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. 2021 Dec 24:8:726694.
doi: 10.3389/fcvm.2021.726694. eCollection 2021.

Integrated Pharmacogenetics Analysis of the Three Fangjis Decoctions for Treating Arrhythmias Based on Molecular Network Patterns

Penglu Wei  1 , Dehuai Long  1 , Yupei Tan  2 , Wenlong Xing  1 , Xiang Li  1 , Kuo Yang  3 , Hongxu Liu  1
Affiliations

Integrated Pharmacogenetics Analysis of the Three Fangjis Decoctions for Treating Arrhythmias Based on Molecular Network Patterns

Penglu Wei et al. Front Cardiovasc Med. .

Abstract

Aim: To explore the diverse target distribution and variable mechanisms of different fangjis prescriptions when treating arrhythmias based on the systems pharmacology. Methods: The active ingredients and their corresponding targets were acquired from the three fangjis [Zhigancao Tang (ZT), Guizhigancao Longgumuli Tang (GLT), and Huanglian E'jiao Tang (HET)] and the arrhythmia-related genes were identified based on comprehensive database screening. Networks were constructed between the fangjis and arrhythmia and used to define arrhythmia modules. Common and differential gene targets were identified within the arrhythmia network modules and the cover rate (CR) matrix was applied to compare the contributions of the fangjis to the network and modules. Comparative pharmacogenetics analyses were then conducted to define the arrhythmia-related signaling pathways regulated by the fangjis prescriptions. Finally, the divergence and convergence points of the arrhythmia pathways were deciphered based on databases and the published literature. Results: A total of 187, 105, and 68 active ingredients and 1,139, 1,195, and 811 corresponding gene targets of the three fangjis were obtained and 102 arrhythmia-related genes were acquired. An arrhythmia network was constructed and subdivided into 4 modules. For the target distribution analysis, 65.4% of genes were regulated by the three fangjis within the arrhythmia network. ZT and GLT were more similar to each other, mainly regulated by module two, whereas HET was divided among all the modules. From the perspective of signal transduction, calcium-related pathways [calcium, cyclic guanosine 3',5'-monophosphate (cGMP)-PKG, and cyclic adenosine 3',5'-monophosphate (cAMP)] and endocrine system-related pathways (oxytocin signaling pathway and renin secretion pathways) were associated with all the three fangjis prescriptions. Nevertheless, heterogeneity existed between the biological processes and pathway distribution among the three prescriptions. GLT and HET were particularly inclined toward the conditions involving abnormal hormone secretion, whereas ZT tended toward renin-angiotensin-aldosterone system (RAAS) disorders. However, calcium signaling-related pathways prominently feature in the pharmacological activities of the decoctions. Experimental validation indicated that ZT, GLT, and HET significantly shortened the duration of ventricular arrhythmia (VA) and downregulated the expression of CALM2 and interleukin-6 (IL-6) messenger RNAs (mRNAs); GLT and HET downregulated the expression of CALM1 and NOS3 mRNAs; HET downregulated the expression of CRP mRNA. Conclusion: Comparing the various distributions of the three fangjis, pathways provide evidence with respect to precise applications toward individualized arrhythmia treatments.

Keywords: arrhythmias; fangjis; network pharmacology; precision medicine; target distribution.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict ofinterest.

Figures

Figure 1
Figure 1
The related targets of the three fangjis and arrhythmia. (A) The overlapping targets among the three fangjis and arrhythmia; (B) The overlapping targets among the three fangjis and the network of arrhythmia.
Figure 2
Figure 2
The distribution of the three fangjis in arrhythmia network. (A–C) marked with red, green, and yellow nodes that represent the targets of Zhigancao Tang (ZT), Guizhigancao Longgumuli Tang (GLT), and Huanglian E'jiao Tang (HET), respectively; (D) The overlapping and unique targets in the arrhythmia network.
Figure 3
Figure 3
The distribution of three fangjis in arrhythmia modules. (A) The module division of arrhythmia network; (B,C) The coverage rate of three fangjis in arrhythmia network and modules.
Figure 4
Figure 4
The Gene Ontology (GO) biological processes of ZT, GLT, and HET.
Figure 5
Figure 5
The pathways of ZT, GLT, and HET with its targets and the relationship.
Figure 6
Figure 6
Representative ECGs of the control and vehicle groups. (A) ECG of the control group; (B–D) ECG of ventricular arrhythmia (VA).
Figure 7
Figure 7
Representative ECGs of the different groups and the effect of the fangjis on ECG. (A) ECG of the control group; (B) ECG of the vehicle group; (C) ECG of the ZT group; (D) ECG of the GLT group; (E) ECG of the HET group; (F) Occurrence time of VA in rats with calcium chloride-induced VA; (G) Duration time of VA in rats with calcium chloride-induced VA.**p < 0.01.
Figure 8
Figure 8
Experimental validation by real-time RT-PCR. *P < 0.05 (A) mRNA expression of CALM1; (B) mRNA expression of CALM2; (C) mRNA expression of CALM3; (D) mRNA expression of CRP; (E) mRNA expression of IL-6; (F) mRNA expression of NOS3.
Figure 9
Figure 9
Schematic depiction target pathways identified in the three fangjis.
Figure 10
Figure 10
Calcium signaling pathway [the Kyoto Encyclipedia of Genes and Genomes (KEGG) database].
See this image and copyright information in PMC

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