Winter, Carla (2018): The impact of the circadian clock on myeloid cell recruitment during atherosclerosis. Dissertation, LMU München: Faculty of Medicine |
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Abstract
Cardiovascular complications, as a consequence of atherosclerosis, are the leading cause of mortality worldwide. Their onset exhibits a circadian incidence with a peak in the morning hours, thus indicating a circadian susceptibility to cardiovascular diseases. Circadian rhythmicity is controlled by the circadian clock and comprises rhythmic changes in physiological processes, immune cell functionality, and immune cell trafficking, hence leading to time-dependent susceptibilities to diseases and its outcomes. Here, we hypothesized a circadian control of leukocyte recruitment during early atherosclerotic lesion development. We observed rhythmic myeloid cell recruitment to atherosclerotic lesions in hypercholesterolemic Apoe-/- mice with elevated myeloid cell recruitment primarily during the transition from the activity to the resting phase. This phenotype was abolished in mice lacking the clock gene Bmal1 in myeloid but not endothelial cells, highlighting a leukocyte-intrinsic regulatory mechanism. Specifically, myeloid cell derived CCL2 exhibited diurnal rhythmicity and blockage of CCL2-CCR2 signaling abrogated rhythmicity in arterial leukocyte recruitment. In contrast, myeloid cell recruitment in the microcirculation peaked during the early activity phase and CCL2-CCR2 signaling blockage had only minor effects. Subsequently, timed pharmacological CCR2 neutralization during the activity phase ameliorated atherosclerosis without disturbing microvascular recruitment, while timed treatment during the resting phase did not affect the development of atherosclerotic lesions. Overall, we discovered a time-dependent leukocyte recruitment pattern to atherosclerotic lesions and with the identification of its underlying mechanism successfully established a novel chrono-pharmacological treatment strategy.
Item Type: | Theses (Dissertation, LMU Munich) |
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Keywords: | Circadian clock, atherosclerosis, chrono-pharmacological treatment strategy |
Subjects: | 600 Technology, Medicine 600 Technology, Medicine > 610 Medical sciences and medicine |
Faculties: | Faculty of Medicine |
Language: | English |
Date of oral examination: | 11. November 2018 |
1. Referee: | Söhnlein, Oliver |
MD5 Checksum of the PDF-file: | 6ae8535594fbd66f47cf7b60a8e70c92 |
Signature of the printed copy: | 0700/UMD 18255 |
ID Code: | 23458 |
Deposited On: | 24. Jan 2019 15:41 |
Last Modified: | 23. Oct 2020 16:13 |