NADPH oxidases, reactive oxygen species, and hypertension: clinical implications and therapeutic possibilities

Reactive oxygen species (ROS) influence many physiological processes including host defense, hormone biosynthesis, fertilization, and cellular signaling. Increased ROS production (termed "oxidative stress") has been implicated in various pathologies, including hypertension, atherosclerosis, diabetes, and chronic kidney disease. A major source for vascular and renal ROS is a family of nonphagocytic NAD(P)H oxidases, including the prototypic Nox2 homolog-based NAD(P)H oxidase, as well as other NAD(P)H oxidases, such as Nox1 and Nox4. Other possible sources include mitochondrial electron transport enzymes, xanthine oxidase, cyclooxygenase, lipoxygenase, and uncoupled nitric oxide synthase. NAD(P)H oxidase-derived ROS plays a physiological role in the regulation of endothelial function and vascular tone and a pathophysiological role in endothelial dysfunction, inflammation, hypertrophy, apoptosis, migration, fibrosis, angiogenesis, and rarefaction, important processes underlying cardiovascular and renal remodeling in hypertension and diabetes. These findings have evoked considerable interest because of the possibilities that therapies against nonphagocytic NAD(P)H oxidase to decrease ROS generation and/or strategies to increase nitric oxide (NO) availability and antioxidants may be useful in minimizing vascular injury and renal dysfunction and thereby prevent or regress target organ damage associated with hypertension and diabetes. Here we highlight current developments in the field of reactive oxygen species and cardiovascular disease, focusing specifically on the recently identified novel Nox family of NAD(P)H oxidases in hypertension. We also discuss the potential role of targeting ROS as a therapeutic possibility in the management of hypertension and cardiovascular disease.     

Oxidative stress and mild hypertension

Reactive oxygen species (ROS) play a crucial role in development of hypertension. An increase in production of superoxide anion and hydrogen peroxide, reduction of nitric oxide synthesis, and a decrease in bioavailability of antioxidants have been demonstrated in human hypertension. Oxidative stress resulted in vascular injury, renal dysfunction, and hypertensive end-organ damage. However, recent clinical trials failed to show cardiovascular benefits of antioxidants. Furthermore, none of the large clinical trials were designed to demonstrate effects of specific antioxidants on blood pressure and development of mild hypertension. Research of ROS, oxidative stress, redox signaling, and hypertension is more important than ever. The role of oxidative stress in the development of mild hypertension will need to be undertaken.     

Revisiting oxidative damage in ALS: microglia, Nox, and mutant SOD1

Mutation in superoxide dismutase-1 (SOD1) causes the inherited degenerative neurological disease familial amyotrophic lateral sclerosis (ALS), a non-cell-autonomous disease: mutant SOD1 synthesis in motor neurons and microglia drives disease onset and progression, respectively. In this issue of the JCI, Harraz and colleagues demonstrate that SOD1 mutants expressed in human cell lines directly stimulate NADPH oxidase (Nox) by binding to Rac1, resulting in overproduction of damaging ROS (see the related article beginning on page 659). Diminishing ROS by treatment with the microglial Nox inhibitor apocynin or by elimination of Nox extends survival in ALS mice, reviving the proposal that ROS mediate ALS pathogenesis, but with a new twist: it's ROS produced by microglia.     

Role of oxidative stress in non-alcoholic steatohepatitis

Oxidative stress plays an important role in the pathogenesis of non-alcoholic steatohepatitis (NASH). Reactive oxygen species (ROS) would derive from mitochondria, cytochrome P-450 2E1, peroxisome, and iron overload in the liver with steatosis. These excessive ROS is considered to cause simple steatosis to progress to NASH. On the other hand, oxidative stress exacerbates insulin sensitivity in hepatocytes, while hepatic steatosis causes oxidative stress. Thus, oxidative stress and insulin resistance might be interactive in NASH. Actually, we have found that the grade of steatosis correlates with serum thioredoxin level, a marker of oxidative stress, in NASH patients. Therefore, we propose that the feedback loop of oxidative stress, insulin resistance, and steatosis would play a significant role in the development of NASH.     

