Chlorogenic acid inhibits hypoxia-induced pulmonary artery smooth muscle cells proliferation via c-Src and Shc/Grb2/ERK2 signaling pathway

• Published in: European journal of pharmacology 2015-03, Vol.751, p.81-88
• Main Authors: Li, Qun-Yi, Zhu, Ying-Feng, Zhang, Meng, Chen, Li, Zhang, Zhen, Du, Yong-Li, Ren, Guo-Qiang, Tang, Jian-Min, Zhong, Ming-Kang, Shi, Xiao-Jin
• Format: Article
• Language: English
• Subjects: Animals; c-Src; Cell Cycle Proteins - genetics; Cell Hypoxia - drug effects; Cell Proliferation - drug effects; Chlorogenic acid; Chlorogenic Acid - pharmacology; Chlorogenic Acid - therapeutic use; DNA - biosynthesis; Down-Regulation - drug effects; G1 Phase - drug effects; GRB2 Adaptor Protein - metabolism; HIF-1α; Hypertension, Pulmonary - chemically induced; Hypertension, Pulmonary - drug therapy; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Male; MAP Kinase Signaling System - drug effects; Mitogen-Activated Protein Kinase 1 - metabolism; Monocrotaline - adverse effects; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Phosphorylation - drug effects; Proliferation; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Pulmonary Artery - cytology; Pulmonary artery smooth muscle cell; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Transcription, Genetic - drug effects; Transcriptional Activation - drug effects
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2015.01.046

Chlorogenic acid (CGA), abundant in coffee and particular fruits, can modulate hypertension and vascular dysfunction. Hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) proliferation has been tightly linked to vascular remodeling in pulmonary arterial hypertension (PAH). Thus, the present study was designed to investigate the effect of CGA on hypoxia-induced proliferation in cultured rat PASMCs. The data showed that CGA potently inhibited PASMCs proliferation and DNA synthesis induced by hypoxia. These inhibitory effects were associated with G1 cell cycle arrest and down-regulation of cell cycle proteins. Treatment with CGA reduced hypoxia-induced hypoxia inducible factor 1α (HIF-1α) expression and trans-activation. Furthermore, hypoxia-evoked c-Src phosphorylation was inhibited by CGA. In vitro ELISA-based tyrosine kinase assay indicated that CGA was a direct inhibitor of c-Src. Moreover, CGA attenuated physical co-association of c-Src/Shc/Grb2 and ERK2 phosphorylation in PASMCs. These results suggest that CGA inhibits hypoxia-induced proliferation in PASMCs via regulating c-Src-mediated signaling pathway. In vivo investigation showed that chronic CGA treatment inhibits monocrotaline-induced PAH in rats. These findings presented here highlight the possible therapeutic use of CGA in hypoxia-related PAH.