Circadian Influence on Metabolism and Inflammation in Atherosclerosis

Abstract

Many aspects of human health and disease display daily rhythmicity. The brain's suprachiasmic nucleus, which interprets recurring external stimuli, and autonomous molecular networks in peripheral cells together, set our biological circadian clock. Disrupted or misaligned circadian rhythms promote multiple pathologies including chronic inflammatory and metabolic diseases such as atherosclerosis. Here, we discuss studies suggesting that circadian fluctuations in the vessel wall and in the circulation contribute to atherogenesis. Data from humans and mice indicate that an impaired molecular clock, disturbed sleep, and shifting light-dark patterns influence leukocyte and lipid supply in the circulation and alter cellular behavior in atherosclerotic lesions. We propose that a better understanding of both local and systemic circadian rhythms in atherosclerosis will enhance clinical management, treatment, and public health policy.

Keywords: atherosclerosis; circadian rhythm; inflammation; life style; metabolism.

Figure 1. The core molecular clock machinery

The core molecular clock, found in all mammalian cells, is composed of both positive (Bmal1 and Clock) and negative (Per, Cry and Rev-erbα) singling branches. The molecular clock regulates the expression of hundreds of clock controlled genes (CCGs) including mediators of inflammation and metabolism. Not depicted here are regulatory mechanism of circadian gene expression by epigenetics and chromatin remodelling.

Figure 2. Circadian influence on atherosclerosis

Circadian rhythms influence the supply of leukocytes and lipids in the circulation as well as the behavior of endothelial cells, smooth muscle cells and macrophages in the vessel wall. Together, these systemic factors and local cellular events mediate atherosclerosis. HSC indicates hematopoietic stem cell.