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

Sandra B Haudek1, Damon Gupta, Oliver Dewald

  • 1DeBakey Heart Center, Baylor College of Medicine and The Methodist Hospital, One Baylor Plaza F620, Houston TX 77030, USA. shaudek@bcm.tmc.edu

Cardiovascular Research
|May 2, 2009
PubMed

Insights

Rho-associated kinase-1 (ROCK-1) is crucial for monocyte differentiation into cardiac fibroblasts, a key driver of fibrosis in heart disease. Inhibiting ROCK-1 reduces fibroblast formation without affecting cell migration, offering a potential therapeutic target.

Area of Science:

  • Cardiovascular Research
  • Fibrosis Mechanisms
  • Cell Biology

Background:

  • Fibrosis in ischaemic/reperfusion cardiomyopathy (I/RC) involves CD34+/CD45+ fibroblasts from monocytic precursors.
  • Monocyte differentiation into fibroblasts occurs after transendothelial migration (TEM) induced by monocyte chemoattractant protein 1 (MCP-1).
  • Rho-associated kinase-1 (ROCK-1) is implicated in fibrosis and leukocyte TEM.

Purpose of the Study:

  • To investigate the role of ROCK-1 in I/RC-induced cardiac fibrosis.
  • To determine if ROCK-1 influences monocyte TEM or subsequent fibroblast differentiation.

Main Methods:

  • Mice with genetic deletion of ROCK-1 were subjected to I/RC.
  • In vitro assays assessed human peripheral blood mononuclear cell (PBMC) migration and differentiation after ROCK-1 silencing.
  • Quantification of alpha-smooth muscle actin+ fibroblasts and CD34+/CD45+ precursors in cardiac tissue.

Main Results:

  • ROCK-1(-/-) mice showed no significant fibrosis or cardiac dysfunction post-I/RC.
  • ROCK-1 deletion markedly reduced I/RC-induced fibroblasts and precursor cells.
  • In vitro, ROCK-1 silencing reduced monocyte-to-fibroblast differentiation by over 20-fold but did not inhibit TEM.

Conclusions:

  • ROCK-1 plays a critical role in the differentiation of monocytes into cardiac fibroblasts.
  • ROCK-1 is not essential for monocyte transendothelial migration.
  • Targeting ROCK-1 may offer a strategy to mitigate non-adaptive cardiac fibrosis.
Abstract

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