Abstract
Shexiang Baoxin Pill (SBP) is an oral formulation of Chinese materia medica for the treatment of angina pectoris. It displays pleiotropic roles in protecting the cardiovascular system. However, the mode of action of SBP in promoting angiogenesis, and in particular the synergy between its constituents is currently not fully understood. The combination of ginsenosides Rb2 and Rg3 were studied in human umbilical vein endothelial cells (HUVECs) for their proangiogenic effects. To understand the mode of action of the combination in more mechanistic detail, RNA-Seq analysis was conducted, and differentially expressed genes (DEGs), pathway analysis and Weighted Gene Correlation Network Analysis (WGCNA) were applied to further identify important genes that a play pivotal role in the combination treatment. The effects of pathway-specific inhibitors were observed to provide further support for the hypothesized mode of action of the combination. Ginsenosides Rb2 and Rg3 synergistically promoted HUVEC proliferation and tube formation under defined culture conditions. Also, the combination of Rb2/Rg3 rescued cells from homocysteine-induced damage. mRNA expression of CXCL8, CYR61, FGF16 and FGFRL1 was significantly elevated by the Rb2/Rg3 treatment, and representative signaling pathways induced by these genes were found. The increase of protein levels of phosphorylated-Akt and ERK42/44 by the Rb2/Rg3 combination supports the notion that it promotes endothelial cell proliferation via the PI3K/Akt and MAPK/ERK signaling pathways. The present study provides the hypothesis that SBP, via ginsenosides Rb2 and Rg3, involves the CXCR1/2 CXCL8 (IL8)-mediated PI3K/Akt and MAPK/ERK signaling pathways in achieving its proangiogenic effects.
Highlights
Shexiang Baoxin Pill (SBP) is a traditional Chinese medicine (TCM) formulation taken orally to treat coronary heart disease (CHD) such as chronic stable angina (Lu et al, 2018)
A Bliss (Bliss, 1939) synergy score of 39.48 was obtained in combination-treated cells (Figure 1) which strongly supported that ginsenoside Rb2 and ginsenoside Rg3 synergistically promote endothelial cell proliferation
A Bliss synergy score above 0 indicates synergism throughout the pairwise concentrations tested, 39.48 provides strong support to suggest that ginsenoside Rb2 and ginsenoside Rg3 can be a good combination in terms of promoting endothelial cell proliferation
Summary
Shexiang Baoxin Pill (SBP) is a traditional Chinese medicine (TCM) formulation taken orally to treat coronary heart disease (CHD) such as chronic stable angina (Lu et al, 2018). Emerging pharmacological studies have revealed that SBP displays pleiotropic roles in protecting the cardiovascular system, as seen by the promotion of angiogenesis, amelioration of inflammation, improvement of endothelium dysfunction, mitigation of dyslipidemia, repression of vascular smooth muscle cell proliferation, and migration and restraint of cardiac remodeling (Lu et al, 2018). SBP has been shown to promote angiogenesis by stimulating proliferation, migration, and nitric oxide (NO) secretion by endothelial progenitor cells (Wu et al, 2009). According to a recent meta-analysis of 25 studies with 439 animals, SBP was shown to reduce myocardial infarction area through an increase of vascular endothelial growth factor (VEGF) and microvessel count in CHD, indicating that SBP’s cardioprotective effects are largely due to promotion of angiogenesis (Zhang et al, 2017). Therapeutic angiogenesis is a heavily investigated and promising method for treatment of refractory angina or myocardial ischemia, among other indications (Attanasio and Schaer, 2011; Mitsos et al, 2012)
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