Novel isoforms of NADPH-oxidase in cerebral vascular control

Reactive oxygen species (ROS) are thought to play an important role in the initiation and progression of a variety of vascular diseases. Furthermore, accumulating evidence indicates that ROS may also serve as important cell signalling molecules for the regulation of normal vascular function. Recently, a novel family of proteins (Nox1, 2 and 4) that act as the catalytic subunit of the superoxide (O2-) producing enzyme NADPH-oxidase has been discovered in vascular cells. There is now preliminary evidence suggesting that NADPH-oxidase-derived ROS may serve as a physiological vasodilator mechanism in the cerebral circulation. Moreover, the activity of NADPH-oxidase is profoundly greater in cerebral versus systemic arteries. Studies have shown that Nox1, Nox2 (also known as gp91phox) and Nox4 are all expressed in cerebral arteries, suggesting that multiple isoforms of NADPH-oxidase may be important for ROS production by cerebral arteries. Enhanced NADPH-oxidase activity is associated with several vascular-related diseases, including hypertension, stroke, subarachnoid haemorrhage and Alzheimer's dementia; however, the consequences of this for cerebral vascular function are controversial. For example, there is some evidence suggesting that NADPH-oxidase-derived O2- may play a role in endothelial dysfunction of cerebral arteries and a subsequent rise in cerebral vascular tone, associated with hypertension. However, activation of NADPH-oxidase elicits cerebral vasodilatation in vivo, and this mechanism is enhanced in chronic hypertension. While further supportive evidence is needed, it is an intriguing possibility that NADPH-oxidase-derived ROS may play a protective role in regulating cerebral vascular tone during disease.     

Oxidative stress in atherogenesis and arterial thrombosis: the disconnect between cellular studies and clinical outcomes.

Atherosclerosis is a multifactorial disease for which the molecular etiology of many of the risk factors is still unknown. As no single genetic marker or test accurately predicts cardiovascular death, phenotyping for markers of inflammation may identify the individuals at risk for vascular diseases. Reactive oxygen species (ROS) are key mediators of signaling pathways that underlie vascular inflammation in atherogenesis, starting from the initiation of fatty streak development through lesion progression to ultimate plaque rupture. Various animal models of atherosclerosis support the notion that ROS released from NAD(P)H oxidases, xanthine oxidase, lipoxygenases, and enhanced ROS production from dysfunctional mitochondrial respiratory chain indeed have a causatory role in atherosclerosis and other vascular diseases. Human investigations also support the oxidative stress hypothesis of atherogenesis. This is further supported by the observed impairment of vascular function and enhanced atherogenesis in animal models that have deficiencies in antioxidant enzymes. The importance of oxidative stress in atherosclerosis is further emphasized because of its role as a unifying mechanism across many vascular diseases. The main contraindicator for the role oxidative stress plays in atherosclerosis is the lack of effectiveness of antioxidants in reducing primary endpoints of cardiovascular death and morbidity. However, this lack of effectiveness by itself does not negate the existence or causatory role of oxidative stress in vascular disease. Lack of proven markers of oxidative stress, which could help to identify a subset of population that can benefit from antioxidant supplementation, and the complexity and subcellular localization of redox reactions, are among the factors responsible for the mixed outcomes in the use of antioxidants for the prevention of cardiovascular diseases. To better understand the role of oxidative stress in vascular diseases, future studies should be aimed at using advances in mouse and human genetics to define oxidative stress phenotypes and link phenotype with genotype.     

Oxidative stress,mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight

Mitochondria is one of the main source of oxidative stress (ROS), as it utilizes the oxygen for the energy production. ROS and RNS are normally generated by tightly regulated enzymes. Excessive stimulation of NAD(P)H and electron transport chain leads to the overproduction of ROS, results in oxidative stress, which is a good mediator to injure the cell structures, lipids, proteins, and DNA. Various oxidative events implicated in many diseases due to oxidative stress include alteration in mitochondrial proteins, mitochondrial lipids and mitochondrial DNA, Which in turn leads to the damage to nerve cell as they are metabolically very active. ROS/RNS at moderate concentrations also play roles in normal physiology of many processes like signaling pathways, induction of mitogenic response and in defense against infectious pathogens. Oxidative stress has been considered to be the main cause in the etiology of many diseases, which includes Parkinson’s and Alzheimer diseases. Several PD associated genes have been found to be involved in mitochondrial function, dynamics and morphology as well. This review includes source of free radical generation, chemistry and biochemistry of ROS/RNS and mitochondrial dysfunction and the mechanism involved in neurodegenerative diseases.     

