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- Title
Deficiency of ROCK1 in bone marrow-derived cells protects against atherosclerosis in LDLR<sup>-/-</sup> mice.
- Authors
Hong-Wei Wang; Ping-Yen Liu; Oyama, Naotsugu; Rikitake, Yoshiyuki; Kitamoto, Shiro; Gitlin, Jonathan; Liao, James K.; Boisvert, William A.
- Abstract
Rho kinases (ROCKs) are serine-threonine protein kinases that regulate the actin cytoskeleton. Recent studies suggest that ROCKs also play an important role in cardiovascular disease. However, the isoform- and tissue-specific role of ROCKs in mediating this process is unknown. Using homologous recombination, we generated mutant mice harboring alleles with homozygous deletion of ROCK1 (ROCK1-/-). Most ROCK1-/- mice die perinatally. However, a few ROCK1-/- mice survive to adulthood, are phenotypically normal, and have no apparent compensatory changes in ROCK2. Using these ROCK1-/- mice, we show that ROCK1 in bone marrow-derived macrophages is critical to the development of atherosclerosis, in part, by mediating foam cell formation and macrophage chemotaxis. Lipid accumulation and atherosclerotic lesions were reduced in atherosclerosis-prone LDLR-/- mice, whose bone marrows have been replaced with bone marrows derived from ROCK1-/- mice. Bone marrow-derived ROCK1-deficient macrophages exhibited impaired chemotaxis to monocyte chemotactic protein-1 and showed reduced ability to take up lipids and to develop into foam cells when exposed to modified low-density lipoprotein. These findings indicate that ROCK1 in bone marrow-derived cells is a critical mediator of atherogenesis and suggest that macrophage ROCK1 may be an important therapeutic target for vascular inflammation and atherosclerosis.
- Subjects
PROTEIN kinases; MACROPHAGES; BONE marrow cells; ATHEROSCLEROSIS prevention; ACTIN; CYTOSKELETON; CARDIOVASCULAR diseases; LOW density lipoproteins
- Publication
FASEB Journal, 2008, Vol 22, Issue 10, p3561
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.08-108829