Cardioprotective mechanism of Qixuan Yijianing (芪玄抑甲宁) formula in Graves’ disease mice using miRNA sequencing approach

doi:10.19852/j.cnki.jtcm.20240927.005

Abstract

Abstract:

OBJECTIVE: To investigate the mechanism of Qixuan Yijianing (芪玄抑甲宁,QYN) in minimizing cardiac injury in Graves′ disease (GD) mice using microRNA (miRNA) sequencing analysis.

METHODS: Female BALB/c mice were randomly divided into the modeling and control groups (CG). The modeling group was established with Ad-TSHR289. Following 10 weeks of successful modeling, the mice were randomly assigned to four groups: model (MG), methimazole (MMI), QYN low-dose (LD), and high-dose (HD). After four weeks of treatment, the heart rate, heart volume, and heart index were measured, and the levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), α-hydroxybutyrate dehydrogenase (α-HBD), creatine kinase (CK), and creatine kinase MB isoenzyme (CK-MB) in the serum were detected using a biochemical analyzer. Hematoxylin-eosin and Masson staining were used to determine histological changes in cardiac tissue. The heart tissues in the CG, MG, and HD groups were selected, and miRNA sequencing was used to identify differentially expressed miRNAs. A bioinformatics database was used to predict the target genes of differential miRNAs, and Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted on the predicted target genes.

RESULTS: As compared to the CG group, the MG group's heart rate, heart volume, heart index, AST, CK, CK-MB, LDH, α-HBD, myocardial fiber thickness, and collagen fiber significantly increased, all P < 0.01, while following QYN, these indicators improved in the HD group, all P < 0.01 or P < 0.05. Compared to the CG group, the MG group identified 151 differentially expressed miRNAs, with 42 miRNAs downregulated and 109 miRNAs upregulated; compared to the MG group, the HD group identified 70 differentially expressed miRNAs, 40 were downregulated, and 30 were upregulated. The GO functions of differential miRNA target genes are mostly enriched in cardiac development regulation, cardiac contraction control, heart rate regulation, and so on. The most enriched KEGG pathways include the mitogen-activated protein kinase, ErbB, Hippo, forkhead box protein O, and Wnt signaling pathways.

CONCLUSION: QYN may protect the cardiac structure and function and minimize cardiac damage caused by GD by regulating relevant target genes and signaling pathways through miRNAs which include miR-206-3p, miR-122-5p, and miR-200a-3p.

Key words: Graves' disease, heart, microRNAs, sequence Analysis, RNA, bioinformatics analysis, Qixuan Yijianing

GAO Changjiu, DING Song, Shadi A.D. Mohammed, LU Fang, LIU Changfeng, TENG Zhan, XU Peng, LIU Shumin. Cardioprotective mechanism of Qixuan Yijianing (芪玄抑甲宁) formula in Graves’ disease mice using miRNA sequencing approach[J]. Journal of Traditional Chinese Medicine, 2024, 44(6): 1127-1136.

Figures/Tables 5

Table 1 Effect of QYN on myocardial enzymes in GD mice (U/L, $\bar{x}±s$)

Group	n	AST	CK	CK-MB	LDH	α-HBD
CG	8	272±50	902±139	346±66	733±135	231±58
MG	8	426±68^a	1315±174^a	577±115^a	1036±196^a	390±82^a
MMI	8	357±53	1099±81^b	443±54^b	888±106	336±31
LD	8	336±63^b	1060±135^c	436±79^b	810±104^b	296±68
HD	8	322±74^b	999±172^c	423±89^c	768±146^c	271±79^c

Table 2 Effects of QYN on heart rate, heart volume, and heart index in GD mice ($\bar{x}±s$)

Group	n	Heart rate (times/min)	Width of heart (mm)	Length of heart (mm)	HW/BW (mg/g)
CG	8	334.10±35.94	5.21±0.05	7.83±0.27	4.10±0.25
MG	8	436.90±18.25^a	5.82±0.18^a	8.26±0.26	4.89±0.40^a
MMI	8	383.10±26.24^b	5.66±0.16	8.16±0.24	4.53±0.42
LD	8	381.40±26.53^b	5.53±0.15^b	8.03±0.59	4.33±0.19^c
HD	8	366.30±45.50^c	5.46±0.24^c	7.90±0.30	4.23±0.19^c

Figure 1 Effect of QYN on the morphology of heart tissue in GD mice A: HE staining (hematoxylin-eosin staining), the cross-section of the heart, the cytoplasm is pink, and the nucleus is blue (magnification at × 400; scale bar, 50 μm). A1: CG group; A2: MG group; A3: MMI group; A4: LD group; A5: HD group. B: Masson staining (masson's trichrome stain), heart cross-section, myocardial fibers are red, collagen fibers are blue (magnification at ×400; scale bar, 50 μm). B1: CG group; B2: MG group; B3: MMI group; B4: LD group; B5: HD group; B6: relative proportion of collagen fibers in the hearts of each group (%). For four weeks, the LD and HD groups gavaged Qixuan Yijianing 25, 50 g crude drug·kg-1·d-1, the MMI group gavaged methimazole 3.75 mg·kg-1·d-1, whereas the CG and MG groups gavaged with drinking water 20 mL·kg-1·d-1. CG: control group; MG: model group; MMI: methimazole group; LD: low-dose group; HD: high-dose group. The results are expressed as mean ± standard deviation (n = 3), and the groups were compared using a one-way analysis of variance. P < 0.05 was considered statistically significant. aP < 0.01, vs CG; bP < 0.01, vs MG.

Figure 2 Differential expression of miRNAs and qRT-PCR verification of 5 differentially expressed miRNAs in mice heart tissues A: volcano plot of miRNAs expression between MG and CG; B: compared volcano plot of miRNAs expression in HD and MG; C: histogram of 4 miRNAs differential expression compared between MG and CG; D: histogram of 4 miRNAs differential expression compared between HD and MG (n = 3). For four weeks, the HD groups gavaged Qixuan Yijianing 50 g crude drug·kg-1·d-1, whereas the CG and MG groups gavaged with drinking water 20 mL·kg-1·d-1. miRNA-seq: MicroRNA high-throughput sequencing; qRT-PCR: quantitative real time polymerase chain reaction; CG: control group; MG: model group; HD: high-dose group.

Table 3 intersection miRNA information

miRNA	MG vs CG			HD vs MG
miRNA	P value	log₂FC	Regulated	P value	log₂FC	Regulated
miR-363-3p	0.006660144	2.258448719	up	0.037466332	－0.841642561	down
miR-429-3p	1.63E-05	2.109724791	up	0.002446823	－0.841642561	down
miR-200a-3p	3.62E-24	1.896191583	up	2.02E-11	－1.554896308	down
miR-200b-3p	3.43E-19	1.486466421	up	1.27E-17	－1.615349235	down
miR-122-5p	2.31E-13	1.45085124	up	5.07E-07	－1.136406845	down
miR-499-5p	8.20E-12	0.679754512	up	7.98E-05	0.611763185	up
miR-431-5p	0.045290097	0.614905119	up	0.002417773	－0.841642561	down
miR-741-3p	0.003712164	-1.05012219	down	0.031779657	0.829569488	up
miR-206-3p	5.17E-05	-1.548248689	down	0.006381657	0.80599753	up

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