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. METHODS AND 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.

译文

背景:巨噬细胞在动脉粥样硬化的发展中起着核心作用。但是,调节其功能的信号通路尚不完全清楚。 Rho相关的含有螺旋线圈的激酶(ROCK1和ROCK2)是丝氨酸-苏氨酸蛋白激酶,参与肌动蛋白细胞骨架的调节。最近的研究表明巨噬细胞和骨髓来源的细胞中的ROCK1介导动脉粥样硬化。然而,尚未确定ROCK2在动脉粥样硬化的发病机理中的类似作用。
方法和结果:将野生型,ROCK2(/-)和ROCK2(-/-)小鼠的骨髓移植到受辐照的低密度脂蛋白受体(-/-)小鼠中,用16诱导了动脉粥样硬化周高胆固醇饮食。与野生型骨髓移植小鼠相比,ROCK2(/-)骨髓移植和ROCK2(-/-)骨髓移植小鼠在主动脉中的脂质蓄积少得多(8.46±1.42%和9.80±2.34%与15.64±1.89%;两者均P <0.01)和主动脉下窦动脉粥样硬化病变减少(158.1±44.4和330.1±109.5×10(3)μm(2)与520.2±125.7×10(3)μm(2) ; P均<0.01)。这些发现与部分介导了ROCK2缺陷的小鼠的泡沫细胞形成减少(2.27±0.57对4.10±0.3; P <0.01)和胆固醇外排增加(17.65±0.6对9.75±0.8; P <0.05)相关。通过过氧化物酶体增殖物激活受体-γ/肝X受体/ ATP结合盒转运蛋白A1途径在巨噬细胞中。
结论:ROCK2部分通过抑制过氧化物酶体增殖物激活的受体-γ介导的胆固醇在巨噬细胞中的逆向转运而导致动脉粥样硬化,这有助于泡沫细胞的形成。这些发现表明,巨噬细胞中ROCK2的抑制在预防动脉粥样硬化的发展中可能具有治疗益处。

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