Kennedy David J, Kuchibhotla Sai D, Guy Ella, Park Young Mi, Nimako George, Vanegas DiFernando, Morton Richard E, Febbraio Maria
Department of Cell Biology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Arterioscler Thromb Vasc Biol. 2009 Oct;29(10):1481-7. doi: 10.1161/ATVBAHA.109.191940. Epub 2009 Jul 16.
CD36 has been shown to play a role in atherosclerosis in the apolipoprotein E-knockout (apoE(o)) mouse. We observed no difference in aortic lesion area between Western diet (WD)-fed LDLR(o) and LDLR(o)/CD36(o) mice. The objective was to understand the mechanism of CD36-dependent atherogenesis.
ApoE(o) mice transplanted with bone marrow from LDLR(o)/CD36(o) mice had significantly less aortic lesion compared with those transplanted with LDLR(o) marrow. Reciprocal macrophage transfer into hyperlipidemic apoE(o) and LDLR(o) animals showed that foam cell formation induced by in vivo modified lipoproteins was dependent on the lipoprotein, not macrophage type. LDLR(o) and LDLR(o)/CD36(o) mice were fed a cholesterol-enriched diet (HC), and we observed significant lesion inhibition in LDLR(o)/CD36(o) mice. LDL/plasma isolated from HC-fed LDLR(o) mice induced significantly greater jnk phosphorylation, cytokine release, and reactive oxygen species secretion than LDL/plasma from WD-fed LDLR(o) mice, and this was CD36-dependent. HC-fed LDLR(o) mice had higher circulating levels of cytokines than WD-fed mice.
These data support the hypothesis that CD36-dependent atherogenesis is contingent on a proinflammatory milieu that promotes the creation of specific CD36 ligands, not solely hypercholesterolemia, and may explain the greater degree/accelerated rate of atherosclerosis observed in syndromes associated with inflammatory risk.
已证实CD36在载脂蛋白E基因敲除（apoE⁻）小鼠的动脉粥样硬化中发挥作用。我们观察到，喂食西方饮食（WD）的低密度脂蛋白受体基因敲除（LDLR⁻）小鼠和LDLR⁻/CD36⁻小鼠之间的主动脉病变面积没有差异。目的是了解CD36依赖性动脉粥样硬化的发生机制。
与移植LDLR⁻骨髓的apoE⁻小鼠相比，移植LDLR⁻/CD36⁻小鼠骨髓的apoE⁻小鼠主动脉病变明显更少。将巨噬细胞相互转移至高脂血症的apoE⁻和LDLR⁻动物体内，结果显示体内修饰脂蛋白诱导的泡沫细胞形成取决于脂蛋白，而非巨噬细胞类型。给LDLR⁻和LDLR⁻/CD36⁻小鼠喂食富含胆固醇的饮食（HC），我们观察到LDLR⁻/CD36⁻小鼠的病变受到显著抑制。与喂食WD的LDLR⁻小鼠的LDL/血浆相比，从喂食HC的LDLR⁻小鼠分离出的LDL/血浆诱导的c-Jun氨基末端激酶（JNK）磷酸化、细胞因子释放和活性氧分泌显著增加，且这是CD36依赖性的。喂食HC的LDLR⁻小鼠的循环细胞因子水平高于喂食WD的小鼠。
这些数据支持以下假说，即CD36依赖性动脉粥样硬化取决于促炎环境，该环境促进特定CD36配体的产生，而非仅取决于高胆固醇血症，这可能解释了在与炎症风险相关的综合征中观察到的动脉粥样硬化程度更高/进展速度更快的现象。
