Factor Xa induces mitogenesis of vascular smooth muscle cells via autocrine production of epiregulin.
Factor Xa has been reported to elicit smooth muscle cell proliferation via autocrine release of platelet-derived growth factor. However, this study has shown that factor Xa-induced mitogenesis of rat aortic smooth muscle cell is independent of platelet-derived growth factor. We also could not observe any platelet-derived growth factor isoforms in the cultured medium of factor Xa-stimulated cells. Our finding that the cultured medium of factor Xa-stimulated cells strongly induces rat aortic smooth muscle cell mitogenesis in the absence of factor Xa activity led us to explore the existence of a novel autocrine pathway. The autocrine growth factor was purified from the cultured medium and was identified to be epiregulin. Recombinant epiregulin was also able to induce the mitogenesis. The secretion of epiregulin from factor Xa-stimulated rat aortic smooth muscle cell required mRNA expression and protein synthesis of the growth factor. The mitogenic effect of factor Xa on rat aortic smooth muscle cell was significantly reduced by anti-epiregulin antibody or by antisense oligodeoxynucleotide to epiregulin. Several lines of experimental evidence clearly indicate that the autocrine production of epiregulin, an epidermal growth factor-related ligand, is induced in the factor Xa-stimulated mitogenic process of rat aortic smooth muscle cell.
Koo
Bon-Hun
BH
Department of Biochemistry, College of Science, Yonsei University, Seoul 120-749, Korea.
Kim
Doo-Sik
DS
D000818:Animals; D001011:Aorta / Q000473:pathology; D015153:Blotting, Western; D002455:Cell Division; D002478:Cells, Cultured; D003470:Culture Media / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004815:Epidermal Growth Factor / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D066260:Epiregulin; D015951:Factor Xa / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013936:Thymidine / Q000737:chemistry; D013997:Time Factors
D003470:Culture Media; D066260:Epiregulin; C587882:Ereg protein, rat; D008024:Ligands; D016376:Oligonucleotides, Antisense; D010982:Platelet-Derived Growth Factor; D020033:Protein Isoforms; D012333:RNA, Messenger; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015951:Factor Xa; D013936:Thymidine