title: Fibronectin peptides as potential regulators of hepatic fibrosis through apoptosis of hepatic stellate cells.
abstract: The turnover of extracellular matrix (ECM) components can generate signals that regulate several cellular functions such as proliferation, differentiation, and apoptosis. During liver injury, matrix metalloproteases (MMPs) production is enhanced and increased levels of peptides derived from extracellular matrix proteins can be generated. Synthetic peptides with sequences present in extracellular matrix proteins were previously found to induce both stimulating and apoptotic effects on several cell types including the inflammatory cells monocytes/macrophages. Therefore, in inflammatory liver diseases, locally accumulated peptides could be also important in regulating hepatic fibrosis by inducing apoptosis of hepatic stellate cells (HSC), the primary cellular source of extracellular matrix components. Here, we describe the apoptotic effect of fibronectin peptides on the cell line of human hepatic stellate cells LX-2 based on oligonucleosomal DNA fragmentation, caspase-3 and -9 activation, Bcl-2 depletion, and accumulation of Bax protein. We also found that these peptides trigger the activation of Src kinase, which in turn mediated the increase of JNK and p38 activities. By the use of specific inhibitors we demonstrated the involvement of Src, JNK, and p38 in apoptosis induced by fibronectin peptides on HSC. Moreover, fibronectin peptides increased iNOS expression in human HSC, and specific inhibition of iNOS significantly reduced the sustained activity of JNK and the programmed cell death caused by these peptides. Finally, the possible regulatory effect of fibronectin peptides in liver fibrosis was further supported by the ability of these peptides to induce metalloprotease-9 (MMP-9) expression in human monocytes.
authors: Departamento de Bioquímica y Genética, Universidad de Navarra, Pamplona, Spain.
authors: Teresa
authors: T
authors: Mòdol
authors: Natalia
authors: N
authors: Brice
authors: Marina
authors: M
authors: Ruiz de Galarreta
authors: Antonia
authors: A
authors: García Garzón
authors: María J
authors: MJ
authors: Iraburu
authors: Juan J
authors: JJ
authors: Martínez-Irujo
authors: María J
authors: MJ
authors: López-Zabalza
mesh_terms: D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D053938:DNA Fragmentation; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D010455:Peptides; D051028:bcl-2-Associated X Protein; D053148:Caspase 3; D020780:Matrix Metalloproteinase 9