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. 2024 Sep 1;10(17):e37019.
doi: 10.1016/j.heliyon.2024.e37019. eCollection 2024 Sep 15.

Astragaloside IV ameliorates pressure overload-induced heart failure by enhancing angiogenesis through HSF1/VEGF pathway

Peizhao Du  1 , Linghao Xu  2   3 , Yuanqi Wang  3 , Tiantian Jiao  3 , Jing Cheng  3 , Chunsheng Zhang  4 , Md Sakibur Rahman Tapu  3 , Jian Dai  1 , Jiming Li  3
Affiliations

Astragaloside IV ameliorates pressure overload-induced heart failure by enhancing angiogenesis through HSF1/VEGF pathway

Peizhao Du et al. Heliyon. .

Abstract

Astragaloside IV(AS-IV), the main active ingredient of Astragalus, has been used as a treatment for heart failure with favorable effects, but its molecular mechanism has not been fully elucidated. Network pharmacological analysis and molecular docking revealed that Heat shock transcription factor 1 (HSF1) is a potential target of AS-IV. We designed cellular and animal experiments to investigate the role and intrinsic molecular mechanisms of AS-IV in ameliorating pressure overload-induced heart failure. In cellular experiments, Myocardial microvascular endothelial cells (MMVECs) were cultured in isolation and stimulated by adding high and low concentrations of AS-IV, and a cell model with down-regulation of HSF1 expression was constructed by using siRNA technology. Changes in the expression of key molecules of HSF1/VEGF signaling pathway and differences in tube-forming ability were detected in different groups of cells using PCR, WB and tube-forming assay. In animal experiments, TAC technology was applied to establish a pressure overload-induced heart failure model in C57 mice, postoperative mice were ingested AS-IV by gavage, and adenoviral transfection technology was applied to construct a mouse model with down-regulation of HSF1 expression.Small animal ultrasound for cardiac function assessment, MASSON staining, CD31 immunohistochemistry, and Western blotting (WB) were performed on the mice. The results showed that AS-IV could promote the expression of key molecules of HSF1/VEGF signaling pathway, enhance the tube-forming ability of MMVECs, increase the density of myocardial capillaries, reduce myocardial fibrosis, and improve the cardiac function of mice with TAC.AS-IV could modulate the HSF1/VEGF signaling pathway to promote the angiogenesis and improve the pressure overload-induced heart failure.

Keywords: Angiogenesis; Astragaloside IV; Heart failure; Heat shock transcription factor 1; Vascular endothelial growth factor.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Network pharmacologic analysis for AS-IV (A)2D structure of AS-IV (B)Common targets of AS-IV and heart failure (C)GO enrichment analysis(p < 0.05) (D) KEGG pathway analysis(p < 0.05) (E) Heatmap representation of enriched terms through Metascape with coloration based on p-values (p < 0.05) (F) Network visualization of enriched clusters based on identity through Metascape. (p < 0.05) (G) Differentially Expressed Genes (DEGs) enriched clusters arranged by significance via Metascape (p < 0.05).
Fig. 2
Fig. 2
Molecular docking for AS-IV and HSF1 (A) Representative images of autodocking for AS-IV and HSF1 (B)Hydrophilicity and hydrophobicity of surface of the protein–ligand complex (C) Interaction maps of the protein–ligand complex (D) Hydrogen bonds in binding site.
Fig. 3
Fig. 3
AS-IV promotes angiogenesis of MMVECs through the HSF1/VEGF pathway (A) MMVECs (200 × ) (B) RT-PCR detection for HSF1 mRNA expression levels of MMVECs in each group (C)WB detection for HSF1, HSP70, HIF-1α, and VEGF expression levels of MMVECs in each group (D) Tube formation assay to test the tube-forming ability of MMVECs in each group and analysis of the results (200 × ) (n = 3.*p < 0.05 vs NC, **p < 0.01 vs NC, #p < 0.05 vs AS-IV LD, ##p < 0.01 vs AS-IV LD, + p < 0.05 vs AS-IV HD, ++ p < 0.01 vs AS-IV HD).
Fig. 4
Fig. 4
Protective effects of AS-IV in pressure-overloaded mice (A)Ultrasonographic examination of the mice's hearts in each group and analysis of the results (B)Gross observation of the mice's hearts in each group and analysis of the results of heart weight ratio detection (C) MASSON-stained sections and analysis of the degree of myocardial fibrosis of mice's hearts in each group (D) Immunohistochemical staining of CD31 and analysis of myocardial capillary density in mice's hearts in each group (n = 4 in TAC group and n = 5 in other group.*p < 0.05 vs SHAM, **p < 0.01vsSHAM, #p < 0.05 vs TAC, ##p < 0.01 vs TAC, + p < 0.05 vs TAC + AS-IV, ++ p < 0.01 vs TAC + AS-IV).
Fig. 5
Fig. 5
Results of WB assays for HSF1, HSP70, HIF-1α, and VEGF of mice's myocardium in each group (n = 4 in TAC group and n = 5 in other group.*p < 0.05 vs SHAM, **p < 0.01vsSHAM, #p < 0.05 vs TAC, ##p < 0.01 vs TAC, + p < 0.05 vs TAC + AS-IV, ++ p < 0.01 vs TAC + AS-IV).
Fig. 6
Fig. 6
AS-IV ameliorates pressure overload-induced heart failure by enhancing angiogenesis through HSF1/VEGF pathway (Draw by figdraw, ID: OPWUS242a8).
figs1
figs1
WB detection for HSF1, HSP70, HIF-1α, and VEGF expression levels of MMVECs in NC and HSF1 siRNA group.
figs2
figs2
WB detection and RT-PCR analysis for HSF1 expression levels of mice in NC and HSF1 Ad group.
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