Dan-Shen-Yin Granules Prevent Hypoxia-Induced Pulmonary Hypertension via STAT3/HIF-1α/VEGF and FAK/AKT Signaling Pathways

Ran-Ran Wang; Tian-Yi Yuan; Di Chen; Yu-Cai Chen; Shu-Chan Sun; Shou-Bao Wang; Ling-Lei Kong; Lian-Hua Fang; Guan-Hua Du

doi:10.3389/fphar.2022.844400

Dan-Shen-Yin Granules Prevent Hypoxia-Induced Pulmonary Hypertension via STAT3/HIF-1α/VEGF and FAK/AKT Signaling Pathways

Front Pharmacol. 2022 Mar 11:13:844400. doi: 10.3389/fphar.2022.844400. eCollection 2022.

Authors

Ran-Ran Wang¹, Tian-Yi Yuan¹, Di Chen¹, Yu-Cai Chen², Shu-Chan Sun¹, Shou-Bao Wang¹, Ling-Lei Kong¹, Lian-Hua Fang¹, Guan-Hua Du¹

Affiliations

¹ State Key Laboratory of Bioactive Substances and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.

Abstract

Traditional Chinese medicine (TCM) plays an important role in the treatment of complex diseases, especially cardiovascular diseases. However, it is hard to identify their modes of action on account of their multiple components. The present study aims to evaluate the effects of Dan-Shen-Yin (DSY) granules on hypoxia-induced pulmonary hypertension (HPH), and then to decipher the molecular mechanisms of DSY. Systematic pharmacology was employed to identify the targets of DSY on HPH. Furthermore, core genes were identified by constructing a protein-protein interaction (PPI) network and analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes (KEGG) analysis. Related genes and pathways were verified using a hypoxia-induced mouse model and hypoxia-treated pulmonary artery cells. Based on network pharmacology, 147 potential targets of DSY on HPH were found, constructing a PPI network, and 13 hub genes were predicted. The results showed that the effect of DSY may be closely associated with AKT serine/threonine kinase 1 (AKT1), signal transducer and activator of transcription 3 (STAT3), and HIF-1 signaling pathways, as well as biological processes such as cell proliferation. Consistent with network pharmacology analysis, experiments in vivo demonstrated that DSY could prevent the development of HPH in a hypoxia-induced mouse model and alleviate pulmonary vascular remodeling. In addition, inhibition of STAT3/HIF-1α/VEGF and FAK/AKT signaling pathways might serve as mechanisms. Taken together, the network pharmacology analysis suggested that DSY exhibited therapeutic effects through multiple targets in the treatment of HPH. The inferences were initially confirmed by subsequent in vivo and in vitro studies. This study provides a novel perspective for studying the relevance of TCM and disease processes and illustrates the advantage of this approach and the multitargeted anti-HPH effect of DSY.

Keywords: Dan-Shen-Yin; hypoxia-induced pulmonary hypertension; mechanism; network pharmacology; traditional chinese medicine.