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González-Montero J, Brito R, Gajardo AIJ, Rodrigo R. Myocardial reperfusion injury and oxidative stress: Therapeutic opportunities. World J Cardiol 2018; 10:74-86. [PMID: 30344955 PMCID: PMC6189069 DOI: 10.4330/wjc.v10.i9.74] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/27/2018] [Accepted: 05/10/2018] [Indexed: 02/06/2023] Open
Abstract
Acute myocardial infarction (AMI) is the leading cause of death worldwide. Its associated mortality, morbidity and complications have significantly decreased with the development of interventional cardiology and percutaneous coronary angioplasty (PCA) treatment, which quickly and effectively restore the blood flow to the area previously subjected to ischemia. Paradoxically, the restoration of blood flow to the ischemic zone leads to a massive production of reactive oxygen species (ROS) which generate rapid and severe damage to biomolecules, generating a phenomenon called myocardial reperfusion injury (MRI). In the clinical setting, MRI is associated with multiple complications such as lethal reperfusion, no-reflow, myocardial stunning, and reperfusion arrhythmias. Despite significant advances in the understanding of the mechanisms accounting for the myocardial ischemia reperfusion injury, it remains an unsolved problem. Although promising results have been obtained in experimental studies (mainly in animal models), these benefits have not been translated into clinical settings. Thus, clinical trials have failed to find benefits from any therapy to prevent MRI. There is major evidence with respect to the contribution of oxidative stress to MRI in cardiovascular diseases. The lack of consistency between basic studies and clinical trials is not solely based on the diversity inherent in epidemiology but is also a result of the methodological weaknesses of some studies. It is quite possible that pharmacological issues, such as doses, active ingredients, bioavailability, routes of administration, co-therapies, startup time of the drug intervention, and its continuity may also have some responsibility for the lack of consistency between different studies. Furthermore, the administration of high ascorbate doses prior to reperfusion appears to be a safe and rational therapy against the development of oxidative damage associated with myocardial reperfusion. In addition, the association with N-acetylcysteine (a glutathione donor) and deferoxamine (an iron chelator) could improve the antioxidant cardioprotection by ascorbate, making it even more effective in preventing myocardial reperfusion damage associated with PCA following AMI.
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Affiliation(s)
- Jaime González-Montero
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 70058, Chile
| | - Roberto Brito
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 70058, Chile
- Internal Medicine Department, University of Chile, Clinical Hospital, Santiago 70058, Chile
| | - Abraham IJ Gajardo
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 70058, Chile
- Internal Medicine Department, University of Chile, Clinical Hospital, Santiago 70058, Chile
| | - Ramón Rodrigo
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 70058, Chile
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Chung CC, Lin YK, Chen YC, Kao YH, Yeh YH, Chen YJ. Factor Xa inhibition by rivaroxaban regulates fibrogenesis in human atrial fibroblasts with modulation of nitric oxide synthesis and calcium homeostasis. J Mol Cell Cardiol 2018; 123:128-138. [PMID: 30213724 DOI: 10.1016/j.yjmcc.2018.09.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 08/19/2018] [Accepted: 09/07/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Rivaroxaban, a widely used factor Xa inhibitor in reducing stroke in atrial fibrillation (AF) patients has multiple biological effects with activation of protease-activated receptor (PAR) signaling. Atrial fibrosis plays a critical role in the pathophysiology of AF. In this study, we evaluated whether rivaroxaban regulates atrial fibroblast activity and its underlying mechanisms. METHODS AND RESULTS Migration, proliferation analyses, nitric oxide (NO) production assay, calcium fluorescence imaging, and western blots were conducted in human atrial fibroblasts with or without rivaroxaban (100 nmol/L or 300 nmol/L) and co-administration of L-NAME (L-NG-nitro arginine methyl ester, 100 μmol/L), EGTA (Ethylene glycol tetra-acetic acid, 1 mmol/L), thrombin (0.5 U/mL), PAR1 agonist peptide (TFLLR-NH2, 100 μmol/L), PAR1 inhibitor (SCH79797, 0.5 μmol/L) and PAR2 inhibitor (GB83, 10 μmol/L). Atrial fibrosis was examined in isoproterenol (100 mg/kg, subcutaneous injection)-treated rats with or without rivaroxaban (10 mg/kg/day orally for 14 consecutive days). Rivaroxaban reduced the migration, pro-collagen type I production, and proliferation of atrial fibroblasts. Rivaroxaban decreased phosphorylated endothelial NO