Rho kinase-1 mediates cardiac fibrosis by regulating fibroblast precursor cell differentiation
Haudek SB, Gupta D, Dewald O, Schwartz RJ, Wei L, Trial J, Entman ML (2009)
Publication Type: Journal article
Publication year: 2009
Journal
Book Volume: 83
Pages Range: 511-518
Journal Issue: 3
DOI: 10.1093/cvr/cvp135
Abstract
AimsHighly 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 resultsWe 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 α-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.ConclusionOur 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 with CRIS profile
Involved external institutions
Houston Texas Medical Center
United States (USA) (US)
Universitätsklinikum Bonn
Germany (DE)
Texas A&M University Health Science Center (TAMHSC)
United States (USA) (US)
Indiana University
United States (USA) (US)
United States (USA) (US)
Universitätsklinikum Bonn
Germany (DE)
Texas A&M University Health Science Center (TAMHSC)
United States (USA) (US)
Indiana University
United States (USA) (US)
How to cite
APA:
Haudek, S.B., Gupta, D., Dewald, O., Schwartz, R.J., Wei, L., Trial, J., & Entman, M.L. (2009). Rho kinase-1 mediates cardiac fibrosis by regulating fibroblast precursor cell differentiation. Cardiovascular Research, 83(3), 511-518. https://doi.org/10.1093/cvr/cvp135
MLA:
Haudek, Sandra B., et al. "Rho kinase-1 mediates cardiac fibrosis by regulating fibroblast precursor cell differentiation." Cardiovascular Research 83.3 (2009): 511-518.
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