title: CRP promotes MMP-10 expression via c-Raf/MEK/ERK and JAK1/ERK pathways in cardiomyocytes.
abstract: C-reactive protein (CRP) was reported to be a predictor for left ventricular (LV) remodeling. Matrix metalloproteinase (MMP)-10 participates in the LV remodeling process. However, the intrinsic relationship between CRP and MMP-10 in cardiomyocytes remains unclear. The purpose of this study is to observe whether CRP may promote MMP-10 expression, and if so, to clarify signaling pathways to be involved in CRP-induced MMP-10 expression in cardiomyocytes. We observed in cultured cardiomyocytes that CRP at a dose of 5 μg/ml increased MMP-10 expression and activity in a time-dependent manner, as measured by real-time polymerase chain reaction (PCR), western blots, and casein zymography analysis. We hypothesized that signal pathways of mitogen-activated protein kinases (MAPKs) and Janus kinases (JAKs)/signal transducers and activators of transcription (STATs) might be involved in CRP-induced MMP-10 expression. Our results showed that CRP markedly activated c-Raf/MEK/ERK and JAK1/ERK signaling pathways but not JAK1/STAT3 signaling pathway by using the phosphor-specific antibodies against these pathways, and blockages of c-Raf/MEK/ERK and JAK1/ERK signaling pathways by the specific ERK1/2 inhibitor U0126 and JAK1 inhibitor piceatannol could significantly decrease CRP-induced MMP-10 expression. In addition, we demonstrated that the DNA binding sites of AP-1 and STAT3 in the nucleus of cardiomyocytes mediated CRP-induced MMP-10 expression. In conclusion, we demonstrated that CRP promoted MMP-10 expression and activity in cardiomyocytes, and clarified that c-Raf/MEK/ERK and JAK1/ERK signaling pathways were involved in MMP-10 expression regulation via activation of DNA binding sites for AP-1 and STAT3 in cardiomyocytes. Our findings suggest that CRP acts as a predictor for LV remodeling might be associated with its promotion effect on MMP-10 expression and activity.
authors.affiliation: State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Disease & Fuwai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, PR China.
authors.forename: Chuanjue
authors.initials: C
authors.lastname: Cui
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shi
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Liu
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Bai
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Shenghua
authors.initials: S
authors.lastname: Liu
authors.forename: Shengshou
authors.initials: S
authors.lastname: Hu
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Wei
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002097:C-Reactive Protein / Q000378:metabolism*; D002478:Cells, Cultured; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053506:Matrix Metalloproteinase 10 / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D002070:Butadienes; D009570:Nitriles; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D013267:Stilbenes; D018808:Transcription Factor AP-1; C113580:U 0126; C041525:3,3',4,5'-tetrahydroxystilbene; D002097:C-Reactive Protein; D053613:Janus Kinase 1; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D053506:Matrix Metalloproteinase 10