Cryptochromes are photoreceptors that mediate the circadian entrainment by light in plants and animals. They are also involved in magnetic field sensing in some animals. Recent studies suggest that cryptochromes play an essential role in metabolism and cardiovascular disease. However, the tissue-specific function of cryptochromes in atherosclerosis is unknown. We transplanted bone marrow from wild-type (WT) and cryptochrome 1/2 knockout (Cry1/2 KO) mice into irradiated recipient low-density lipoprotein receptor knockout (LDLR-/- ) mice and induced atherosclerosis with a high cholesterol diet for 12 weeks. There was a reduction in atherosclerotic plaques and macrophage accumulation in the aorta of LDLR-/- mice that received Cry1/2 KO bone marrow compared to mice that received WT bone marrow. Bone marrow-derived macrophages (BMDMs) from Cry1/2 KO mice exhibited impaired uptake of low-density lipoprotein, and subsequently, impaired foam cell formation. Analysis of macrophage mRNA circadian oscillations revealed that the circadian rhythm of the LDLR mRNAs was lost in Cry1/2 KO BMDMs. Reinstalling the circadian oscillatory LDLR mRNAs using adenovirus into the BMDMs was able to rescue the lipid uptake and foam cell formation function. However, the noncircadian oscillatory LDLR mRNAs exhibited reduced ability to rescue the macrophage functions. These findings indicate that cryptochromes in bone marrow-derived cells are critical mediators of atherosclerosis through regulation of the LDLR mRNA circadian rhythm. Therapeutic measures targeting cryptochromes in the macrophage may have important implications for atherosclerosis.

中文翻译：

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骨髓来源细胞中昼夜节律基因隐花色素的缺乏可防止 LDLR -/- 小鼠的动脉粥样硬化

隐花色素是光感受器，通过光在植物和动物中调节昼夜节律。它们还参与一些动物的磁场感应。最近的研究表明，隐花色素在新陈代谢和心血管疾病中起着至关重要的作用。然而，隐花色素在动脉粥样硬化中的组织特异性功能尚不清楚。我们将来自野生型 (WT) 和隐花色素 1/2 敲除 (Cry1/2 KO) 小鼠的骨髓移植到经照射的受体低密度脂蛋白受体敲除 (LDLR-/-) 小鼠中，并通过高胆固醇饮食诱导动脉粥样硬化 12周。与接受 WT 骨髓的小鼠相比，接受 Cry1/2 KO 骨髓的 LDLR-/- 小鼠的主动脉中的动脉粥样硬化斑块和巨噬细胞积聚减少。来自 Cry1/2 KO 小鼠的骨髓源性巨噬细胞 (BMDM) 表现出低密度脂蛋白摄取受损，随后泡沫细胞形成受损。巨噬细胞 mRNA 昼夜节律振荡的分析表明，LDLR mRNA 的昼夜节律在 Cry1/2 KO BMDM 中丢失。使用腺病毒将昼夜节律振荡 LDLR mRNA 重新安装到 BMDM 中能够挽救脂质摄取和泡沫细胞形成功能。然而，非昼夜节律振荡的 LDLR mRNA 表现出拯救巨噬细胞功能的能力降低。这些发现表明，骨髓衍生细胞中的隐花色素是通过调节 LDLR mRNA 昼夜节律而导致动脉粥样硬化的关键介质。针对巨噬细胞中的隐花色素的治疗措施可能对动脉粥样硬化具有重要意义。