Abstract
Cardiovascular diseases (CVD) are still the first cause of death worldwide. Their main origin is the development of atherosclerotic plaque, which consists in the accumulation of lipids and inflammatory leucocytes within the vascular wall of large vessels. Beyond dyslipidemia, diabetes, obesity, hypertension and smoking, the alteration of circadian rhythms, in shift workers for instance, has recently been recognized as an additional risk factor. Accordingly, targeting a pro-atherogenic pathway at the right time window, namely chronotherapy, has proven its efficiency in reducing plaque progression without affecting healthy tissues in mice, thus providing the rationale of such an approach to treat CVD and to reduce drug side effects. Nuclear receptors are transcriptional factors involved in the control of many physiological processes. Among them, Rev-erbs and RORs control metabolic homeostasis, inflammatory processes and the biological clock. In this review, we discuss the opportunity to dampen atherosclerosis progression by targeting such ligand-activated core clock components in a (chrono-)therapeutic approach in order to treat CVD.
Highlights
In 2016, 17.9 million people died from Cardiovascular diseases (CVD), which is 31% of deaths worldwide, with more than three out of four occurring in low- and mid-income countries
Because 85% of these deaths are due to ischemic heart diseases and stroke, according to the WHO, atherosclerosis may be seen as the primary cause of CVDs, even if some strokes may result from events independent of plaque rupture
Atherosclerosis is commonly defined as a chronic inflammatory disease of the vascular wall consisting in the internalization of lipids, mainly small dense LDL and VLDL-remnants [1], that trigger the recruitment of leucocytes, including neutrophils, monocytes/macrophages, dendritic cells, T cells, B cells and mastocytes [2,3] (Figure 1)
Summary
In 2016, 17.9 million people died from CVD, which is 31% of deaths worldwide, with more than three out of four occurring in low- and mid-income countries. In addition to cholesterol metabolism, macrophages overwhelmed by massive cholesterol uptake, macrophages eventually become foam cells, where the accumulation of lipids produce cytokines, such as NLRP3 inflammasome-processed IL-18 and IL-1β interleukins, which, together with ILleads to necrosis and apoptosis, forming the necrotic core. Levels of circulating and infiltrated leucocytes, as well as the activity of the immune system (cytokine secretion, pathogen response and phagocytosis [18]), exhibit diurnal oscillations These studies did not show a direct relationship between clock disruption and atherogenesis, it was later shown that shift work and acute circadian misalignment were associated with subclinical atherosclerosis, measured as higher intima-media thickness and an elevated systemic inflammation, even after adjusting for age and common risk factors [19,20,21,22]. NRs are transcription factors that can be bound and activated by natural lipophilic ligands and by synthetic ligands, representing interesting both pharmacological targets to modulate the clock and common atherosclerosis risk factors
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