Deficiency of ROCK1 in bone marrow-derived cells protects against atherosclerosis in LDLR-/- mice

Hong Wei Wang, Ping Yen Liu, Naotsugu Oyama, Yoshiyuki Rikitake, Shiro Kitamoto, Jonathan Gitlin, James K. Liao, William A. Boisvert

Research output: Contribution to journalArticle

52 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3561-3570
Number of pages10
JournalFASEB Journal
Volume22
Issue number10
DOIs
Publication statusPublished - 2008 Oct 1

Fingerprint

Bone Marrow Cells
Macrophages
Atherosclerosis
Bone
Foam Cells
Bone Marrow
Chemotaxis
Foams
Lipids
rho-Associated Kinases
Chemokine CCL2
Protein-Serine-Threonine Kinases
Aptitude
LDL Lipoproteins
Homologous Recombination
Actins
Actin Cytoskeleton
Protein Isoforms
Blood Vessels
Tissue

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Wang, H. W., Liu, P. Y., Oyama, N., Rikitake, Y., Kitamoto, S., Gitlin, J., ... Boisvert, W. A. (2008). Deficiency of ROCK1 in bone marrow-derived cells protects against atherosclerosis in LDLR-/- mice. FASEB Journal, 22(10), 3561-3570. https://doi.org/10.1096/fj.08-108829
Wang, Hong Wei ; Liu, Ping Yen ; Oyama, Naotsugu ; Rikitake, Yoshiyuki ; Kitamoto, Shiro ; Gitlin, Jonathan ; Liao, James K. ; Boisvert, William A. / Deficiency of ROCK1 in bone marrow-derived cells protects against atherosclerosis in LDLR-/- mice. In: FASEB Journal. 2008 ; Vol. 22, No. 10. pp. 3561-3570.
@article{a5d72be3d8c4486abd31d75060a6daed,
title = "Deficiency of ROCK1 in bone marrow-derived cells protects against atherosclerosis in LDLR-/- mice",
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.",
author = "Wang, {Hong Wei} and Liu, {Ping Yen} and Naotsugu Oyama and Yoshiyuki Rikitake and Shiro Kitamoto and Jonathan Gitlin and Liao, {James K.} and Boisvert, {William A.}",
year = "2008",
month = "10",
day = "1",
doi = "10.1096/fj.08-108829",
language = "English",
volume = "22",
pages = "3561--3570",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "10",

}

Wang, HW, Liu, PY, Oyama, N, Rikitake, Y, Kitamoto, S, Gitlin, J, Liao, JK & Boisvert, WA 2008, 'Deficiency of ROCK1 in bone marrow-derived cells protects against atherosclerosis in LDLR-/- mice', FASEB Journal, vol. 22, no. 10, pp. 3561-3570. https://doi.org/10.1096/fj.08-108829

Deficiency of ROCK1 in bone marrow-derived cells protects against atherosclerosis in LDLR-/- mice. / Wang, Hong Wei; Liu, Ping Yen; Oyama, Naotsugu; Rikitake, Yoshiyuki; Kitamoto, Shiro; Gitlin, Jonathan; Liao, James K.; Boisvert, William A.

In: FASEB Journal, Vol. 22, No. 10, 01.10.2008, p. 3561-3570.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Deficiency of ROCK1 in bone marrow-derived cells protects against atherosclerosis in LDLR-/- mice

AU - Wang, Hong Wei

AU - Liu, Ping Yen

AU - Oyama, Naotsugu

AU - Rikitake, Yoshiyuki

AU - Kitamoto, Shiro

AU - Gitlin, Jonathan

AU - Liao, James K.

AU - Boisvert, William A.

PY - 2008/10/1

Y1 - 2008/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=54049151208&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=54049151208&partnerID=8YFLogxK

U2 - 10.1096/fj.08-108829

DO - 10.1096/fj.08-108829

M3 - Article

C2 - 18556458

AN - SCOPUS:54049151208

VL - 22

SP - 3561

EP - 3570

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 10

ER -