ROCK1 mediates leukocyte recruitment and neointima formation following vascular injury

Vascular Medicine Research Unit, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 06/2008; 118(5):1632-44. DOI: 10.1172/JCI29226
Source: PubMed


Although Rho-associated kinase (ROCK) activity has been implicated in cardiovascular diseases, the tissue- and isoform-specific roles of ROCKs in the vascular response to injury are not known. To address the role of ROCKs in this process, we generated haploinsufficient Rock1 (Rock1(+/-)) and Rock2 (Rock2(+/-)) mice and performed carotid artery ligations. Following this intervention, we found reduced neointima formation in Rock1(+/-) mice compared with that of WT or Rock2(+/-) mice. This correlated with decreased vascular smooth muscle cell proliferation and survival, decreased levels proinflammatory adhesion molecule expression, and reduced leukocyte infiltration. In addition, thioglycollate-induced peritoneal leukocyte recruitment and accumulation were substantially reduced in Rock1(+/-) mice compared with those of WT and Rock2(+/-) mice. To determine the role of leukocyte-derived ROCK1 in neointima formation, we performed reciprocal bone marrow transplantation (BMT) in WT and Rock1(+/-) mice. Rock1(+/-) to WT BMT led to reduced neointima formation and leukocyte infiltration following carotid ligation compared with those of WT to WT BMT. In contrast, WT to Rock1(+/-) BMT resulted in increased neointima formation. These findings indicate that ROCK1 in BM-derived cells mediates neointima formation following vascular injury and suggest that ROCK1 may represent a promising therapeutic target in vascular inflammatory diseases.

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    • "However, differences in function between the two isoforms have been observed in ROCK I and II knockout studies. ROCK II knockout mice show intrauterine growth retardation caused by deregulation of the placenta, limited axonal growth after trauma to the central nervous system, and enhanced adipogenesis (Thumkeo et al. 2003; Noguchi et al. 2007; Duffy et al. 2009), whereas studies of ROCK I knockout mice have suggested that the protein is involved in cardiac fibrosis development, cardiomyocyte apoptosis, insulin resistance, and acute inflammation (Zhang YM et al. 2006; Noma et al. 2008; Lee et al. 2009; Vemula et al. 2010). "
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