synthase (eNOS) (Thr 495, an inhibitory phosphorylated site of eNOS), and calcium (Ca2+) entry, and increased NO production. Moreover, L-NAME blocked the effects of rivaroxaban on fibroblast collagen and NO production. In the presence of EGTA, the migratory capability was similarly decreased in atrial fibroblasts with and without treatment with rivaroxaban (100 nmol/L), which suggests that rivaroxaban decreases migratory capability of atrial fibroblasts by inhibiting Ca2+ entry. Additionally, rivaroxaban significantly attenuated the effects of thrombin, and TFLLR-NH2 on migratory, proliferative, and pro-collagen type I production capability in atrial fibroblasts. SCH79797 or GB83 decreased pro-collagen type I production, migration, and proliferation capability in fibroblasts, but combined SCH79797 or GB83 with and without rivaroxaban had similar fibroblast activity. Moreover, rivaroxaban significantly decreased atrial fibrosis in isoproterenol-treated rats. CONCLUSIONS Rivaroxaban (100-300 nmol/L) regulates atrial fibroblast activity and atrial fibrosis by increasing NO production and decreasing Ca2+ entry through inhibition of PAR signaling.
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Affiliation(s)
- Cheng-Chih Chung
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yung-Kuo Lin
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yao-Chang Chen
- Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan
| | - Yu-Hsun Kao
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yung-Hsin Yeh
- Cardiovascular Department, Chang Gung Memorial Hospital, Linkou, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Jen Chen
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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Results, meta-analysis and a first evaluation of U NOxR, the urinary nitrate-to-nitrite molar ratio, as a measure of nitrite reabsorption in experimental and clinical settings. Amino Acids 2018; 50:799-821. [PMID: 29728915 DOI: 10.1007/s00726-018-2573-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 04/19/2018] [Indexed: 02/07/2023]
Abstract
We recently found that renal carbonic anhydrase (CA) is involved in the reabsorption of inorganic nitrite (NO2-), an abundant reservoir of nitric oxide (NO) in tissues and cells. Impaired NO synthesis in the endothelium and decreased NO bioavailability in the circulation are considered major contributors to the development and progression of renal and cardiovascular diseases in different conditions including diabetes. Isolated human and bovine erythrocytic CAII and CAIV can convert nitrite to nitrous acid (HONO) and its anhydride N2O3 which, in the presence of thiols (RSH), are further converted to S-nitrosothiols (RSNO) and NO. Thus, CA may be responsible both for the homeostasis of nitrite and for its bioactivation to RSNO/NO. We hypothesized that enhanced excretion of nitrite in the urine may contribute to NO-related dysfunctions in the renal and cardiovascular systems, and proposed the urinary nitrate-to-nitrite molar ratio, i.e., UNOxR, as a measure of renal CA-dependent excretion of nitrite. Based on results from clinical and experimental animal studies, here, we report on a first evaluation of UNOxR. We determined UNOxR values in preterm neonates, healthy children, and adults, in children suffering from type 1 diabetes mellitus (T1DM) or Duchenne muscular dystrophy (DMD), in elderly subjects suffering from chronic rheumatic diseases, type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), or peripheral arterial occlusive disease (PAOD). We also determined UNOxR values in healthy young men who ingested isosorbide dinitrate (ISDN), pentaerythrityl tetranitrate (PETN), or inorganic nitrate. In addition, we tested the utility of UNOxR in two animal models, i.e., the LEW.1AR1-iddm rat, an animal model of human T1DM, and the APOE*3-Leiden.CETP mice, a model of human dyslipidemia. Mean UNOxR values were lower in adult patients with rheumatic diseases (187) and in T2DM patients of the DALI study (74) as compared to healthy elderly adults (660) and healthy young men (1500). The intra- and inter-variabilities of UNOxR were of the order of 50% in young and elderly healthy subjects. UNOxR values were lower in black compared to white boys (314 vs. 483, P = 0.007), which is in line with reported lower NO bioavailability in black ethnicity. Mean UNOxR values were lower in DMD (424) compared to healthy (730) children, but they were higher in T1DM children (1192). ISDN (3 × 30 mg) decreased stronger UNOxR compared to PETN (3 × 80 mg) after 1 day (P = 0.046) and after 5 days (P = 0.0016) of oral administration of therapeutically equivalent doses. In healthy young men who ingested NaNO3 (0.1 mmol/kg/d), UNOxR was higher than in those who ingested the same dose of NaCl (1709 vs. 369). In LEW.1AR1-iddm rats, mean UNOxR values were lower than in healthy rats (198 vs. 308) and comparable to those in APOE*3-Leiden.CETP mice (151).
