DNA damage and repair in atherosclerosis: current insights and future perspectives

Abstract

Atherosclerosis is the leading cause of morbidity and mortality among Western populations. Over the past two decades, considerable evidence has supported a crucial role for DNA damage in the development and progression of atherosclerosis. These findings support the concept that the prolonged exposure to risk factors (e.g., dyslipidemia, smoking and diabetes mellitus) leading to reactive oxygen species are major stimuli for DNA damage within the plaque. Genomic instability at the cellular level can directly affect vascular function, leading to cell cycle arrest, apoptosis and premature vascular senescence. The purpose of this paper is to review current knowledge on the role of DNA damage and DNA repair systems in atherosclerosis, as well as to discuss the cellular response to DNA damage in order to shed light on possible strategies for prevention and treatment.

Figure 1

A simplified overview of atherosclerosis. The figure shows that one of the earliest events in atherosclerosis is an altered endothelial function (dysfunction), causing increased permeability to lipids, recruitment of circulating monocytes and T lymphocytes, formation of foam cells from macrophages that bind oxidatively modified LDL, secretion of inflammatory mediators and growth factors, and the accumulation of smooth muscle cells leading to the formation of an atherosclerotic plaque. In addition, the plaque environment may also induce DNA modification of vascular cells by action of endogenous DNA-damaging agents, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS).

Figure 2

DNA damage and DDR pathways. The genome is exposed to several kinds of damage, such as SSB, DSB, bulky adducts, base mismatch, insertion and deletion. The choice of repair pathway depends on the type of lesion.