Myeloid
            <i>Bmal1</i>
            deletion increases monocyte recruitment and worsens atherosclerosis

Huo, Mingyu; Huang, Yü; Qu, Dan; Zhang, Hongsong; Wong, Wing Tak; Chawla, Ajay; Tian, Xiao Yu

doi:10.1096/fj.201601030r

Cited by 66 publications

(52 citation statements)

References 41 publications

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“…In mice, disrupted rhythms or clock gene deletion are associated with exacerbation of many disease states, including diabetes [27], cardiovascular disease[28, 29], inflammation [30, 31], and neurodegeneration [32]. In humans, circadian rhythm disturbances, often caused by employment and lifestyle issues such as night shift work, are associated with increased risk of diseases such as diabetes, breast cancer, and coronary artery disease [33–36].…”

Section: The Mammalian Circadian Clockmentioning

confidence: 99%

Circadian Rhythms in AD Pathogenesis: a Critical Appraisal

Musiek¹

2017

Curr Sleep Medicine Rep

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Purpose of the Review A wide array of sleep and circadian deficits have been observed in patients with Alzheimer’s Disease (AD). However, the vast majority of these studies have focused on later-stage AD, and do not shed light on the possibility that circadian dysfunction contributes to AD pathogenesis. The goal of this review it to examine the evidence supporting or refuting the hypothesis that circadian dysfunction plays an important role in early AD pathogenesis or AD risk in humans. Recent Findings Few studies have addressed the role of the circadian system in very early AD, or prior to AD diagnosis. AD appears to have a long presymtomatic phase during which pathology is present but cognition remains normal. Studies evaluating circadian function in cognitively-normal elderly or early-stage AD have thus far not incorporated AD biomarkers. Thus, the cause-and-effect relationship between circadian dysfunction and early-stage AD remains unclear. Summary Circadian dysfunction becomes apparent in AD as dementia progresses, but it is unknown at which point in the pathogenic process rhythms begin to deteriorate. Further, it is unknown if exposure to circadian disruption in middle age increases AD risk later in life. This review address gaps in current knowledge on this topic, and proposes several critical directions for future research which might help to clarify the potential pathogenic role of circadian clock dysfunction in AD.

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Section: The Mammalian Circadian Clockmentioning

confidence: 99%

Circadian Rhythms in AD Pathogenesis: a Critical Appraisal

Musiek¹

2017

Curr Sleep Medicine Rep

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“…Previous studies in mice have shown that genetic disruption of the circadian molecular timekeeping mechanism causes cardiovascular pathology [15][16][17][18][19] . Mice lacking functional Bmal1, and Clock ∆19 mutants, both of which have impaired or arrhythmic circadian clocks, had increased pathological vascular remodeling compared to mice with functional clocks 17 .…”

mentioning

confidence: 99%

Circadian disruption with constant light exposure exacerbates atherosclerosis in male ApolipoproteinE-deficient mice

