Oxidative Stress and Cardiovascular Disease

Interest in the role of uncontrolled oxidative processes in response to oxidative stress in the onset and progression of disease, and as contributing factors in organ and system dysfunctions related to ageing, is underlined by the volume of research work and reviews devoted to this area since 1990. These studies cover diverse fields, from the chemistry of oxidative reactions of susceptible substrates in a test-tube, to the occurrence and detection of oxidative processes in living systems, and the relevance of these events in pathophysiology. Although these processes are considered factors in altering or modulating biological functions, it is difficult to reach reliable quantitative estimates of their contribution to multifactorial events such as diseases. This review discusses the links between oxidative stress, with special relevance to lipid oxidation, and cardiovascular functions and disease.

Oxygen is a key factor in energy metabolism in the animal kingdom since it participates in the major energy-releasing reactions, such as substrate utilization and formation of high-energy compounds. Oxygen is also directly involved in oxidative reactions catalysed by several enzymes, such as the oxygenases, resulting in the formation of a large number of bioactive products from lipids (e.g. the eicosanoids), or the hydroxylating enzymes involved in the formation of neurotransmitters from amino acids (e.g. the catecholamines), or in the metabolism of xenobiotics (e.g. hydroxylations or other types of oxygen-dependent reactions).

Under aerobic conditions, in addition to the participation of oxygen to redox reactions, highly reactive unstable and short-lived chemical entities, the so-called reactive oxygen species (ROS) are produced. ROS can be considered as the outcome of oxidative stress, a condition that, in addition to resulting from endogenous processes, can also be induced by a wide range of environmental factors, including UV exposure, pathogen invasion (hypersensitive reactions) and tissue reperfusion after oxygen deprivation. The term ROS, generally referring to the superoxide anion radical (O2 ), H2O2, and the hydroxylradical (OH’—), includes also hypochlorous acid (HOCl), chloramines, singlet oxygen and peroxyradicals. ROS are highly reactive and interact with major biomolecules: they bind to proteins, break DNA strands, react with vital cellular components, and alter structural lipids in biomembranes by attacking double bonds of polyunsaturated fatty acids (PUFA) in membrane phospholipids.

The oxidative modification of proteins and lipids is commonly defined as protein oxidation and lipid peroxidation, respectively. Free iron (Fe3+) and, in general, bivalent metal ions accelerate the decomposition of lipid hydroperoxydes (LOOH—) into compounds such as alkoxyl and peroxyl radicals, 4-hydroxynonenal (4-HNE) and malonylaldehyde (MDA). These compounds, in addition to being end products of peroxidative decomposition of polyenoic fatty acids in the lipid peroxidation process, are also reactive compounds that in turn can continue, amplify and extend the process beyond the initial oxidative event by oxidizing cellular thiol groups.

Lipid peroxidation can spread throughout the cell, and disrupt lipid membranes, even at sites not immediately associated with those where ROS have originated. Lipid peroxidation may be considered a major alteration in ROS-induced cellular derangements for various reasons. Interactions between ROS and cellular structures mainly take place at interfaces between water and cells. Cell membranes, the most obvious site for these interactions, are largely composed of structural lipids. The route oxygen takes from the atmosphere to animal cells and tissues involves a sequence of highly expanded cellular membranes and of membrane-bound particles: red blood cells (highly enriched in oxygen), other types of circulating cells, lipoproteins of different size and composition and endothelial cells.

The area of the surface of red blood cell membranes is in the order of about 0.5 m2/mL blood and that the global surface of the lipoprotein particles is over 1 m2/mL blood, an enormous value that suggests a high surface of exposure to lipid peroxidation. Of particular relevance in this respect is the role of erythrocytes, loaded with `quanta’ of oxygen, and endowed with highly expanded membranes (the peculiar shape of these cells results in a very high surface/volume ratio) enriched in PUFA in structural lipids. Erythrocytes in the arteries continually `bombard’ endothelial cells with `quanta’ of oxygen, and create a persisting highly oxygenated `background’ condition for the major components of vessel walls. In addition, the endothelium interacts with subpopulations of polymorpho-nuclear neutrophils (PMN) and leuckocytes that, upon activation, release ROS.