Cardiovascular disease is a leading cause of death worldwide that caused 17.3 million deaths globally. As one of the most important cardiovascular diseases, coronary heart disease(CHD) causes the most death and disability. It represents a substantial societal burden in developed countries and accounts for one-third of all deaths in the adult population[2, 3]. The mortality of CHD is supposed to increase in developing countries from approximately 9 million in 1990 to about 19 million by 2020. Notably, a new study suggested that patients with cardiovascular disease are more likely to be infected with COVID-19. Data from the National Health Commission showed that 17 percent of COVID-19 patients had the comorbidity of CHD. High blood pressure, cholesterol levels, diabetes, obesity have been considered as major determining factors of CHD. Women with onset of type 1 diabetes before age 10 have a 60-times increased risk of CHD. In addition, life behaviors, such as alcohol intake and cigarette consumption[9, 10], environmental toxic metal contaminants and the degree of ApoB are also related to the augment of CHD data. Apart from those, it is reported that HIV infection caused a substantially increased risk of CHD. Currently, modification of lifestyles, percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) and medication therapy such as nitrates, beta receptor-blockers, stains, antiplatelet drugs are the mainstream therapeutic methods for CHD. Nevertheless, there are many limitations in the treatment of CHD, such as side effects of drugs especially Western drugs, lack of comprehensive management, patients’ resistance to changing lifestyles.
Traditional Chinese medicine (TCM), originated from China, which is characterized by its minor side effects and synergistic therapeutic efficacies, has been long used in clinical practice and plays indispensable roles in various diseases. In particular, it has broadened the ideas of therapeutic approaches and achieved crucial effects in CHD[15, 16]. According to the TCM theory, the pathogenesis of coronary heart disease may be phlegm turbidity, cold coagulation, qi stagnation and blood stasis. At present, there are many TCM preparations and Chinese patent drugs for relieving chest congestion, activating Qi and promoting blood circulation for removing blood stasis, which show remarkable effects in CHD. Particularly, SheXiang XinTongNing(XTN), a commercially available Chinese patent medicine which has been widely used in clinical treatment of CHD. XTN is composed of 6 herbs, including Moschus (Shexiang, SX), Ligusticum chuanxiong (Chuanxiong, CX), Rhizoma Corydalis(Yanhusuo, YHS), Panax ginseng(Renshen, RS), Borneolum Syntheticum(Bingpian, BP) and Styrax(Suhexiang, SHX). Among them, SX is the principal drug and plays a role in resuscitation; CX mainly promotes blood circulation and activates qi; YHS principally regulates qi-flowing for relieving pain. The combination of CX and YHS are the assistant drugs, playing a prominent role in improving the two essentials (qi and blood) of human bodies to alleviate the diseases; BP is the adjuvant drug which exerts functions in activating brain and clearing away for resuscitation. In addition, it enhances the effects of principal and assistant drugs. The formulae conforms to the theory of TCM and the six kinds of herbs have a synergistic effect, so as to achieve a prominent efficacy in relieving CHD. However, it is precisely because of the multiple components and multiple targets of TCM that the mechanism of TCM is difficult to be clarified. Although XTN has been applied in clinic for a long time, the underlying mechanisms of XTN are still vague.
Network Pharmacology is a systematic method to study the mechanisms of drugs and diseases based on the network construction of drugs, constituents, genes, protein targets, and diseases. It coincides well with the holistic ideas of ‘network target, multicomponent therapeutics’ of TCM and contributes greatly to the prediction of potential drugs and the screening of the components, targets as well as pathways of drugs. In previous study, the network pharmacology has been used in elucidating the key components and mechanisms of TCM involved in their therapeutic effects, such as the mechanisms of Erxian Decoction against TNF-α induced osteoblast apoptosis, the mechanisms of Huayu-Qiangshen-Tongbi formula on rheumatoid arthritis, the anticancer mechanisms of Compound Kushen Injection against hepatocellular carcinoma.
In this study, a network pharmacology approach was adopted to illuminate the underlying mechanisms of XTN against CHD through following steps: (1) Screening the chemical components of the six herbs contained in XTN; (2) Predicting the candidate targets of XTN related to CHD; (3) Illustrating a drug-components-targets network and a protein interaction(PPI) network; (4) Functional analysis of XTN for investigating the mechanisms of XTN acting on CHD.
As a consequence, our study could provide novel insights into the mechanisms of XTN treating CHD. More generally, offers support for further study. The flowchart of our study was shown in Fig. 1.