Cardiovascular Disease (CVD) and Oxidative Stress
Cardiovascular Diseases (CVD) are multifactorial disorders and, according to the World Health Organization (WHO), are the leading causes of death worldwide. CVD represents 31% of deaths globally in 2013, causing approximately 17.5 million deaths per year. The 2016 CVD statistics update by the American Heart Association (AHA) reported that about one in three persons in the U.S. was affected with one or more CVD types in 2013, which has also an economic impact. Globally, its costs are constantly rising, with an estimate in 2010 of $863 billion and an expectation of $1044 billion by 2030.
The basis of CVD encompasses damage and remodelling of blood vessels that can result in blood flow restrictions affecting the heart and nervous system. There are several disorders that comprise CVD, namely coronary artery disease (CAD), stroke, hypertension, heart failure, rheumatic aetiologies, congenital heart disease and peripheral vascular disease. In 2011, the AHA included preeclampsia (PE) as a risk factor of CVD. Within the CVD spectrum, other well-known risk factors, such as obesity, diabetes, tobacco smoking, a sedentary and unhealthy lifestyle, family history, genetic predisposition and oxidative stress, also play an important role in CVD. Aging is another risk factor, though a non-modifiable one since it increases CVD prevalence mainly due to the accumulation of oxidative damage.
In 1985, the term oxidative stress was coined to describe a disturbance in the balance of reactive oxygen species (ROS) and antioxidants. However, its definition has been changing over the years due to the wide variety of outcomes it can produce.
Currently, oxidative stress is defined as an event where a transient or permanent perturbation in the ROS balance-state generates physiological consequences within the cell, for which the precise outcome depends on ROS targets and concentrations.
Besides cellular damage, ROS have also been shown to be involved as messengers in signalling pathways in a balanced “normal” state. In a homeostatic living system, ROS concentrations fluctuate in a controlled manner and are preserved through antioxidants and other enzymes. Once this homeostatic state starts to fail and ROS levels cannot be controlled, oxidative stress becomes apparent. Oxidative stress plays at least two roles within the cell, the generation of cellular damage, and the involvement in several signalling pathways in its balanced normal state. So far, a substantial amount of time and effort has been expended in the search for a clear link between cardiovascular disease (CVD) and the effects of oxidative stress. In this review, the main focus will be CVD and the influence that oxidative stress has on these pathologies.
There are different types of ROS, such as superoxide, hydroxyl radicals, hydrogen peroxide, singlet oxygen, peroxynitrite and nitric oxide. Overwhelming quantities of ROS are involved in several pathologies, such as cancer, neurodegenerative diseases, diabetes and cardiovascular diseases (CVD), due to its role promoting inflammation, damaging DNA and proteins, as well as lipid peroxidation. The ROS influence on endothelial underlying molecules that can promote apoptosis, necrosis and therefore thrombosis of atherosclerotic plaques, makes oxidative stress a crucial hallmark of CVD and is defined as its early causative factor.
Current pharmacological approaches for CVD are focused on the use of statins, angiotensin receptor blockers (ARBs) and antiplatelet agents. Although the main goal of these therapies is either to lower blood pressure, regulate lipid content in the bloodstream and to prevent the formation of atherosclerotic plaques, some of them have shown effects that are involved in the production or scavenging of ROS.
Statins are commonly used to treat CVD but they do not have a direct influence on ROS; instead, they have an indirect antioxidant effect that inhibits a specific reductase pathway. It is evident that commonly used therapies have become the first step towards the unveiling of the relationship between drugs and ROS-mediated malignancies, such as CVD. There is still much to confirm, and novel and more specific targeted therapies have appeared in recent years with a positive promise of improving cardiovascular care.
Due to the prevalence of the disease across the global population and the projected incidence rate to double between now and 2050, there is a critical need to develop new treatments that prevent or inhibit CVD risk. It has become very apparent that oxidative stress is the major contributing factor in CVD genesis, and therefore, new therapeutic approaches to combat its effects hold the potential to ameliorate endothelial dysfunction and therefore prevent CVD development.
OXIDATIVE STRESS and DIET
It is well known that nutrients are crucial drivers of the cellular performance in our bodies. As such, it is not surprising that there is a remarkable interest in the relation between dietary habits and an association with oxidative stress. Even though the exact mechanisms and pathways in which antioxidant nutrients could be involved have not been fully elucidated yet, a link between fruit,vegetables, nuts and dietary patterns has been commonly reported. Vitamin precursors, such as carotenes, vitamins A, E and C, as well as selenium, zinc, magnesium and resveratrol, are known to have antioxidant properties and can provide protection against oxidative damage and control of the glucose balance. Nutritional studies with specific nuts, such as pistachios and almonds, have shown a reduced lipid peroxidation and a protective effect against oxidative stress in subjects with diabetes and metabolic syndrome.
