A novel mechanism of plasmin-induced mitogenesis in fibroblasts

Abstract

To cite this article: Mandal SK, Rao LVM, Tran TTT, Pendurthi UR. A novel mechanism of plasmin-induced mitogenesis in fibroblasts. J Thromb Haemost 2005; 3: 163-9.Summary. The plasminogen activator/plasmin system is believed to play an important role in diverse pathophysiological processes, including wound healing, vascular remodeling and pulmonary fibrosis. Our recent studies show that plasmin upregulates the expression of Cyr61, a growth factor-like gene that has been implicated in cell proliferation and migration. In the present study, we investigated whether plasmin promotes fibroblast proliferation and, if so, determine the role of Cyr61 in the plasmin-induced response. Human lung fibroblasts were exposed to varying concentrations of plasmin and DNA synthesis was monitored by measuring the incorporation of 3 H-thymidine into DNA. Plasmin increased DNA synthesis of fibroblasts in a dose-dependent manner. Protease-activated receptor-1 (PAR-1)-specific antibodies, but not PAR-2-specific antibodies, reduced the plasmin-induced DNA synthesis. Consistent with this, plasmin had no substantial effect on the DNA synthesis in PAR-1-deficient mouse fibroblasts. Plasmin activated both p38 and p44/42 MAPKs and specific inhibitors of these pathways inhibited the plasmin-induced DNA synthesis. Plasmin-induced increase in the DNA synthesis was completely abrogated by anti-Cyr61 antibodies. Interestingly, thrombin, which is a potent inducer of Cyr61, had only a minimal effect on fibroblast proliferation. Additional experiments suggested that plasmin cleaved cell/extracellular matrixassociated Cyr61 and the conditioned media from plasmintreated cells could support the cell proliferation. Overall, these data suggest that plasmin promotes fibroblast proliferation by a novel pathway, involving two independent steps. In the first step, plasmin induces Cyr61 expression via activation of PAR-1, and in the second step, plasmin releases Cyr61 deposited in the extracellular matrix, thus making it accessible to act on cells.

Proteolysis of CCN1 by Plasmin: Functional Implications

“…Our recent studies on fibroblasts showed that both plasmin and thrombin induced CCN1 mRNA expression (11,29), but the CCN1 antigen was found only in cell lysates of thrombin-stimulated cells (30). These data suggested that plasmin might be liberating/cleaving newly synthesized CCN1, which associates with cells or ECM.…”

Plasminogen Activation–Induced Pericellular Fibronectin Proteolysis Promotes Fibroblast Apoptosis

“…Sustained plasminogen activation in these cells, however, induces anoikis, a mechanism thought to contribute to loss of blood vessel integrity and cerebral hemorrhage (41). Additional studies have shown that plasmin-mediated release of growth factors from the ECM may stimulate fibroblast proliferation (42) and that increased PAI-1 expression contributes to fibroblast senescence (43). Finally, studies in vascular smooth muscle cells show that plasmin-mediated activation of latent TGF-b1 promotes mesenchymal cell survival (17,44).…”

A Novel Function of Thrombin-activatable Fibrinolysis Inhibitor during Rat Liver Regeneration and in Growth-promoted Hepatocytes in Primary Culture

“…Recently, Nicholl et al (43) demonstrated that plasmin induces smooth muscle cell proliferation via the ERK1/2 signaling cascade. Plasmin also induces the expression of the cysteine-rich angiogenic inducer 61 through the activation of protein activated receptor and increases the growth of fibroblasts (44). In hepatocytes, plasmin regulates the expression of pro-apoptotic protein Bim (EL) via the ERK1/2 signaling pathway (45).…”