title: Chlorogenic acid inhibits hypoxia-induced pulmonary artery smooth muscle cells proliferation via c-Src and Shc/Grb2/ERK2 signaling pathway.
abstract: 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.
authors: Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University, 12 Wu Lu Mu Qi M Road, Shanghai 200040, China.
authors: Qun-Yi
authors: QY
authors: Li
authors: Department of Pathology, Huashan Hospital North, Fudan University, 108 Lu Xiang Road, Shanghai 201907, China.
authors: Ying-Feng
authors: YF
authors: Zhu
authors: Ascepion Pharmaceuticals, Inc., 68 Xinqing Road, Suzhou 215125, China.
authors: Meng
authors: M
authors: Zhang
authors: Department of Pharmacy, Xuhui District Central Hospital, 966 Huai Hai M Road, Shanghai 200031, China. Electronic address: 270596714@qq.com.
authors: Li
authors: L
authors: Chen
authors: Shanghai Institute of Pharmaceutical Industry, 1320 West Beijing Road, Shanghai 200040, China.
authors: Zhen
authors: Z
authors: Zhang
authors: School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology, 3501 Daxue Road, Jinan 250353, China.
authors: Yong-Li
authors: YL
authors: Du
authors: Department of Pathology, Huashan Hospital North, Fudan University, 108 Lu Xiang Road, Shanghai 201907, China.
authors: Guo-Qiang
authors: GQ
authors: Ren
authors: Department of Pathology, Huashan Hospital North, Fudan University, 108 Lu Xiang Road, Shanghai 201907, China.
authors: Jian-Min
authors: JM
authors: Tang
authors: Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University, 12 Wu Lu Mu Qi M Road, Shanghai 200040, China.
authors: Ming-Kang
authors: MK
authors: Zhong
authors: Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University, 12 Wu Lu Mu Qi M Road, Shanghai 200040, China. Electronic address: xiaojin_shi@hotmail.com.
authors: Xiao-Jin
authors: XJ
authors: Shi
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D018797:Cell Cycle Proteins / Q000235:genetics; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002726:Chlorogenic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D004247:DNA / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D016686:Monocrotaline / Q000009:adverse effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D051380:GRB2 Adaptor Protein; C495950:Grb2 protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D002726:Chlorogenic Acid; D016686:Monocrotaline; D004247:DNA; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1
keywords: Chlorogenic acid; HIF-1α; Hypoxia; Proliferation; Pulmonary artery smooth muscle cell; c-Src