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Oxidative Stress - A Delicate Balance
Oxidative stress is a term used to describe an imbalance or dysregulation in the body's ability to clear or repair the damaging effects of reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS, including free radicals, are produced during normal metabolic processes and are necessary for human life.
When the body is unable to produce or make sufficient use of antioxidants, such as glutathione—an endogenous antioxidant, then ROS/RNS and free radical levels can increase unchecked, causing excessive cellular oxidation. The cellular environment can itself become overwhelmingly oxidative. In the normal course of aging, the human body becomes progressively less able to respond to homeostatic imbalances and becomes inundated with ROS/RNS, and other free radical species.1
Effect of Oxidative Stress on Red Blood Cells
Normal blood flow, while necessary for delivering oxygen and nutrients to cells, is also critical for clearing metabolic wastes and oxidative species. Consequently, disruption in blood flow promotes an oxidative state where ROS accumulate. Red blood cells are particularly vulnerable to oxidative environments throughout the body and, as a consequence of their iron content, are capable of producing their own free radicals.2 This process, called autoxidation, occurs when oxygenated hemoglobin is degraded and releases a superoxide (a free radical ROS). Concurrently, the ferrous (Fe2+) state iron in hemoglobin is oxidized to ferric (Fe3+) hemoglobin, producing methemoglobin which is incapable of transporting oxygen.3
Peroxides in the body can degrade hemoglobin proteins and cause red blood cells to release heme and iron.3 Also, the very force required for erythrocytes to squeeze through microscopic capillaries can cause red cell membranes to leak ions and cause further destruction of the lipid membrane.4 When ROS initiate peroxidation of the lipid membrane, membrane proteins often become cross-linked and red blood cells stiffer and less deformable.3
Production of methemoglobin, modification and degradation of proteins, cross-linking of membrane proteins, lipid peroxidation, hemoglobin cross-linking, and impaired surface properties are all mechanisms by which oxidative stress functionally modifies red blood cells.2 Collectively, these mechanisms alter red blood cell properties, including reduced membrane fluidity and increased aggregation, leading to increased blood viscosity and impaired flow.5
Human Defenses to Oxidative Stress
The blood has mechanisms that respond to oxidative stress. Methemoglobin reductase is an enzyme responsible for converting methemoglobin back to ferrous hemoglobin, restoring its capacity for oxygen transport. Superoxide disumutase (SOD) is an enzyme, which acts as an antioxidant, converting superoxide free radicals into hydrogen peroxide and oxygen. Since hydrogen peroxide is also a strong oxidizer, the body utilizes two other antioxidant enzymes, catalase and glutathione peroxidase, to remove it.3
Vitamin E, often valued for its antioxidant properties, provides α-tocopherol which is important for red cell membrane stability. Poor vitamin E intake can result in destruction of erythrocytes due to membrane instability.3
Turbulent Blood Flow Promotes Oxidative Stress
Because of its effect on erythrocyte membranes, oxidative stress has been shown to cause an unfavorable change in blood flow. However, the reverse is also true: blood flow abnormalities also promote oxidative stress, creating the environment for a vicious pathophysiologic cycle. In a comprehensive review published in the American Journal of Cardiology in 2003, cardiologists at Emory University proposed that physical forces such as turbulent shear flow are a strong regulator of reactive oxygen species production.6
Extensively reviewed in a book titled The Origin of Atherosclerosis as well as throughout this website, areas of turbulent blood flow and vulnerable low shear are prone to atherosclerotic lesions. Blood is thickest and most abrasive at these areas, and the injury caused by abrasive oscillatory blood flow initiates inflammatory gene expression and adhesion molecule synthesis on the endothelial walls.7,8 The adhesion molecules recruit and transmigrate circulating monocytes into the underlying subendothelial space where they mature into macrophages.9 These macrophages scavenge lipids and lipoproteins from the circulation.
Here, lipid particles are susceptible to oxidation by free radicals, a process which propagates further inflammation and plaque development.10 The Emory researchers identified hemodynamic shear forces as critical to initiation and regulation of endothelial damage and plaque development. With this knowledge, the same group of cardiovascular researchers at Emory conducted preliminary studies to determine whether oxidative stress was associated with these areas prone to plaque formation. They found that endothelial cells exposed to static conditions showed no increase in superoxide production, while cells exposed to unidirectional laminar blood flow showed very small increases.
