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.
Wang
Hong-Wei
HW
Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02139, USA.
Liu
Ping-Yen
PY
Oyama
Naotsugu
N
Rikitake
Yoshiyuki
Y
Kitamoto
Shiro
S
Gitlin
Jonathan
J
Liao
James K
JK
Boisvert
William A
WA
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