Rho-Associated Coiled-Coil-Containing Kinase 2 Deficiency in Bone Marrow–Derived Cells Leads to Increased Cholesterol Efflux and Decreased Atherosclerosis
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- Qian Zhou
- From the Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (Q.Z., M.Y., T.S., X.H., K.K., G.T.O., P.P.O., K.Z., J.K.L.); Department of Cardiology, University Hospital Freiburg, Freiburg, Germany (Q.Z., H.S., M.M., C.B.); Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (X.H.); Division of Life and Pharmaceutical Science, Ewha Womans University, Seoul, Korea (G.T.O....
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- Yu Mei
- From the Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (Q.Z., M.Y., T.S., X.H., K.K., G.T.O., P.P.O., K.Z., J.K.L.); Department of Cardiology, University Hospital Freiburg, Freiburg, Germany (Q.Z., H.S., M.M., C.B.); Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (X.H.); Division of Life and Pharmaceutical Science, Ewha Womans University, Seoul, Korea (G.T.O....
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- Takuhito Shoji
- From the Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (Q.Z., M.Y., T.S., X.H., K.K., G.T.O., P.P.O., K.Z., J.K.L.); Department of Cardiology, University Hospital Freiburg, Freiburg, Germany (Q.Z., H.S., M.M., C.B.); Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (X.H.); Division of Life and Pharmaceutical Science, Ewha Womans University, Seoul, Korea (G.T.O....
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- Xinbing Han
- From the Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (Q.Z., M.Y., T.S., X.H., K.K., G.T.O., P.P.O., K.Z., J.K.L.); Department of Cardiology, University Hospital Freiburg, Freiburg, Germany (Q.Z., H.S., M.M., C.B.); Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (X.H.); Division of Life and Pharmaceutical Science, Ewha Womans University, Seoul, Korea (G.T.O....
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- Karol Kaminski
- From the Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (Q.Z., M.Y., T.S., X.H., K.K., G.T.O., P.P.O., K.Z., J.K.L.); Department of Cardiology, University Hospital Freiburg, Freiburg, Germany (Q.Z., H.S., M.M., C.B.); Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (X.H.); Division of Life and Pharmaceutical Science, Ewha Womans University, Seoul, Korea (G.T.O....
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- Goo Taeg Oh
- From the Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (Q.Z., M.Y., T.S., X.H., K.K., G.T.O., P.P.O., K.Z., J.K.L.); Department of Cardiology, University Hospital Freiburg, Freiburg, Germany (Q.Z., H.S., M.M., C.B.); Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (X.H.); Division of Life and Pharmaceutical Science, Ewha Womans University, Seoul, Korea (G.T.O....
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- Pat P. Ongusaha
- From the Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (Q.Z., M.Y., T.S., X.H., K.K., G.T.O., P.P.O., K.Z., J.K.L.); Department of Cardiology, University Hospital Freiburg, Freiburg, Germany (Q.Z., H.S., M.M., C.B.); Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (X.H.); Division of Life and Pharmaceutical Science, Ewha Womans University, Seoul, Korea (G.T.O....
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- Kunzhong Zhang
- From the Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (Q.Z., M.Y., T.S., X.H., K.K., G.T.O., P.P.O., K.Z., J.K.L.); Department of Cardiology, University Hospital Freiburg, Freiburg, Germany (Q.Z., H.S., M.M., C.B.); Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (X.H.); Division of Life and Pharmaceutical Science, Ewha Womans University, Seoul, Korea (G.T.O....
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- Hannah Schmitt
- From the Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (Q.Z., M.Y., T.S., X.H., K.K., G.T.O., P.P.O., K.Z., J.K.L.); Department of Cardiology, University Hospital Freiburg, Freiburg, Germany (Q.Z., H.S., M.M., C.B.); Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (X.H.); Division of Life and Pharmaceutical Science, Ewha Womans University, Seoul, Korea (G.T.O....
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- Martin Moser
- From the Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (Q.Z., M.Y., T.S., X.H., K.K., G.T.O., P.P.O., K.Z., J.K.L.); Department of Cardiology, University Hospital Freiburg, Freiburg, Germany (Q.Z., H.S., M.M., C.B.); Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (X.H.); Division of Life and Pharmaceutical Science, Ewha Womans University, Seoul, Korea (G.T.O....
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- Christoph Bode
- From the Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (Q.Z., M.Y., T.S., X.H., K.K., G.T.O., P.P.O., K.Z., J.K.L.); Department of Cardiology, University Hospital Freiburg, Freiburg, Germany (Q.Z., H.S., M.M., C.B.); Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (X.H.); Division of Life and Pharmaceutical Science, Ewha Womans University, Seoul, Korea (G.T.O....
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- James K. Liao
- From the Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (Q.Z., M.Y., T.S., X.H., K.K., G.T.O., P.P.O., K.Z., J.K.L.); Department of Cardiology, University Hospital Freiburg, Freiburg, Germany (Q.Z., H.S., M.M., C.B.); Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (X.H.); Division of Life and Pharmaceutical Science, Ewha Womans University, Seoul, Korea (G.T.O....
抄録
<jats:sec> <jats:title>Background—</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> The bone marrows from wild-type, ROCK2 <jats:sup>+/−</jats:sup> , and ROCK2 <jats:sup>−/−</jats:sup> mice were transplanted into irradiated recipient low-density lipoprotein receptor <jats:sup>−/−</jats:sup> mice, and atherosclerosis was induced with a 16-week high-cholesterol diet. Compared with wild-type bone marrow–transplanted mice, ROCK2 <jats:sup>+/−</jats:sup> bone marrow–transplanted and ROCK2 <jats:sup>−/−</jats:sup> 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%; <jats:italic>P</jats:italic> <0.01 for both) and decreased atherosclerotic lesions in the subaortic sinus (158.1±44.4 and 330.1±109.5×10 <jats:sup>3</jats:sup> μm <jats:sup>2</jats:sup> versus 520.2±125.7×10 <jats:sup>3</jats:sup> μm <jats:sup>2</jats:sup> ; <jats:italic>P</jats:italic> <0.01 for both). These findings correlated with decreased foam cell formation (2.27±0.57 versus 4.10±0.3; <jats:italic>P</jats:italic> <0.01) and increased cholesterol efflux (17.65±0.6 versus 9.75±0.8; <jats:italic>P</jats:italic> <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. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>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.</jats:p> </jats:sec>
収録刊行物
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- Circulation
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Circulation 126 (18), 2236-2247, 2012-10-30
Ovid Technologies (Wolters Kluwer Health)
