACGACTGCTCA	-	66	Stem ring primers
	hsa-miR-27a-5p F	CCAGCGTGAGGGCTTAGC	60		Forward primers
	microRNA_uniRev	CAGTGCAGGGTCCGAGGTAT	60		Reverse primers
hsa-miR-139-3p	hsa-miR-139-3p-RT	GTCGTATCCAGTGCAGGGTCCGAGGTATTCGCACTGGATACGACACTCCA	-	67	Stem ring primers
	hsa-miR-139-3p F	CCAGCGTGTGGAGACGC	60		Forward primers
	microRNA_uniRev	CAGTGCAGGGTCCGAGGTAT	60		Reverse primers
hsa-U6	hsa-U6 snRNA For	CTCGCTTCGGCAGCACATA	60	85	Forward primers
hsa-U6	hsa-U6 snRNA Rev	CGAATTTGCGTGTCATCCT	60	85	Reverse primers

表2 CHF合并HUA患者与健康志愿者一般资料比较

Tab.2 Baseline characteristics of patients with chronic heart failure (CHF) complicated by hyperuricemia (HUA) and healthy volunteers (Mean±SD, n=30)

Characteristic	Observation group	Control group	P
Gender (%)			0.417
Male	60	70
Female	40	30
Age (year)	67.03±18.10	63.07±13.08	0.335
SUA (μmol/L)	528.36±83.48	314.74±58.76	<0.001
LVEF (%)	38.81±9.43	65.30±2.28	<0.001
ALT (U/L)	30.80±23.04	25.73±13.66	0.305
AST (U/L)	28.20±16.53	21.20±9.95	0.051
SCr (μmol/L)	96.10±22.06	65.80±13.67	<0.001
BUN (mmol/L)	7.19±1.79	5.27±1.30	<0.001
TC (mmol/L)	4.44±1.20	4.94±0.90	0.067

图1 差异miRNA火山图

Fig.1 Volcano plots of the differentially expressed exosomal miRNAs in CHF patients with HUA. Red and green dots represent the genes with significant differential expression, and gray dots represent the genes without substantial differential expression. Upregulated miRNAs are labeled in red, and downregulated ones are marked in green.

表3 CHF合并HUA患者部分表达上调的差异miRNA

Tab.3 Partial upregulated exosomal miRNAs in CHF patients with HUA versus healthy volunteers

Upregulated miRNAs	BaseMean	Log FC	P
MiR-27a-5p	4.740923	5.8306	0.000179
MiR-193b-3p	64.58635	2.2848	0.000523
MiR-210-5p	4.917714	5.8752	0.000554
MiR-508-5p	4.249289	1.9014	0.002869

表4 CHF合并HUA患者部分表达下调的差异miRNA

Tab.4 Partial downregulated exosomal miRNAs in CHF patients with HUA versus healthy volunteers

Downregulated miRNAs	BaseMean	Log FC	P
MiR-139-3p	81.70276	-2.1076	<0.001
MiR-4446-3p	17.05699	-3.4115	<0.001
MiR-654-3p	104.6556	-2.3092	<0.001
MiR-150-3p	20.40789	-2.1551	<0.01

图2 血清外泌体miR-27a-5p(A)及miR-139-3p(B)表达情况

Fig.2 Relative levels of exosomal miR-27a-5p (A) and miR-139-3p (B) in CHF patients with HUA (group T) and healthy volunteers (group C). **P<0.01.

图3 miRanda、RNAhybridl软件预测miR-27a-5p (A)和miR-139-3p (B)靶基因的韦恩图

Fig.3 Venn diagram of the target genes of miR-27a-5p (A) and miR-139-3p (B) predicted by miRanda and RNAhybridl software.

表5 筛选出的部分靶基因

Tab.5 Partial upregulated and downregulated exosomal miRNAs in CHF patients with HUA versus healthy volunteers

miRNAs	Target gene
MiR-27a-5p	ENST00000466134
	ENST00000474114
	ENST00000262319
	ENST00000415452
	ENST00000395748
	ENST00000502307
	ENST00000511560
MiR-139-3p	ENST00000649865
	ENST00000531373
	ENST00000650285
	ENST00000261405
	ENST00000262719
	ENST00000358784
	ENST00000480614

表6 血清外泌体miR-27a-5p、miR-139-3p 诊断CHF合并HUA的效能分析

Tab.6 Diagnostic performance of exosomal miR-27a-5p, exosomal miR-139-3p, and their combination for detection of CHF combined with HUA

Diagnostic performance	miR-27a-5p	miR-139-3p	Combination detection
AUC (95% CI)	0.708 (0.562-0.855)	0.734 (0.593-0.876)	0.899 (0.812-0.987)
P	0.013	0.005	0.000
Cut-off value	0.652	1.603	0.483
Sensitivity (%)	91.7	83.3	79.2
Specificity (%)	41.7	58.3	91.7
J value	0.334	0.416	0.709

图4 miR-27a-5p、miR-139-3p预测CHF合并HUA的ROC曲线

Fig.4 ROC curves of the diagnostic potentials of exosomal miR-27a-5p and exosomal miR-139-3p for CHF combined with HUA.

图5 差异表达miRNA GO(A)和KEGG(B)富集分析气泡图

Fig.5 GO (A) and KEGG enrichment analyses (B) of the target genes of exosomal miR-27a-5p and exosomal miR-139-3p.

图6 大鼠干预后miR-27a-5p(A)及miR-139-3p(B)相对表达量比较

Fig.6 Comparison of relative expression of miR-27a-5p (A) and miR-139-3p (B) in 4 groups of rats after intervention. *P<0.05, **P<0.01.

图7 大鼠心肌组织中p-AMPK和p-mTOR蛋白水平表达

Fig.7 Expression of p-AMPK and p-mTOR proteins in rat myocardial tissue in the 4 groups. **P<0.01 vs Control; ##P<0.01 vs Model; △P<0.05 vs HSJZF, △△P<0.01 vs HSJZF.

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外泌体miRNA差异表达可作为诊断慢性心力衰竭合并高尿酸血症患者新型分子标志物及靶基因功能分析

Differential expressions of exosomal miRNAs in patients with chronic heart failure and hyperuricemia: diagnostic values of miR-27a-5p and miR-139-3p

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