Several studies have shown that, although some of these antioxidant nutrients can decrease oxidative stress or ameliorate CVDs, unintended detrimental side-effects can occur. Vitamin C intake to reduce oxidative damage has also shown a molecular association with early-onset of obesity, and resveratrol has been reported to induce oxidative breakage of DNA in leukaemia. Therefore, a simple nutritional supplementation needs to be carefully balanced to avoid these unwanted secondary effects, but still maintain its prime purpose.
Though the influence of oxidative stress in CVD genesis has been clearly elucidated, the main factor that remains is the deciphering of the precise mechanisms involved in CVD pathophysiology. Despite this lack of information, several advances have been made regarding possible targets involved in CVD pathogenesis, such as inflammation, oxidation, adhesion molecules, LDLs, endothelial tissue, leucocytes and other factors. Their disturbance or alteration can potentially lead to endothelial dysfunction, which is the main factor in CVD development. It has also become evident that numerous interlinked cellular metabolic cascades form the basis of CVD, and are intricately linked and modulated by ROS.
Oxidative Stress in Cancer and Fibrosis
Oxidative stress is defined as the imbalance between the production of reactive oxygen species (ROS) and the capability of the cell to elicit an effective antioxidant response. While there are some positive roles regarding innate immunity and inflammatory signalling in the immune cells, most ROS are harmful to cells due to the accumulation of irreversible damages to proteins, lipids, and most importantly, to DNA leading to mutations and cell death. ROS and oxidative stress have been implicated in many diseases, including fibrosis and cancer.
In recent years, antioxidants have drawn much attention as potential therapeutic interventions due to their ability to fight oxidative stress (and thereby negate its role) in fibrosis and cancer development. The main function of antioxidants is to scavenge or neutralize free radical formation and to inhibit the deleterious downstream effects of ROS.
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Oxidative Stress in COPD
Oxidative stress is now recognized as a major predisposing factor in the pathogenesis of COPD. COPD is a major and increasing global health problem that is set to become the third leading cause of death worldwide by 2020. It currently affects about 10% of the population over 45 years of age, rising to 50% in heavy smokers. The major etiologic factor driving this disease is likely to be oxidative and carbonyl stress in the lungs following long-term exposure to cigarette smoke or the combustion products of biomass fuels.
Oxidative stress arises as a result of endogenous antioxidant defences being genetically impaired and/or overwhelmed by the presence of reactive oxygen species (ROS). This in turn can lead to carbonyl stress, where oxidative damage to the surrounding tissues leads to the formation of highly reactive organic molecules that can modify proteins nonenzymatically. COPD is characterized by chronic inflammation and remodelling of the small airways and destruction of the lung parenchyma (emphysema).
The lung is particularly vulnerable to injury from environmental oxidative stress due in part to its anatomic structure. It is constantly exposed to sources of endogenous oxidative stress generated by mitochondrial respiration and inflammatory responses to bacterial and viral infections within the lung. The environmental sources of airborne oxidative stress include oxidant gases and ultrafine particulate material and nanoparticles from industrial pollution and car exhaust fumes. However, the single most important etiologic factor in causing COPD in the western world is cigarette smoking, with inhalation of combustion products from enclosed cooking fires being an important additional etiologic factor in developing countries.
The abundantly produced superoxide radical is a relatively weak oxidizing agent but is the precursor for other more damaging ROS species such as the hydroxyl radical which is elevated in COPD, or the very powerful and damaging peroxynitrite radical formed by the rapid reaction of superoxide with nitric oxide.
Carbonyl Stress in COPD ROS generation has been directly linked to oxidation of proteins, lipids, carbohydrates, and DNA. The major outcome is the formation of reactive carbonyls and their reaction with proteins, otherwise known as protein carbonylation. This accumulation of reactive carbonyls and subsequent protein carbonylation has been commonly referred to as “carbonyl stress,” predominantly associated with chronic disease and aging.
Over 200 cellular antioxidant and detoxification enzymes are under the control of the transcription factor nuclear erythroid-2-related factor 2 (Nrf2), which regulates gene expression through binding to antioxidant response elements within the promoters of the many antioxidant and cytoprotective genes. Patients with COPD have reduced expression of Nrf2-responsive genes due to reduced Nrf2 activity. Upregulation or restoration of Nrf2 activity may, therefore, prove to be of therapeutic benefit in COPD.
The development of novel wide spectrum small-molecule antioxidants with good bioavailability and potency are needed for clinical use in COPD. A number of alternative antioxidant strategies (reviewed elsewhere) have been proposed, some of which have shown promise. The failure of existing antioxidants in COPD studies indicates the need to develop novel more potent antioxidants targeted to the correct intracellular compartment.