Chronic cocaine-induced cardiac oxidative stress and mitogen-activated protein kinase activation: the role of Nox2 oxidase

Chronic cocaine exposure is associated with severe cardiac complications, but the mechanisms of cocaine cardiotoxicity remain unclear, and current therapies are unsatisfactory. We investigated the hypothesis of oxidative stress-mediated cardiotoxicity and the role of NADPH oxidase in this process in a mouse model of chronic escalating "binge" cocaine administration (milligrams per kilogram): days 1 to 4 at 3 x 15 mg, days 5 to 8 at 3 x 20 mg, days 9 to 12 at 3 x 25 mg, and days 13 to 14 at 3 x 30 mg. Compared with vehicle controls, chronic binge cocaine administration significantly increased the cardiac NADPH-dependent O(2)(.) production (1.96- +/- 0.4-fold) as detected by tiron (an O(2)(.) scavenger)-inhibitable lucigenin chemiluminescence and dihydroethidium fluorescence. Cocaine-induced reactive oxygen species (ROS) production was associated with significant increases ( approximately 2-fold) in the protein expressions of Nox2 (an isoform of NADPH oxidase) and its regulatory subunits: p22(phox), p67(phox), p47(phox), p40(phox), and Rac1, and in p47(phox) phosphorylation as detected by immunoblotting (all p < 0.03). Increased Nox2 activity was accompanied by the activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase (MAPK), and c-Jun NH(2)-terminal kinase, notably in the cardiomyocytes. Cell culture experiments revealed that cocaine-induced ROS production was primarily a direct action of cocaine on cardiac myocytes, which caused severe oxidative damage to myocytes and cell death as detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. These could be inhibited by inhibitors to protein kinase C (bisindolymaleimide) or by depletion of Nox2 using small interfering RNA. In conclusion, chronic cocaine administration directly causes severe myocardial oxidative stress through the activation of Nox2 oxidase. Increased ROS production contributes to MAPK activation and the subsequent myocyte damage. Inhibitors to NADPH oxidase or antioxidants may have therapeutic potential in the treatment of cocaine cardiotoxicity.     

氧化应激作用与妊娠期高血压疾病的关系

氧化应激就是指体内氧化与抗氧化的作用失衡,倾向于氧化,进而激活或损伤内皮细胞。近年来,氧化应激在妊娠期高血压疾病发病中所起的作用受到人们的广泛关注。通过研究妊娠期高血压疾病发病时体内氧化应激生物标记物的变化,氧化应激与妊娠期高血压疾病的关系进一步被揭示。     

Paeoniflorin ameliorates glycemic variability-induced oxidative stress and platelet activation in HUVECs and DM rats

Glycemic variability (GV) plays an important role in the pathogenesis of vascular complications associated with diabetes mellitus (DM). Paeoniflorin is an effective Chinese traditional medicine with anti-inflammatory and immune-regulatory effects. Previous studies implicated the beneficial effects of paeoniflorin in treatment for diabetic complications, such as type 2 diabetic nephropathy and diabetes with myocardial ischemic injury. Current evidence suggests that oxidative stress and platelet activation, as well as their interaction, are potentially associated with GV and involved in the pathogenesis of diabetes-associated vascular complications. This study aimed to explore the effects of paeoniflorin on oxidative stress and platelet activation, using human umbilical vein endothelial cells (HUVECs) cultured with different glucose concentrations, and streptozotocin-induced diabetic rats fed different glycemic index diets. Paeoniflorin treatment effectively improved the morphology and cell viability of HUVECs under glucose fluctuation. Moreover, the platelet aggregation rate, CD62p expression, and reactive oxygen species (ROS) concentration decreased, while glutathione peroxidase (GSH-px) levels increased in paeoniflorin-treated groups. In conclusion, our study found that paeoniflorin ameliorates oxidative stress and platelet activation induced by glycemic variability both in vivo and in vitro, suggesting a novel potential strategy for treatment of diabetic complications.

Glycemic variability (GV) plays an important role in the pathogenesis of vascular complications associated with diabetes mellitus (DM).     

Novel Nox homologues in the vasculature: focusing on Nox4 and Nox5

The Noxes (NADPH oxidases) are a family of ROS (reactive oxygen species)-generating enzymes. Of the seven family members, four have been identified as important sources of ROS in the vasculature: Nox1, Nox2, Nox4 and Nox5. Although Nox isoforms can be influenced by the same stimulus and co-localize in cellular compartments, their tissue distribution, subcellular regulation, requirement for cofactors and NADPH oxidase subunits and ability to generate specific ROS differ, which may help to understand the multiplicity of biological functions of these oxidases. Nox4 and Nox5 are the newest isoforms identified in the vasculature. Nox4 is the major isoform expressed in renal cells and appear to produce primarily H2O2. The Nox5 isoform produces ROS in response to increased levels of intracellular Ca2+ and does not require the other NADPH oxidase subunits for its activation. The present review focuses on these unique Noxes, Nox4 and Nox5, and provides novel concepts related to the regulation and interaction in the vasculature, and discusses new potential roles for these isoforms in vascular biology.     

Oxidative stress,DNA damage,and breast cancer

Oxidative stress is a disturbance in the balance between the production of reactive oxygen species (ROS) and antioxidant defenses. It occurs when excessive production of ROS overwhelms the antioxidant defense system or when there is a significant decrease or lack of antioxidant defenses. Oxidative stress, in turn, is known to cause DNA damage and mutations of tumor suppressor genes that are critical initial events in carcinogenesis. Interestingly, early findings of the studies suggest that environmental factors, such as high psychological stress and poor nutritional profile (eg, low antioxidant and high fat intake), increase ROS production. Given that breast cancer is a complex disorder in which gene-environment interactions play a significant role in the development of cancer, oxidative stress may be an excellent model for exploring mechanisms mediating gene-environment interactions for nurse scientists and advanced practice nurses. Such investigations may help to suggest future strategies for nonpharmacological interventions for decreasing cancer risk.     

Oxidative stress, reactive oxygen species

Hypertension is a risk factor for cardiovascular and cerebrovascular outcome. Hypertension is associated with oxidative stress. Alteration in endothelial function is an initial step in the pathogenesis of atherosclerosis. A balance between ambient levels of super oxide and released nitric oxide(NO) plays an important role in the maintenance of endothelial function. It is well known that reactive oxygen species, including hydroxy radicals, directly scavenge NO and produce toxic peroxynitrite. Angiotensin II and mechanical stress generate the reactive oxygen species through the activation of NADH/NADPH oxidase in hypertension. Several investigators have shown that oxidative stress is involved in enhanced vascular growth, vascular inflammation, and impaired endothelium-dependent in hypertension. In this review, we would like to explain the role of oxidative stress in hypertensive organ damages.     

Role of oxidative stress in the etiology of type 2 diabetes and the effect of antioxidant supplementation on glycemic control.

Oxidative stress is a situation in which the amount of reactive oxygen species (ROS) exceeds the levels of neutralizing substances referred to as antioxidants. Numerous studies have shown that oxidative stress is associated with type 2 diabetes, and there is compelling biochemical evidence that suggests that ROS may even play a role, if only secondary, in the pathogenesis of type 2 diabetes. These observations have provided sufficient impetus for the use of antioxidant supplements as adjunct therapy for control of blood sugar in diabetic patients. However, there is currently no optimum regimen of antioxidant supplementation for diabetic patients. Studies are required to determine appropriate doses of relevant individual micronutrients that perhaps should be used in combination to diminish oxidative stress and improve glycemic control in individuals afflicted with type 2 diabetes.     

A review on the role of antioxidants in the management of diabetes and its complications.

