Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian University, Munich 80336, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian University, Munich 80336, Germany.
Cell Metab. 2018 Jul 3;28(1):175-182.e5. doi: 10.1016/j.cmet.2018.05.002. Epub 2018 May 31.
Onset of cardiovascular complications as a consequence of atherosclerosis exhibits a circadian incidence with a peak in the morning hours. Although development of atherosclerosis extends for long periods of time through arterial leukocyte recruitment, we hypothesized that discrete diurnal invasion of the arterial wall could sustain atherogenic growth. Here, we show that myeloid cell recruitment to atherosclerotic lesions oscillates with a peak during the transition from the activity to the resting phase. This diurnal phenotype is regulated by rhythmic release of myeloid cell-derived CCL2, and blockade of its signaling abolished oscillatory leukocyte adhesion. In contrast, we show that myeloid cell adhesion to microvascular beds peaks during the early activity phase. Consequently, timed pharmacological CCR2 neutralization during the activity phase caused inhibition of atherosclerosis without disturbing microvascular recruitment. These findings demonstrate that chronic inflammation of large vessels feeds on rhythmic myeloid cell recruitment, and lay the foundation for chrono-pharmacology-based therapy.
动脉粥样硬化导致的心血管并发症的发作呈昼夜节律性，早晨时达到高峰。尽管动脉白细胞募集使动脉粥样硬化的发展持续了很长时间，但我们假设动脉壁的离散昼夜入侵可以维持动脉粥样硬化的生长。在这里，我们发现，在从活动期到休息期的过渡期间，向动脉粥样硬化病变募集的髓样细胞呈周期性波动，达到峰值。这种昼夜表型受髓样细胞来源的 CCL2 的节律性释放调节，阻断其信号通路可消除白细胞的振荡性黏附。相比之下，我们发现髓样细胞黏附在微血管床中的峰值出现在活动早期。因此，在活动期进行定时药理学 CCR2 中和治疗可抑制动脉粥样硬化，而不会干扰微血管募集。这些发现表明，大血管的慢性炎症依赖于周期性的髓样细胞募集，并为基于时间药理学的治疗奠定了基础。
