Rho kinase-1 mediates cardiac fibrosis by regulating fibroblast precursor cell differentiation

Sandra B. Haudek, Damon Gupta, Oliver Dewald, Robert J. Schwartz, Lei Wei, Joann Trial, Mark L. Entman

Research output: Contribution to journalArticle

75 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)511-518
Number of pages8
JournalCardiovascular research
Volume83
Issue number3
DOIs
StatePublished - Aug 2009

Keywords

  • Cardiac fibroblasts
  • Endothelial transmigration
  • Fibrosis
  • Monocytes
  • Rho-associated kinase-1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

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    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