Reactive Oxygen Species Generation and Atherosclerosis.

Atherosclerosis is the key component of most cardiovascular diseases, including stroke and myocardial infarction. An inflamed endothelium recruits inflammatory cells, such as monocytes, via the expression of various mediators and chemokines. This, in addition to the accumulation of cholesterol and smooth muscle cells (SMCs) in the intima, leads to the transformation of monocytes into foam cells, which consume dead cells and lipids. The atherogenic process involves multiple cell types, that is, endothelial cells (ECs), SMCs, immune cells, and stem/progenitor cells, in which levels of both intracellular and extracellular reactive oxygen and nitrogen species play a fundamental role in vascular cell homoeostasis and eventually affects the development of atherosclerosis. Fine-tuning of cellular redox status is a prerequisite for the well-being of vascular system. Although too much oxidative stress can be detrimental, some basal levels are crucial for proper cell signaling. Recently, a number of publications in ATVB and other journals have demonstrated substantial progress in research into oxidative stress vascular disease, especially atherosclerosis. In the present article, we highlight these updated publications, providing insights into the mechanisms of reactive oxygen species (ROS) generation in pathophysiological conditions of the vessel wall, and the contribution of redox imbalance to lesion formation via influencing vascular cell (dys)functions. Oxidative stress is defined as a cellular condition where the damaging effect of oxidant is greater than the beneficial effect of antioxidants. Major oxidants are based on O 2 molecules, which are taken in during respiration, with higher reactivity than molecular O 2 , and are known as ROS. ROS are, thus, broadly defined as oxygen-containing chemical species with higher reactive properties. Major ROS include superoxide (O 2 ·) and hydroxyl (HO·) free radicals, as well as nonradical molecules, such as hydrogen peroxide (H 2 O 2 ). Primary sources of oxidative stress in vessel wall are mitochondria, uncoupled nitric oxide synthase, lipoxygenase, myeloperoxidase, xanthine oxidase (XO), and importantly NAD(P)H oxidases (Figure 1). However, the influence of ROS-producing enzymes, especially NADPH oxidases, in the development of atherosclerosis is ambiguous. Nox4-derived mitochondrial ROS were detrimental in older mice with atherosclerosis, and dominant negative mutant form of Nox4 decreased atherosclerosis formation. On the other hand, Nox4 knockout aggravated atherosclerosis, especially in diabetic mice. High levels of oxidative stress can be counteracted by complex antioxidant cell systems that are crucial for the maintenance of redox balance. The key player that plays a primary role in the regulation of antioxidant gene response is nuclear factor erythroid 2–related factor 2 (Nrf2), encoded by the Nfe2l2 gene. However, depending on the mouse model used and cell type analyzed or even sex of animals, Nrf2 showed both proand antiatherogenic properties. Wire injury induces higher neointima formation in Nfe2l2 mice than in control animals. Global knockout of Nfe2l2 in Apoe mice decreased the formation of atherosclerotic lesions. Transplantation of Nfe2l2 bone marrow to Apoe or Ldlr recipients attenuated atherosclerosis, what underlines proatherogenic activity of Nrf2 in myeloid cells. However, increased formation of plaque in Ldr mice transplanted with Nfe2l2 bone marrow was also reported. On the other hand, activation of Nrf2 in SMCs or ECs was protective against atherosclerosis. Furthermore, knockouts of potent antioxidant enzymes, for example, Gpx1, Prdx2, Hmox1, can also aggravate plaque formation. Importantly, basal levels of ROS were crucial for the activation of endoplasmic reticulum (ER) stress response, maintenance of SMC contractile phenotype, or differentiation of SMC from stem cells. Thus, the regulation of oxidative stress is complex, and investigation of its role in the pathogenesis of atherosclerosis remains an important subject of many studies. Therefore, the aim of this article is to summarize the latest advances in the research on the role of oxidative stress in the modulation of cells that can affect the development of atherosclerosis.