1. Bmal1 Deletion in Myeloid Cells Attenuates Atherosclerotic Lesion Development and Restrains Abdominal Aortic Aneurysm Formation in Hyperlipidemic Mice.
- Author
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Yang G, Zhang J, Jiang T, Monslow J, Tang SY, Todd L, Puré E, Chen L, and FitzGerald GA
- Subjects
- ARNTL Transcription Factors genetics, Angiotensin II pharmacology, Animals, Aortic Aneurysm, Abdominal chemically induced, Atherosclerosis etiology, Atherosclerosis pathology, Cells, Cultured, Crosses, Genetic, Diet, High-Fat, Gene Deletion, Gene Expression, Hyperlipidemias etiology, Inflammation, Integrases genetics, Macrophages, Peritoneal chemistry, Macrophages, Peritoneal physiology, Mice, Mice, Knockout, Muramidase genetics, Promoter Regions, Genetic genetics, Receptors, LDL deficiency, Receptors, LDL genetics, ARNTL Transcription Factors deficiency, ARNTL Transcription Factors physiology, Aortic Aneurysm, Abdominal prevention & control, Atherosclerosis prevention & control, Hyperlipidemias complications, Myeloid Cells chemistry
- 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.
- Published
- 2020
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