Endothelial cells exposed to oscillatory blood flow produced an obvious increase in superoxide production. The oxidative impact remained even after removing the stimulus of oscillatory blood flow. The researchers highlighted earlier studies linking oscillatory shear to hydrogen peroxide production and glutathione depletion. Conversely, laminar shear was shown to stimulate glutathione production. Areas of laminar flow are favorable because they inhibit atherosclerotic plaque formation in vivo while areas of turbulent flow promote oxidation and plaque formation. Elevated blood viscosity and the forces of turbulent blood flow in these areas initiate oxidation and are the reason for oxidized LDL accumulation in atherosclerotic plaques.
Normal Aging - Oxidative Stress Thickens the Blood
Evidence of linkages between oxidative stress, blood flow, and blood viscosity was documented in a cohort of the Baltimore Longitudinal Study of Aging. In this study conducted at the U.S. National Institute of Aging, exponential increases in high-shear (450 s-1) blood viscosity, decreased cerebral blood flow at right and left common carotid arteries (r = -0.21, p < 0.01 and r = 0.27, p < 0.002, respectively), and increased oxidative stress (r = 0.44; p < 0.001) were all associated with the ages of patients [Read more about it at "Blood Thickens as You Get Older"].11 In the Baltimore Longitudinal Study of Aging, oxidative stress was measured using a fluorescent method used to detect membrane lipid peroxidation and malondialdehyde accumulation. Oxidative stress was shown to increase blood viscosity and decrease cerebral blood flow.
These age-associated changes provide insights to the mechanism behind cognitive decline induced by inefficient oxygen delivery, metabolite clearance, and β-amyloid protein clearance from neurons.11 In addition to discussing this mechanism, the National Institute of Aging researchers also focused on the importance of normal age-associated increases in blood viscosity as a mediator of oxidative stress and cognitive decline in the etiology of dementia and Alzheimer's disease.
Blood Viscosity - A Sensitive Marker for Oxidative Stress
The link between oxidative stress and blood viscosity is not limited to a normal aging population. A separate study of 154 subjects with varying stages of diabetes mellitus (DM) and healthy controls showed that more than 76% of oxidative stress in apparently healthy subjects was associated with elevated whole blood viscosity, with 95% prevalence in the prediabetes group and 92% prevalence in the diabetes group.12
In this 2010 clinical study, the measured markers of erythrocyte oxidative stress included erythrocyte glutathione (GSH), methemoglobin, and malondialdehyde (MDA). The strong associations between oxidative stress of red blood cells and altered blood viscosity, in healthy subjects as well as those with diabetes and prediabetes, suggests that blood viscosity can serve as a sensitive marker for underlying oxidative stress. For this reason, adding whole blood viscosity diagnostics to a traditional diagnostic panel may assist in earlier detection and intervention against conditions initiated or exacerbated by asymptomatic oxidative stress. According to the study authors, this is particularly important for those with subclinical hyperglycemia (i.e. prediabetes).12
Clinical Implications of Oxidative Stress
In recent years, the importance of oxidative stress has gained appreciation and acknowledgement by clinicians and researchers alike. An extensive body of evidence has linked oxidative stress to neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, cardiovascular diseases such as atherosclerosis and hypertension, pulmonary disorders such as asthma and chronic obstructive pulmonary disease, autoimmune diseases such as rheumatoid arthritis, many types of cancers and tumors, diabetes, liver disease, aging, and acute exercise to name a few.13,14
Although these disease states are diverse and employ a range of different diagnostic markers, these diseases may share etiologic pathways wherein oxidative stress plays the same contributing role. At sufficiently high concentrations, reactive oxygen species can damage cells, disrupting lipids, proteins, and genetic material.15
A study of pre-diabetic and diabetic patients with cardiovascular complications showed that hyperglycemia in non-smokers resulted in depletion of glutathione in red blood cells, leading to increased cell membrane rigidity and blood viscosity.16
Blood viscosity is a biophysical marker that is sensitive to oxidative stress and can provide additional clinical insight for the assessment of related disease states.
13. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. The international journal of biochemistry & cell biology. 2007;39(1):44-84.