Circadian rhythms of risk factors and management in atherosclerotic and hypertensive vascular disease: Modern chronobiological perspectives of an ancient disease

Abstract

Atherosclerosis, a chronic inflammatory disease of the arteries that appears to have been as prevalent in ancient as in modern civilizations, is predisposing to life-threatening and life-ending cardiac and vascular complications, such as myocardial and cerebral infarctions. The pathogenesis of atherosclerosis involves intima plaque buildup caused by vascular endothelial dysfunction, cholesterol deposition, smooth muscle proliferation, inflammatory cell infiltration and connective tissue accumulation. Hypertension is an independent and controllable risk factor for atherosclerotic cardiovascular disease (CVD). Conversely, atherosclerosis hardens the arterial wall and raises arterial blood pressure. Many CVD patients experience both atherosclerosis and hypertension and are prescribed medications to concurrently mitigate the two disease conditions. A substantial number of publications document that many pathophysiological changes caused by atherosclerosis and hypertension occur in a manner dependent upon circadian clocks or clock gene products. This article reviews progress in the research of circadian regulation of vascular cell function, inflammation, hemostasis and atherothrombosis. In particular, it delineates the relationship of circadian organization with signal transduction and activation of the renin-angiotensin-aldosterone system as well as disturbance of the sleep/wake circadian rhythm, as exemplified by shift work, metabolic syndromes and obstructive sleep apnea (OSA), as promoters and mechanisms of atherogenesis and risk for non-fatal and fatal CVD outcomes. This article additionally updates advances in the clinical management of key biological processes of atherosclerosis to optimally achieve suppression of atherogenesis through chronotherapeutic control of atherogenic/hypertensive pathological sequelae.

Keywords: Circadian rhythm; atherosclerosis; chronotherapy; clock genes; hypertension; sleep.

Figure 1.. Circadian oscillating and non-oscillating risk factors for atherosclerosis and its coronary and cerebral complications.

Various metabolic and functional processes are in association with risk factors, with or without circadian oscillation, which promote the development of atherosclerotic and hypertensive vascular disease and its life-fatal complications, namely coronary and cerebral ischemia and infarction.

Figure 2.. Circadian rhythmic regulation of clock gene expression and modulation of circadian variations of risk factors for the pathogenesis of atherosclerotic and hypertensive vascular disease.

In engagement with the circadian receptor RORα, BMAL1 and CLOCK form a heterodimeric complex to positively regulate expression of target genes coding for PERs and CRYs, two factors that repress the transcription activity of BMAL1/CLOCK complex, as part of the negative feedback loop of circadian rhythm. Generated at high levels during atherogenesis, oxidative products of cholesterol or oxysterols bind to RORα proteins, contributing to the transcriptional control of the Bmal1 and Clock genes. The circadian clock gene changes underlie the development of adverse events in atherosclerotic and hypertensive vascular disease.

Figure 3.. Disturbance of circadian rhythms, clock gene expression, deregulation of RAAS/AR and risk for cardiovascular health and disease.

RAAS, renin-angiotensin-aldosterone system; AR, adenosine receptor.