Chalfant

Howatt

Tannock

et al. 2020

Sci Rep

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Disruption of the circadian system caused by disordered exposure to light is pervasive in modern society and increases the risk of cardiovascular disease. The mechanisms by which this happens are largely unknown. ApolipoproteinE-deficient (ApoE −/−) mice are studied commonly to elucidate mechanisms of atherosclerosis. In this study, we determined the effects of light-induced circadian disruption on atherosclerosis in ApoE −/− mice. We first characterized circadian rhythms of behavior, light responsiveness, and molecular timekeeping in tissues from ApoE −/− mice that were indistinguishable from rhythms in ApoE +/+ mice. These data showed that ApoE −/− mice had no inherent circadian disruption and therefore were an appropriate model for our study. We next induced severe disruption of circadian rhythms by exposing ApoE −/− mice to constant light for 12 weeks. Constant light exposure exacerbated atherosclerosis in male, but not female, ApoE −/− mice. Male ApoE −/− mice exposed to constant light had increased serum cholesterol concentrations due to increased VLDL/LDL fractions. taken together, these data suggest that ApoE −/− mice are an appropriate model for studying lightinduced circadian disruption and that exacerbated dyslipidemia may mediate atherosclerotic lesion formation caused by constant light exposure. More than 600,000 people die every year in the U.S. from heart disease 1. Atherosclerosis, the progressive accumulation of plaques in arteries, is the primary cause of cardiovascular disease (CVD), stroke, and myocardial infarction 2. There are several well-established CVD risk factors including smoking, hypertension, elevated low-density lipoprotein (LDL) cholesterol, obesity, diabetes, and inflammation 3-5. Epidemiological and clinical studies have shown that circadian disruption also increases the risk of CVD 6-8. Circadian rhythms are 24-hour oscillations in gene expression, physiology, and behavior. These rhythms are entrained, or synchronized, with environmental cycles. This allows organisms to anticipate predictable daily changes in the environment to increase their fitness 9-11. Mammalian circadian rhythms are generated by molecular clocks that are located in nearly every tissue in the body 12. These clocks are organized hierarchically. The retina detects and sends information about the light-dark cycle to the master clock in the suprachiasmatic nucleus (SCN). The SCN, in turn, coordinates the timing of clocks located throughout the body 12. At the molecular level, the timekeeping mechanism is a negative transcription/translation feedback loop 13. The transcription factors BMAL1 and CLOCK dimerize and drive the transcription of the Period and Cryptochrome genes. Then PERIOD and CRYPTOCHROME feed back and inhibit the transcription factor activity of BMAL1 and CLOCK, thereby suppressing their own transcription. This feedback loop takes approximately 24-hour to complete and therefore generates a 24-hour molecular rhythm. Recent meta-analyses show that shift workers, who experience chronic circadian disru...

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“…In the same line, Rev-erbα diminishes atherogenic lipoproteins plasma levels (82), modulates the inflammatory profile of macrophages toward an anti-inflammatory phenotype (83) while its activation reduced atherogenesis (84). Accordingly, BMAL1 regulates macrophage polarization as well as the cyclic trafficking of Ly6C hi monocytes and myeloid Bmal1 deletion increased monocyte recruitment and worsened atherosclerosis (Figures 2, 3) (85). Pro-inflammatory recruitment through the CCL2 (MCP-1)-CCR2 axis plays an important role in plaque development (86).…”

Section: Clock Control Of Nlrp3 Inflammasome Activation Il-1β Producmentioning

confidence: 92%

Circadian Control of Inflammasome Pathways: Implications for Circadian Medicine

Pourcet

Duez

2020

Front. Immunol.

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The innate immune system senses "non-self" molecules derived from pathogens (PAMPs) as well as endogenous damage-associated molecular patterns (DAMPs) and promotes sterile inflammation that is necessary for injury resolution, tissue repair/regeneration, and homeostasis. The NOD-, LRR-and pyrin domain containing protein 3 (NLRP3) is an innate immune signaling complex whose assembly and activation can be triggered by various signals ranging from microbial molecules to ATP or the abnormal accumulation of crystals, thus leading to IL-1β and IL-18 maturation and secretion. Deregulation of the NLRP3 signaling cascade is associated with numerous inflammatory and metabolic diseases including rheumatoid arthritis, gout, atherosclerosis or type 2 diabetes. Interestingly, the circadian clock controls numerous inflammatory processes while clock disruption leads to or exacerbates inflammation. Recently, the biological clock was demonstrated to control NLRP3 expression and activation, thereby controlling IL-1β and IL-18 secretion in diverse tissues and immune cells, particularly macrophages. Circadian oscillations of NLRP3 signaling is lost in models of clock disruption, contributing to the development of peritonitis, hepatitis, or colitis. Sterile inflammation is also an important driver of atherosclerosis, and targeting the production of IL-1β has proven to be a promising approach for atherosclerosis management in humans. Interestingly, the extent of injury after fulminant hepatitis or myocardial infarction is time-of-day dependent under the control of the clock, and chronotherapy represents a promising approach for the management of pathologies involving deregulation of NLRP3 signaling.

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Myeloid Bmal1 deletion increases monocyte recruitment and worsens atherosclerosis

Cited by 66 publications

References 41 publications

Circadian Rhythms in AD Pathogenesis: a Critical Appraisal

Circadian Rhythms in AD Pathogenesis: a Critical Appraisal

Circadian disruption with constant light exposure exacerbates atherosclerosis in male ApolipoproteinE-deficient mice

Circadian Control of Inflammasome Pathways: Implications for Circadian Medicine

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