Plasminogen activation induced pericellular fibronectin proteolysis promotes fibroblast apoptosis.
Apoptosis of fibroblasts/myofibroblasts is a critical event in the resolution of tissue repair responses; however, mechanisms for the regulation of (myo)fibroblast apoptosis/survival remain unclear. In this study, we demonstrate counter-regulatory interactions between the plasminogen activation system and transforming growth factor-beta1 (TGF-beta1) in the control of fibroblast apoptosis. Plasmin treatment induced fibroblast apoptosis in a time- and dose-dependent manner in association with proteolytic degradation of extracellular matrix proteins, as detected by the release of soluble fibronectin peptides. Plasminogen, which was activated to plasmin by fibroblasts, also induced fibronectin proteolysis and fibroblast apoptosis, both of which were blocked by alpha2-antiplasmin but not by inhibition of matrix metalloproteinase activity. TGF-beta1 protected fibroblasts from apoptosis induced by plasminogen but not from apoptosis induced by exogenous plasmin. The protection from plasminogen-induced apoptosis conferred by TGF-beta1 is associated with the up-regulation of plasminogen activator-1 (PAI-1) expression and inhibition of plasminogen activation. Moreover, lung fibroblasts from mice genetically deficient in PAI-1 lose the protective effect of TGF-beta1 against plasminogen-induced apoptosis. These findings support a novel role for the plasminogen activation system in the regulation of fibroblast apoptosis and a potential role of TGF-beta1/PAI-1 in promoting (myo)fibroblast survival in chronic fibrotic disorders.
Horowitz
Jeffrey C
JC
University of Michigan Medical Center, 6301 MSRB III, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-5642, USA. jchorow@umich.edu
Rogers
David S
DS
Simon
Richard H
RH
Sisson
Thomas H
TH
Thannickal
Victor J
VJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D004789:Enzyme Activation / Q000187:drug effects; D005341:Fibrinolysin / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism*; D005355:Fibrosis / Q000201:enzymology; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology; D010958:Plasminogen / Q000378:metabolism* / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D058258:Serpin E2; D015843:Serpins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D000979:alpha-2-Antiplasmin / Q000494:pharmacology
D005353:Fibronectins; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; D053773:Transforming Growth Factor beta1; D000979:alpha-2-Antiplasmin; D010958:Plasminogen; D005341:Fibrinolysin; D020782:Matrix Metalloproteinases