Bmal1 Deletion in Myeloid Cells Attenuates Atherosclerotic Lesion Development and Restrains Abdominal Aortic Aneurysm Formation in Hyperlipidemic Mice

Abstract

Objective: Although the molecular components of circadian rhythms oscillate in discrete cellular components of the vasculature and many aspects of vascular function display diurnal variation, the cellular connections between the molecular clock and inflammatory cardiovascular diseases remain to be elucidated. Previously we have shown that pre- versus postnatal deletion of Bmal1 (brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1), the nonredundant core clock gene has contrasting effects on atherogenesis. Here we investigated the effect of myeloid cell Bmal1 deletion on atherogenesis and abdominal aortic aneurysm formation in mice. Approach and Results: Mice lacking Bmal1 in myeloid cells were generated by crossing Bmal1 flox/flox mice with lysozyme 2 promoter-driven Cre recombinase mice on a hyperlipidemic low-density lipoprotein receptor-deficient background and were fed on a high-fat diet to induce atherosclerosis. Atherogenesis was restrained, concomitant with a reduction of aortic proinflammatory gene expression in myeloid cell Bmal1 knockout mice. Body weight, blood pressure, blood glucose, triglycerides, and cholesterol were unaltered. Similarly, myeloid cell depletion of Bmal1 also restrained Ang II (angiotensin II) induced formation of abdominal aortic aneurysm in hyperlipidemic mice. In vitro, RNA-Seq analysis demonstrated a proinflammatory response in cultured macrophages in which there was overexpression of Bmal1. Conclusions: Myeloid cell Bmal1 deletion retards atherogenesis and restrains the formation of abdominal aortic aneurysm and may represent a potential therapeutic target for inflammatory cardiovascular diseases.

Impact of Time-Restricted Feeding to Late Night on Adaptation to a 6 h Phase Advance of the Light-Dark Cycle in Mice

“…Despite an increasing awareness of the hazards of circadian disruption, modern lifestyle is subject to frequent desynchronization due to shift working, artificial light, and transmeridian air flight. While the molecular clock may be adjusted by small molecules that target clock proteins ( Cho et al, 2012 ; Solt et al, 2012 ; Wallach and Kramer, 2015 ), we have found that inhibiting circadian rhythms may also mitigate circadian disorders ( Yang et al, 2019 , 2020 ).…”

Deficiency of circadian gene cryptochromes in bone marrow‐derived cells protects against atherosclerosis in LDLR −/− mice

“…36 Deficiency of BMAL1 during the development stage or adulthood has different consequences on the atherosclerotic processes. 14,16 Thus, the specific peripheral clock roles of Cry1/Cry2 in BMDCs, independent of the whole-body central clock rhythm, require further study. Disruption of the core circadian machinery is not always detrimental to cardiovascular physiology.…”

“…37 BMAL1 deficiency in smooth muscle cells prevents experimental aortic aneurysm 38 and deletion of BMAL1 in myeloid cells provides protection from both atherogenesis and abdominal aortic aneurysm. 16 Mice with CLOCK deficiency also exhibited an attenuated inflammatory response with altered inhibin signaling. 39 We reasoned that individual circadian genes may have different roles in different tissues.…”

“…15 In myeloid cells, deletion of BMAL1 protects mice from developing abdominal aortic aneurysm and atherosclerosis. 16 However, global or hepatic ablation of BMAL1 enhances atherosclerosis, 17 indicating the versatile roles of circadian genes in different tissues.…”

Postnatal deletion of Bmal1 in mice protects against obstructive renal fibrosis via suppressing Gli2 transcription

“…Systolic blood pressure was measured in conscious mice using a computerized noninvasive tail-cuff system as we previously described. 21 Briefly, mice were pre-trained for three consecutive days for adapting the environment and the whole procedure. Before recording, mice may have a rest for about 5 minutes until the animal remained comfortably and quietly in the holder.…”