Reactive Oxygen Species in Biology and Human Health

Shamim I. Ahmad, Shamim I. Ahmad

• Publisher: CRC Press
• Year: 2017
• ISBN:
  9781315352640
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Molecular Biology
• Index: Biological Sciences

Unlike other narrowly focused books, Reactive Oxygen Species in Biology and Human Health provides a comprehensive overview of ROS. It covers the current status of research and provides pointers to future research goals. Additionally, it authoritatively reviews the impact of reactive oxygen species with respect to various human diseases and discusses antioxidants and other compounds that counteract oxidative stress.

Comprised of seven sections, the first section describes the introduction, detection, and production of ROS, emphasizing phenolic compounds and vitamin E for their abilities to act as antioxidants. This section also highlights the role of lipoprotein-associated oxidative stress. Section two addresses the importance of iron accumulation in the brain resulting in the development of a group of neurodegenerative disorders (NDs) and identifies several causative genes for neurodegeneration with brain iron accumulation (NBIA) associated with Parkinsonism-related disorders.

The third section discusses a number of NDs, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Huntington's disease (HD), epilepsy, and multiple sclerosis (MS). Section four addresses autoimmune diseases caused by ROS, including asthma, autoimmune liver diseases, rheumatoid arthritis, thyroid disease, primary biliary cirrhosis, and systemic lupus. Section five analyzes a number of different cancers, including lung cancer, breast cancer, and melanoma, along with possible treatment regimens.

Section six discusses cardiovascular diseases (CVDs) induced by ROS, presents the ROS-associated complex biochemical processes inducing inflammation as an important cause of CVDs, and explains the roles carotenoids play in preventing CVDs. The final section addresses other human diseases induced by oxidative stress, including sickle cell disease, nonalcoholic steatohepatitis, retinopathy, fibromyalgia, chronic obstructive pulmonary disease, asthma, pulmonary hypertension, infertility, and aging of human skin.

Section VII
Other Uncommon Diseases Induced by Oxidative Stress

24 Oxidative Stress and Sickle Cell Disease

Danilo Grünig Humberto da Silva, Edis Belini junior, Claudia Regina Bonini-Domingos, and Eduardo Alves de Almeida

Contents

1. Abstract
2. 24.1 More than a Hundred-Year-Old Disorder
3. 24.2 From an Amino Acid Substitution to Chronic and Systemic Oxidative Consequences
   1. 24.2.1 Sickle Erythrocytes: An Immeasurable Source of Reactive Oxygen Species
   2. 24.2.2 Vaso-Occlusive Events and Hemolysis: Overwhelming and Chronic Oxidative Stress Sources
4. 24.3 One Single-Point Mutation but Different Genetic Pathways Involved in Oxidative Stress Regulation
   1. 24.3.1 Keap1-Cul3/NRF2 Pathway: A Promising Target for SCD Phenotypic Modulation
5. 24.4 Conclusion
6. References

Abstract

Sickle cell disease (SCD) embraces a group of genetic hemolytic disorders associated with high morbidity and mortality. SCD is characterized by a complex pathophysiology initiated by hemoglobin'S (HbS) polymerization that triggers a cascade of pathological events, including vaso-occlusion episodes, hemolysis, endothelial dysfunction, inflammation, hypercoagulability, reperfusion injury, and hypoxemia, leading to devastating clinical manifestations. Although SCD is one of the first disorders to be clearly defined at the molecular level, the genetic understanding of the basis for the disease expression variability is still not fully explained. In this intriguing scenario, oxidative stress plays a major role because it acts as both causing and being caused by SCD complications.

