Deficiency of ROCK1 in bone marrow-derived cells protects against atherosclerosis in LDLR-/- mice.
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.
Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02139, USA.
Hong-Wei
HW
Wang
Ping-Yen
PY
Liu
Naotsugu
N
Oyama
Yoshiyuki
Y
Rikitake
Shiro
S
Kitamoto
Jonathan
J
Gitlin
James K
JK
Liao
William A
WA
Boisvert
D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology / Q000276:immunology*; D002633:Chemotaxis; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D011973:Receptors, LDL / Q000235:genetics; D054460:rho-Associated Kinases / Q000235:genetics*
D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases