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. 2022 Sep 16:16:3145-3168.
doi: 10.2147/DDDT.S372143. eCollection 2022.

Guanmaitong Granule Attenuates Atherosclerosis by Inhibiting Inflammatory Immune Response in ApoE-/- Mice Fed High-Fat Diet

Mengqi Yang  1 , Huachen Jiao  2 , Yan Li  2 , Lei Zhang  1 , Juan Zhang  2 , Xia Zhong  1 , Yitao Xue  2
Affiliations

Guanmaitong Granule Attenuates Atherosclerosis by Inhibiting Inflammatory Immune Response in ApoE-/- Mice Fed High-Fat Diet

Mengqi Yang et al. Drug Des Devel Ther. .

Abstract

Background: Atherosclerosis (AS) is the leading cause of cardiovascular diseases, such as myocardial infarction and stroke. Guanmaitong granule (GMTG) is a TCM (Traditional Chinese medicine) prescribed to treat AS. However, its mechanism remains unclear.

Methods: We obtained reliable ingredients and targets of GMTG using the HERB database. AS-related targets were obtained from HERB and GeneCards databases. The target database was constructed by intersecting the ingredients of GMTG with the AS-related targets. STRING and Cytoscape were used to create protein-protein interaction (PPI) network and screen core targets. GO enrichment analysis and KEGG pathway analyses were performed using R. Finally, the ApoE-/- mice AS model was induced by a high-fat diet (HFD) for in vivo validation of core pathways and targets.

Results: A total of 124 ingredients and 418 potential targets of GMTG for treating AS were obtained. Numerous ingredients and targets were related to Panax notoginseng, Salvia miltiorrhiza, and Astragalus. Most core targets and pathways were involved in the inflammatory immune response. GMTG could decrease serum triglycerides, total cholesterol, low-density lipoprotein-cholesterol, and oxidized low-density lipoprotein level and increase the serum high-density lipoprotein-cholesterol level. Furthermore, GMTG reduced the plaque burden and promoted plaque remodeling by reducing plaque area, lipid deposition, foam cell content, and collagen fiber content in the plaque in the aortic root of ApoE-/- mice. GMTG inhibited systemic and plaque inflammatory immune response and increased plaque stability by inhibiting the excessive release of the TLR4/MyD88/NF-κB pathway-induced inflammatory cytokines, tumor necrosis factor, interleukin-6, and interleukin-1 beta.

Conclusion: Radix notoginseng, Radix salviae liguliobae, and Radix astragali are the main ingredients of GMTG for treating AS. Further, GMTG could regulate the level of serum lipids and inhibit inflammatory immune response, which resulted in anti-AS effects such as plaque stabilization, reduction of plaque burden, and plaque remodeling. GMTG is a promising multi-target treatment for AS.

Keywords: Guanmaitong granule; atherosclerosis; inflammatory immune response; plaque burden; plaque remodeling.

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Conflict of interest statement

The authors declare that there are no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Flow Chart.
Figure 2
Figure 2
TCM Herb-Ingredient network of GMTG for AS treatment. The red node represents the main TCM herbs of GMTG. The blue node represents the unique ingredient of each TCM herb. The gray edge represents the interaction between TCM herbs and ingredients.
Figure 3
Figure 3
The PPI network of targets in GMTG for AS treatment. The node represents the potential target of AS treatment. The darker node has a higher degree value. The edge represents the interaction between target.
Figure 4
Figure 4
Network of core ingredients and core targets. (A) The node represents the TCM herb and target, the darker node has a higher degree. The edge represents the interaction between target, the darker edge has a closer betweenness. (B) The node represents target, the darker node has a higher degree.
Figure 5
Figure 5
GO Enrichment Analysis. (A) Biological Process, (B) Cellular Component, (C) Molecular Function, (D) Results of three Ontologies.
Figure 6
Figure 6
KEGG pathway Enrichment Analysis. The red node represents target, the yellow node represents pathway, the line represents the relationship between pathway and target.
Figure 7
Figure 7
(A) Oil red staining of thoracic aorta, (B) HE staining. The black arrow represents plaque, the red arrow represents cholesterol crystals, the green arrow represents lymphocyte infiltration.
Figure 8
Figure 8
GMTG treatment reduced levels of serum lipid. (A) TG, (B) TG, (C) HDL-C, (D) LDL-C, (E) ox-LDL. Data are presented as mean ± SD (n = 3). **P<0.01, ****P<0.0001, vs NC group; #P<0.05, ##P<0.01, ####P<0.0001, ns means no statistical significance, vs MOD group.
Figure 9
Figure 9
GMTG treatment alleviates levels of serum inflammatory cytokines. (A) TNF-α, (B) IL-6, (C) IL-1B. Data are presented as mean ± SD (n = 3). **P<0.01, ****P<0.0001, vs NC group; #P<0.05, ##P<0.01, ###P<0.001, vs MOD group.
Figure 10
Figure 10
GMTG treatment alleviates atherosclerotic plaque lesions and pathological damage in ApoE−/− Mice. (A) Oil red staining of the thoracic aorta, (B) HE staining, (C) Oil red staining of the aortic root, (D) Area of atherosclerosis plaque, (E) Proportion of lipid, (F) Movat staining, nucleus and elastic fibers were black, proteoglycans were blue, collagen fibers were red, muscle fibers were pink, and foam cells were pale purple. (G) Proportion of collagen fibers, (H) Proportion of foam cells. Data are presented as mean ± SD (n = 3). *P<0.05, **P<0.01, ns means no statistical significances MOD group.
Figure 11
Figure 11
GMTG treatment regulates mRNA expressions of TLR4, MyD88, NF-κB in ApoE−/− Mice. (A) The relative mRNA expression of TLR4, (B) MyD88, (C) and NF-κB of the RT-qPCR results. Data are presented as mean ± SD (n = 3). **P<0.01, ****P<0.0001, vs NC group; ####P<0.0001, vs MOD group.
Figure 12
Figure 12
GMTG treatment regulates protein expressions of TLR4, MyD88, and NF-κB in ApoE−/− mice. (A) The positive area of TLR4, (B) MyD88, (C) and NF-κB of IHC results. Data are presented as mean ± SD (n = 3). **P<0.01, ****P<0.0001, vs NC group; ##P<0.01, ####P<0.0001, vs MOD group.
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