24.1 More Than a Hundred-Year-Old Disorder

Sickle cell disease (SCD) is a multisystem disease; clinically, it is one of the most important hemoglobinopathies, associated with episodes of acute illness and progressive organ damage, and is one of the most common severe monogenic disorders worldwide (Weatherall et al. 2005). Knowledge of a disease heralded by painful episodes and leading to early death has existed in Africa for much more than a century (Stuart and Nagel 2004). However, in 1910, Herrick first described the characteristic sickle-shaped erythrocytes (Herrick [1910] 2001). Later, Pauling et al. (1949) showed the abnormal electrophoretic mobility of hemoglobin in an affected individual, identifying hemoglobin'S (HbS) and defining SCD as the first "molecular disease." HbS and normal hemoglobin (HbA) were among the first proteins sequenced, and this analysis showed that the charge difference detected by Pauling and his collaborators was due to a mutation from glutamate to valine at the sixth site of the two β chains of hemoglobin (HBB^glu6val) (Ingram 1957). Subsequent discoveries deciphered the structure of HbS, elucidating the molecular basis of its function (Perutz et al. 1960). These studies placed SCD at the leading edge of investigations to elucidate the molecular basis of human diseases (Frenette and Atweh 2007).

The term SCD embraces a group of genetic conditions in which pathology results from the inheritance of a single nucleotide substitution in beta-globin gene (HBB; c.20A>T; rs334) either homozygously or as a double heterozygote with another interacting gene (Weatherall et al. 2005, Steinberg and Sebastiani 2012, Serjeant 2013). Although more than 15 different genotypes have been identified as causing SCD, homozygosity for the sickle mutation (HbSS) is the most common and severe form of the disease and is often referred to as sickle cell anemia (SCA) (Rees et al. 2010). The other main types of SCD are hemoglobin SC (HbSC) disease and the various forms of HbS/β-thalassemia, being the spectrum of resulting conditions, therefore, influenced by the geography of individual hemoglobin genes and further by a multitude of genes other than the one directly involved (HBB*S) (Nagel 1991, Rees et al. 2010, Serjeant 2013). In this way, SCD is a strikingly variable condition. The incidence of most clinical complications varies markedly both with time in the same individual and between different individuals (Rees and Gibson 2012).

The pathophysiological hallmark of SCD is the intracellular polymerization of HbS upon deoxygenation (Bunn 1997). The elongated polymers damage red blood cells (RBCs) by increasing the cytoplasmic viscosity, inducing cation leaks through the membrane, which causes dehydration, and increasing the expression of adhesion molecules, allowing sickle cells to form homotypic aggregations and heterotypic adhesion to endothelial cells and white blood cells (WBCs) (Kaul et al. 1989, Frenette 2002). These changes lead to RBCs occluding and damaging blood vessels. This, vaso-occlusion causes tissue ischemia, resulting in a further cascade of pathological events, including hemolysis, endothelial dysfunction, inflammation, hypercoagulability, reperfusion injury, and hypoxemia (Stuart and Nagel 2004, Rees et al. 2010). These complications have a cyclic nature in which a chronic and systemic oxidative stress acts as both causing and being caused by them. Thus, oxidative stress biomarkers are potentially useful both to identify patients at high risk of oxidative damage and to evaluate antioxidant therapies (Nur et al. 2011).

Although many general principles of molecular genetics and cell biology have been established in SCD, its phenotypic heterogeneity and variable clinical severity have not been fully explained (Sangokoya et al. 2010). Several genetic association studies have been done trying to link single nucleotide polymorphisms (SNPs) with particular complications of SCD (Fertrin and Costa 2010, Menzel et al. 2010, Sebastiani et al. 2010, Flanagan et al. 2011, Bhatnagar et al. 2013, Galarneau et al. 2013). However, studies investigating genetic markers directly involved in regulating oxidative stress and vice versa are scarce, taking into consideration the fact that SCD is characterized by a lifelong continuous oxidative stress (Jeney et al. 2002, Kato et al. 2009), which might be involved in transcriptional, translational, or posttranslational regulation of many physiologic pathways. Moreover, a long-term goal of association studies of interrelated genetic and oxidative markers is to identify genes and pathways that might be therapeutically manipulated in novel treatment approaches.

24.2 From an Amino Acid Substitution to Chronic and Systemic Oxidative Consequences

24.2.1 Sickle Erythrocytes: An Immeasurable Source of Reactive Oxygen Species

The primary event responsible for all the complications of SCD is the polymerization of deoxygenated HbS due to the crucial role of the mutation to valine. On deoxygenation within the microcirculation, HbS molecules alter their configuration, and hydrophobic contacts are formed between valine of one HbS molecule and alanine, phenylalanine, and leucine from an adjacent HbS molecule (Wishner et al. 1975, Fronticelli and Gold 1976, Dykes et al. 1979, Carragher et al. 1988). This crystallization produces a polymer nucleus, which grows and fills the erythrocyte, disrupting its architecture and flexibility and promoting cellular dehydration, with physical and oxidative cellular stress (Brittenham et al. 1985). Nevertheless, HbS polymerization is reversible; fibers melt as oxygen is taken up by the HbS and the normal discoid shape returns (Stuart and Nagel 2004). This way, one of the important pro-oxidant sources in SCD is sickle erythrocytes. The unstable auto-oxidative HbS and increased metabolic turnover due to recurrent HbS polymerization and depolymerization cause increased reactive oxygen species (ROS) generation (Hebbel et al. 1988, Banerjee and Kuypers 2004) and increased lipid oxidation products when compared with HbA-containing erythrocytes (Rice-Evans et al. 1986, Hebbel et al. 1988, Sheng et al. 1998, Aslanet al. 2000). This increased and unremitting ROS generation results in excessive antioxidant consumption and thus antioxidant deficiency in sickle erythrocytes (Banerjee and Kuypers 2004, Reid et al. 2006, Chaves et al. 2008). Thus, the ability to deal with oxidant stress is compromised and challenged in SCD, resulting in an unbalanced redox state, an altered thiol redox metabolism, and protein and lipid damage, leading to premature aging of these cells.

Direct measures of ROS, such as superoxide (O₂⠁^-), hydrogen peroxide (H₂O₂), and hydroxyl radicals (⠁OH), are too unstable to be clinically useful as biomarkers (Rees and Gibson 2012). However, indirect markers of oxidative damage to tissues and proteins are abundant, RBC glutathione (GSH) concentrations and glutamine:glutamate are perhaps the best-established markers (Rees and Gibson 2012). For instance, glutamine:glutamate ratios correlated inversely with tricuspid regurgitant jet (TRJ) velocities, a marker of pulmonary hypertension risk (Morris et al. 2008). Many other markers of oxidative stress have been studied, all broadly correlating with other indicators of severity without adding specific new information (Rees and Gibson 2012) and with contradictory results among some studies (Silva et al. 2013). Thus, it is worthy to seek new, more specific and sensitive oxidative stress markers related to RBC redox metabolism in SCD patients. In this way, Kuypers (2014) suggested the investigation of ergothioneine (ergo), another RBC antioxidant thiol, that is the second most abundant one. However, the reasons for this abundance in hematopoietic tissues have not been investigated. Interestingly, HbS, which increases Hb pro-oxidant activity, selectively depletes ergo over GSH, suggesting that ergo has a specialized GSH-independent function in protecting RBCs against pro-oxidative hemoglobin. The implications of the presence of HbS in erythrocyte redox metabolism and the related markers studied have been the subject of recent reviews (Silva et al. 2013, Kuypers 2014).

24.2.2 Vaso-Occlusive Events and Hemolysis: Overwhelming and Chronic Oxidative Stress Sources

The formation of HbS polymers negatively affects the RBC ability to maintain its normal morphology, and it has long been considered that the radical shape change in sickle erythrocytes under low oxygen leads to their inability to properly deform and pass through the microvasculature (Knee et al. 2007, Vekilov 2007). Moreover, HbS polymers cause damage to the RBC membrane. In addition, the mutated globin can undergo autoxidation and precipitate on the inner surface of the RBC membrane, causing membrane damage via iron-mediated generation of ROS (Browne et al. 1998). Among many changes that result from the damage to the sickled RBC membrane is their propensity to adhere (Hebbel 2008, Kaul et al. 2009), leading to vaso-occlusive events (VOE) with ischemia–reperfusion injury. The vaso-occlusive process is now believed to comprise a multistep process involving interactions among sickled RBC, activated leukocytes, endothelial cells, platelets, and plasma proteins. Recurrent V...