Diabetes is a prevalent systemic disease affecting a significant proportion of the population worldwide. The effects of diabetes are devastating and well documented. There is increasing evidence that in certain pathologic states, especially chronic diseases, the increased production and/or ineffective scavenging of reactive oxygen species (ROS) may play a critical role. High reactivity of ROS determines chemical changes in virtually all cellular components, leading to lipid peroxidation. Production of ROS and disturbed capacity of antioxidant defense in diabetic subjects have been reported. It has been suggested that enhanced production of free radicals and oxidative stress is central event to the development of diabetic complications. This suggestion has been supported by demonstration of increased levels of indicators of oxidative stress in diabetic individuals suffering from complications. Therefore, it seems reasonable that antioxidants can play an important role in the improvement of diabetes. There are many reports on effects of antioxidants in the management of diabetes. In this paper, after complete bibliography and criticizing all relevant articles, the relationships between diabetes and oxidative stress and use of antioxidants in the management of diabetes and its complications have been well reviewed. This review well indicates that oxidative stress is involved in the pathogenesis of diabetes and its complications. Use of antioxidants reduces oxidative stress and alleviates diabetic complications.     

Oxidative stress and iron homeostasis: mechanistic and health aspects

Iron is an essential cofactor for important biological activities and biochemical reactions, including the transport of oxygen via red blood cells and its reduction to water during respiration. While iron's bioavailability is generally limited, pathological accumulation of the metal within tissues aggravates the generation of reactive oxygen species (ROS) and elicits toxic effects, which are mainly related to oxidative stress. Here, we describe the role of iron in ROS-induced toxicity and discuss molecular mechanisms and physiological aspects of ROS- and iron-mediated signaling. In addition, we review our current understanding of the regulation of iron homeostasis at the cellular and systemic levels, and focus on the pathogenesis and management of iron overload disorders.     

Corneal endothelial cells and acoustic cavitation in phacoemulsification

Postoperative complications of phacoemulsification, such as corneal edema caused by human corneal endothelial cell (CEC) injury, are still a matter of concern. Although several factors are known to cause CEC damage, the influence of ultrasound on the formation of free radicals during surgery should be considered. Ultrasound in aqueous humor induces cavitation and promotes the formation of hydroxyl radicals or reactive oxygen species (ROS). ROS-induced apoptosis and autophagy in phacoemulsification have been suggested to significantly promote CEC injury. CEC cannot regenerate after injury, and measures must be taken to prevent the loss of CEC after phacoemulsification or other CEC injuries. Antioxidants can reduce the oxidative stress injury of CEC during phacoemulsification. Evidence from rabbit eye studies shows that ascorbic acid infusion during operation or local application of ascorbic acid during phacoemulsification has a protective effect by scavenging free radicals or reducing oxidative stress. Both in experiments and clinical practice, hydrogen dissolved in the irrigating solution can also prevent CEC damage during phacoemulsification surgery. Astaxanthin (AST) can inhibit oxidative damage, thereby protecting different cells from most pathological conditions, such as myocardial cells, luteinized granulosa cells of the ovary, umbilical vascular endothelial cells, and human retina pigment epithelium cell line (ARPE-19). However, existing research has not focused on the application of AST to prevent oxidative stress during phacoemulsification, and the related mechanisms need to be studied. The Rho related helical coil kinase inhibitor Y-27632 can inhibit CEC apoptosis after phacoemulsification. Rigorous experiments are required to confirm whether its effect is realized through improving the ROS clearance ability of CEC.     

Antioxidant enzymes and human diseases

Objectives: To describe the importance of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase working together in human cells against toxic reactive oxygen species, their relationship with several pathophysiologic processes and their possible therapeutic implications.

Conclusions: Reactive oxygen species (ROS) are involved in the cell growth, differentiation, progression, and death. Low concentrations of ROS may be beneficial or even indispensable in processes such as intracellular signaling and defense against micro-organisms. Nevertheless, higher amounts of ROS play a role in the aging process as well as in a number of human disease states, including cancer, ischemia, and failures in immunity and endocrine functions. As a safeguard against the accumulation of ROS, several non-enzymatic and enzymatic antioxidant activities exist. Therefore, when oxidative stress arises as a consequence of a pathologic event, a defense system promotes the regulation and expression of these enzymes.