AIMS: Highly proliferative, CD34+/CD45+ fibroblasts derived from monocytic, blood-borne precursor cells play a critical role in the development of fibrosis in a murine ischaemic/reperfusion cardiomyopathy (I/RC) model. The differentiation of human monocytes into fibroblasts in vitro occurs after transendothelial migration (TEM) induced by monocyte chemoattractant protein 1 (MCP-1). Because Rho-associated kinase-1 (ROCK-1) has been implicated in fibrosis and leukocyte TEM, we investigated its involvement in I/RC. METHODS AND RESULTS: We subjected mice with genetic deletion of ROCK-1 to I/RC. We found that ROCK-1(-/-) mice did not develop the fibrosis and cardiac dysfunction characteristic for I/RC: compared with wild-type, ROCK-1(-/-) hearts showed markedly lower numbers of I/RC-induced alpha-smooth muscle actin+ fibroblasts and CD34+/CD45+ fibroblast precursors. Isolated cardiac fibroblasts from ROCK-1(-/-) mice undergoing I/RC were large and slowly proliferating, similar to fibroblasts isolated from sham-treated hearts. We also performed in vitro assays in which human peripheral blood mononuclear cells (PBMC) migrated through endothelial cells in response to MCP-1. Prior to migration, PBMC were incubated with ROCK-1-targeting small interfering RNA to silence ROCK-1 expression. We found that an 80% reduction of ROCK-1 protein did not inhibit TEM, but significantly reduced the amount of mononuclear cells that differentiated into fibroblasts by >20-fold. CONCLUSION: Our data implicate an important role for ROCK-1 in the differentiation, but not in the TEM of monocytes that mature into cardiac fibroblasts. These cells mediate non-adaptive fibrosis.
AIMS: Highly proliferative, CD34+/CD45+ fibroblasts derived from monocytic, blood-borne precursor cells play a critical role in the development of fibrosis in a murine ischaemic/reperfusion cardiomyopathy (I/RC) model. The differentiation of human monocytes into fibroblasts in vitro occurs after transendothelial migration (TEM) induced by monocyte chemoattractant protein 1 (MCP-1). Because Rho-associated kinase-1 (ROCK-1) has been implicated in fibrosis and leukocyte TEM, we investigated its involvement in I/RC. METHODS AND RESULTS: We subjected mice with genetic deletion of ROCK-1 to I/RC. We found that ROCK-1(-/-) mice did not develop the fibrosis and cardiac dysfunction characteristic for I/RC: compared with wild-type, ROCK-1(-/-) hearts showed markedly lower numbers of I/RC-induced alpha-smooth muscle actin+ fibroblasts and CD34+/CD45+ fibroblast precursors. Isolated cardiac fibroblasts from ROCK-1(-/-) mice undergoing I/RC were large and slowly proliferating, similar to fibroblasts isolated from sham-treated hearts. We also performed in vitro assays in which human peripheral blood mononuclear cells (PBMC) migrated through endothelial cells in response to MCP-1. Prior to migration, PBMC were incubated with ROCK-1-targeting small interfering RNA to silence ROCK-1 expression. We found that an 80% reduction of ROCK-1 protein did not inhibit TEM, but significantly reduced the amount of mononuclear cells that differentiated into fibroblasts by >20-fold. CONCLUSION: Our data implicate an important role for ROCK-1 in the differentiation, but not in the TEM of monocytes that mature into cardiac fibroblasts. These cells mediate non-adaptive fibrosis.
Authors: Oliver Dewald; Nikolaos G Frangogiannis; Martin Zoerlein; Georg D Duerr; Christina Klemm; Pascal Knuefermann; George Taffet; Lloyd H Michael; James D Crapo; Armin Welz; Mark L Entman Journal: Proc Natl Acad Sci U S A Date: 2003-02-13 Impact factor: 11.205
Authors: Yvette Langdon; Panna Tandon; Erika Paden; Jennifer Duddy; Joan M Taylor; Frank L Conlon Journal: Development Date: 2012-01-25 Impact factor: 6.868
Authors: Katarzyna A Cieslik; George E Taffet; Signe Carlson; Jesus Hermosillo; Joann Trial; Mark L Entman Journal: J Mol Cell Cardiol Date: 2010-10-23 Impact factor: 5.000