title: Rho-associated coiled-coil-containing kinase 2 deficiency in bone marrow-derived cells leads to increased cholesterol efflux and decreased atherosclerosis.
abstract: BACKGROUND
  Macrophages play a central role in the development of atherosclerosis. However, the signaling pathways that regulate their function are not well understood. The Rho-associated coiled-coil-containing kinases (ROCK1 and ROCK2) are serine-threonine protein kinases that are involved in the regulation of the actin cytoskeleton. Recent studies suggest that ROCK1 in macrophages and bone marrow-derived cells mediates atherogenesis. However, a similar role for ROCK2 in the pathogenesis of atherosclerosis has not been determined.
  
  
  RESULTS
  The bone marrows from wild-type, ROCK2(+/-), and ROCK2(-/-) mice were transplanted into irradiated recipient low-density lipoprotein receptor(-/-) mice, and atherosclerosis was induced with a 16-week high-cholesterol diet. Compared with wild-type bone marrow-transplanted mice, ROCK2(+/-) bone marrow-transplanted and ROCK2(-/-) bone marrow-transplanted mice showed substantially less lipid accumulation in the aorta (8.46±1.42% and 9.80±2.34% versus 15.64±1.89%; P<0.01 for both) and decreased atherosclerotic lesions in the subaortic sinus (158.1±44.4 and 330.1±109.5×10(3)μm(2) versus 520.2±125.7×10(3)μm(2); P<0.01 for both). These findings correlated with decreased foam cell formation (2.27±0.57 versus 4.10±0.3; P<0.01) and increased cholesterol efflux (17.65±0.6 versus 9.75±0.8; P<0.05) in ROCK2-deficient mice that are mediated, in part, through the peroxisome proliferator-activated receptor-γ/liver X receptor/ATP-binding cassette transporter A1 pathway in macrophages.
  
  
  CONCLUSIONS
  ROCK2 contributes to atherosclerosis, in part, by inhibiting peroxisome proliferator-activated receptor-γ-mediated reverse cholesterol transport in macrophages, which contributes to foam cell formation. These findings suggest that inhibition of ROCK2 in macrophages may have therapeutic benefits in preventing the development of atherosclerosis.
authors.affiliation: Vascular Medicine Research Unit, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.forename: Yu
authors.initials: Y
authors.lastname: Mei
authors.forename: Takuhito
authors.initials: T
authors.lastname: Shoji
authors.forename: Xinbing
authors.initials: X
authors.lastname: Han
authors.forename: Karol
authors.initials: K
authors.lastname: Kaminski
authors.forename: Goo Taeg
authors.initials: GT
authors.lastname: Oh
authors.forename: Pat P
authors.initials: PP
authors.lastname: Ongusaha
authors.forename: Kunzhong
authors.initials: K
authors.lastname: Zhang
authors.forename: Hannah
authors.initials: H
authors.lastname: Schmitt
authors.forename: Martin
authors.initials: M
authors.lastname: Moser
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: James K
authors.initials: JK
authors.lastname: Liao
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000493:pharmacokinetics / Q000633:toxicity; D005487:Foam Cells / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000494:pharmacology; D000071518:Liver X Receptors; D008264:Macrophages / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D011828:Radiation Chimera; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D054460:rho-Associated Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002791:Cholesterol, Dietary; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D002784:Cholesterol; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases