Curriculum in cardiologyEndothelial dysfunction: clinical strategies for treating oxidant stress
Section snippets
Endothelial function and dysfunction
The vascular endothelium is a metabolically responsive tissue. This cellular monolayer has an ability to modulate both the contents of the vascular lumen and the adjacent compartment of vascular smooth muscle. Arguably, the most important substance responsible for endothelium-dependent vascular relaxation is nitric oxide (NO). NO is not only involved in relaxation of vascular smooth muscle but also partially mediates inhibition of platelet activation, adhesion, and aggregation, prevention of
Reactive oxygen species in endothelial dysfunction
Reactive oxygen species (ROS) consist of molecular oxygen and all of its aerobic cellular metabolites, including superoxide (O2−), hydroxyl radical (OH−), NO, and lipid radicals. Although they are not free radicals, hydrogen peroxide (H2O2), peroxynitrite (ONOO−), and hypochlorous acid (HOCL) have oxidative properties and contribute to oxidant stress. Oxidants play a critical role in vascular homeostasis and function, mediating growth, apoptosis, and survival of endothelial and vascular smooth
NAD(P)H oxidase
NAD(P)H oxidase catalyzes the reduction of O2 through electron donation from NADPH or NADH, thereby generating O2−. Relative to other enzymatic pathways, vascular NAD(P)H oxidase is the predominant source of vascular O2− cells. Preclinical data suggest that NAD(P)H–dependent O2− production promotes endothelial dysfunction. Angiotensin II is known to stimulate vascular smooth muscle (VSMC) O2− production through enhanced NAD(P)H oxidase activity.2 In experimental angiotensin-mediated
The antioxidant paradox
The assumption that oxidative stress mediates atherosclerotic endothelial dysfunction would implicate a potential for antioxidant therapies to ameliorate and perhaps reverse vascular pathology. A growing body of preclinical evidence exists to support the salubrious effects of antioxidants on endothelial function. Vitamin C, a potent water-soluble scavenger of free radicals, reduces monocyte adhesion to endothelial cells, inhibits LDL oxidation, decreases inactivation of NO, and stimulates eNOS
Lipid-lowering therapies
A variety of mechanisms, ranging from transient free fatty acid loading to overt hypercholesterolemia, can impair endothelial function. Oxidation of LDL cholesterol (oxLDL) is critical to the pathogenesis of endothelial dysfunction. Indeed, oxLDL exerts profound effects on the arterial vasomotor response, analogous to the effect observed in hypercholesterolemia or atherosclerosis. Vascular injury early in atherosclerosis renders the vascular wall permeable to lipoproteins such as VLDL
Insulin-sensitizing agents
Endothelial dysfunction is thought to be present in a wide spectrum of insulin-resistant states, including types II diabetes, obesity, and Syndrome X. Antioxidants improve endothelial dysfunction in non–insulin-dependent diabetes, suggesting a causal relation between oxidative stress and endothelial dysfunction.38 A plausible explanation for this association implicates hyperglycemia and its oxidative sequelae. Elevated glucose levels, through glyco-oxidation of glucose and formation of advanced
Homocyst(e)ine-lowering therapies
An independent risk factor for vascular disease, hyperhomocysteinemia is thought to promote vascular disease through endothelial dysfunction. Several lines of evidence suggest that hyperhomocysteinemia modulates endothelial responses through oxidant-dependent mechanisms. Upon exposure to the plasma, homocysteine (Hcy) auto-oxidizes to become homocystine, generating H2O2, superoxide, and hydroxyl radicals. Hcy-mediated reductions in gluthathione peroxidase augment H2O2 levels, and the surge in O2
Estrogens
Endothelium-dependent vasodilation is increased in premenopausal women and decreased in perimenopausal women relative to men, suggesting an estrogen-mediated benefit. Accordingly, improvements in endothelium-dependent vasodilation have been demonstrated with administration of estrogen.48 The predominant mechanism appears to be an upregulation of the transcription of nitric oxide synthase, although exogenous estrogen also limits LDL oxidation. Despite these benefits, conjugated estrogen therapy
Conclusions
Common to many disease processes that propagate endothelial dysfunction is a pathway of stress-induced activation of intracellular oxidative signaling and secondary modulation of vascular inflammatory gene expression, resulting in further oxidant elaboration. Accordingly, antioxidant strategies targeting these pathologic oxidative mechanisms have emerged as viable therapies to restore normal endothelial responses (Table I). Although not prescribed for their antioxidant potential per se, many
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2020, Behavioural Brain ResearchCitation Excerpt :Examples of these diseases include diabetes, Alzheimer, atherosclerosis, traumatic brain injury and post-traumatic stress disorder (PTSD) [7–11]. Further evidence on the central role of ROS in mediating the etiology and pathogenesis of the above disorders comes from studies performed on preclinical and clinical models which showed that inactivating ROS or limiting their production is linked with improved treatment outcome and/or prevention of many of the above disorders [12]. In humans, vitamin C (ascorbic acid) is an essential water-soluble nutrient.
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2016, Environmental Toxicology and PharmacologyFluvastatin Decreases Oxidative Stress in Kidney Transplant Patients
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Peroxynitrite and fibrinolytic system-The effects of peroxynitrite on t-PA-induced plasmin activity
2015, International Journal of Biological MacromoleculesCitation Excerpt :Inflammatory processes and increased generation of reactive oxygen species (ROS) are implicated both in etiology and pathophysiology of numerous cardiovascular disorders [1]. Oxidative stress, associated with inflammatory process, alters normal functions of all components of the haemostatic system, including the dysfunction of endothelium, a considerable decrease of its antithrombotic properties [2] and changes of the haemostatic balance in favor of pro-coagulant conditions [3]. Oxidative and nitrative modifications of haemostatic proteins influence their physiological activities.