Physicians' Academy for Cardiovascular Education

Circadian fluctuations influence atherosclerotic processes

Circadian Control of Inflammatory Processes in Atherosclerosis and Its Complications

Steffens S, Winter C, Schloss MJ, et al. - Arterioscler Thromb Vasc Biol. 2017;37:1022-1028.

Background

It is known that fluctuations of glucocorticoids, catecholamines, blood viscosity and platelet reactivity during the day, correlate with plaque rupture and thrombus formation. Also, heart rate and blood pressure are higher in the early morning hours, leading to increased cardiac energy and oxygen demand, and to a higher frequency of acute cardiovascular (CV) events, ischemic stroke or arrhythmias [1]. As shift workers, who work at night and sleep during the day, have a disruption in their circadian rhythm they have an increased risk for an acute event [2]. Also in mice, it was noticed that infarct size, fibrosis and adverse remodeling were larger after ischemia onset at the sleep-to-wake transition period.

Circadian rhythms and their regulation

Circadian rhythms are 24-hour cycles that adjust physiological activities to environmental changes, and regulate sleep–wake cycles, feeding, body temperature, blood pressure, heart rate, hormone secretion, and lipid metabolism among others. In addition, the peak of proliferation of bone marrow cells follows a circadian rhythm, since it occurs at noon and troughs at around midnight, and there are similar daily patterns for myeloid and erythroid progenitors [3].

Circadian rhythms are regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, which receives signals from the eye and translate light signals into hormone release or sympathetic innervation. The BMAL1 (brain and muscle ARNT [arylhydrocarbon receptor nuclear translocator]-like) and CLOCK (circadian locomotor output cycles kaput) proteins act as transcriptional–translational feedback loops and regulate their own oscillatory expression as well as the rhythmic expression of other proteins, including markers of inflammation [4,5].

Moreover, individual cells throughout the body also contain autonomous peripheral clocks, which are capable of maintaining circadian timing independent of the central clock [6]. CRY (clock transcriptional repressor cryptochrome) and PER (clock transcriptional repressor Period) interfere with the activity of BMAL1 and CLOCK, and represent a negative feedback loop. A third feed-back loop consists of REV-ERB (nuclear receptor reverse-ERB) and retinoic acid ROR (receptor-related orphan receptors). Cell-intrinsic molecular clocks in leukocytes, endothelial cells, macrophages, and smooth muscle cells have been linked to inflammatory processes underlying atherosclerotic lesion development.

Circadian Clocks in Atherosclerosis

There is evidence suggesting that circadian rhythms might be involved in the pathogenesis of atherosclerosis. As mRNA expression levels of clock genes were noticed to be lower in human carotid plaque-derived vascular smooth muscle cells compared to its normal counterparts from the same donors, it is hypothesized that a mismatch of circadian gene expression patterns in atherosclerotic vessels with central clocks might play a role in plaque stability [7].

For example, patients with CAD have lower Cry1 mRNA levels compared with healthy controls, whereas the overexpression of CRY1 reduced the expression of inflammatory markers, plasma lipid levels, and plaque development in Apoe−/− mice [8]. In contrast, REV-ERB knockdown in hematopoietic cells enhanced lesion formation, which was reduced by pharmacological activation of REV-ERB. However, whether all these observations are directly linked to the regulation of circadian rhythms remains unclear.

In this context, it is suggested that the core clock gene Arntl (encoding BMAL1) might also regulate many targets independent of circadian rhythms. Furthermore, the majority of BMAL1 downstream genes appeared to be tissue-specific and therefore, central and peripheral clocks in tissues or cells might play differential pathophysiological roles in atherosclerosis due to their tissue-specificity [9,10].

For example, there is evidence for BMAL1-dependent peripheral circadian clocks in immune cells, which regulate the expression of inflammatory markers such as CCL2. The CCL2-CCR2 axis seems very important in early lesion development in mice. Moreover, the deficiency of circadian clock gene PER2 promotes aortic endothelial dysfunction, which is the initial stage of lesion development [11]. In addition, deficiency of PER2 was associated with decreased production of vasodilator nitric oxide, which might also promote enhanced leukocyte–endothelium adhesion [12]. Also trafficking of leukocytes is mediated by rhythmic expression of chemokines which regulate diurnal oscillations between blood and tissues. In addition to this, it was shown that myeloid-specific deletion or Arntl¬ in Apoe-/- mice accelerated arterial monocyte recruitment, M1 macrophage polarization and atherosclerotic plaque development. A last example of tissue-specific clocks involved in atherosclerosis is the core clock transcriptional regulation of pro-thrombotic mediators von Willebrand factor, fibrinogen, and PAI-1 (plasminogen activation inhibitor-1) by CLOCK and BMAL1 and constitutive Arntl deficiency in mice leads to accelerated arterial thrombus formation [13], which may suggest a causal implication of BMAL1 in the onset of an acute ischemic cardiovascular event.

Also, ex-vivo data showed that ~8% of the genes from macrophages isolated from spleen, lymph node and peritoneum are under circadian control.

Conclusion

Circadian rhythmicity plays a role in atherosclerosis by influencing atherosclerotic plaque development, and by affecting the underlying inflammatory processes. Further studies on circadian clock deficiency are important to understand how unbalanced circadian rhythms may promote atherosclerosis. Moreover, the potential effects of hypercholesterolemia on circadian expression patterns that promote plaque stability remains unclear. In addition, intervention and application of medication may have a time-dependent effect, which could offer novel approaches for preventing and treating atherosclerosis and its complications.

References

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