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Vitamin C, Aging and Alzheimer's Disease. Nutrients 2017; 9:nu9070670. [PMID: 28654021 PMCID: PMC5537785 DOI: 10.3390/nu9070670] [Citation(s) in RCA: 151] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 06/01/2017] [Accepted: 06/13/2017] [Indexed: 02/07/2023] Open
Abstract
Accumulating evidence in mice models of accelerated senescence indicates a rescuing role of ascorbic acid in premature aging. Supplementation of ascorbic acid appeared to halt cell growth, oxidative stress, telomere attrition, disorganization of chromatin, and excessive secretion of inflammatory factors, and extend lifespan. Interestingly, ascorbic acid (AA) was also found to positively modulate inflamm-aging and immunosenescence, two hallmarks of biological aging. Moreover, ascorbic acid has been shown to epigenetically regulate genome integrity and stability, indicating a key role of targeted nutrition in healthy aging. Growing in vivo evidence supports the role of ascorbic acid in ameliorating factors linked to Alzheimer’s disease (AD) pathogenesis, although evidence in humans yielded equivocal results. The neuroprotective role of ascorbic acid not only relies on the general free radical trapping, but also on the suppression of pro-inflammatory genes, mitigating neuroinflammation, on the chelation of iron, copper, and zinc, and on the suppression of amyloid-beta peptide (Aβ) fibrillogenesis. Epidemiological evidence linking diet, one of the most important modifiable lifestyle factors, and risk of Alzheimer's disease is rapidly increasing. Thus, dietary interventions, as a way to epigenetically modulate the human genome, may play a role in the prevention of AD. The present review is aimed at providing an up to date overview of the main biological mechanisms that are associated with ascorbic acid supplementation/bioavailability in the process of aging and Alzheimer’s disease. In addition, we will address new fields of research and future directions.
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Gasparova I, Kubatka P, Opatrilova R, Caprnda M, Filipova S, Rodrigo L, Malan L, Mozos I, Rabajdova M, Nosal V, Kobyliak N, Valentova V, Petrovic D, Adamek M, Kruzliak P. Perspectives and challenges of antioxidant therapy for atrial fibrillation. Naunyn Schmiedebergs Arch Pharmacol 2016; 390:1-14. [PMID: 27900409 DOI: 10.1007/s00210-016-1320-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Accepted: 11/18/2016] [Indexed: 12/26/2022]
Abstract
Atrial fibrillation (AF) is the most common sustained arrhythmia associated with significant morbidity and mortality. The mechanisms underlying the pathogenesis of AF are poorly understood, although electrophysiological remodeling has been described as an important initiating step. There is growing evidence that oxidative stress is involved in the pathogenesis of AF. Many known triggers of oxidative stress, such as age, diabetes, smoking, and inflammation, are linked with an increased risk of arrhythmia. Numerous preclinical studies and clinical trials reported the importance of antioxidant therapy in the prevention of AF, using vitamins C and E, polyunsaturated fatty acids, statins, or nitric oxide donors. The aim of our work is to give a current overview and analysis of opportunities, challenges, and benefits of antioxidant therapy in AF.
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Affiliation(s)
- Iveta Gasparova
- Institute of Biology, Genetics and Medical Genetics, Faculty of Medicine, Comenius University and University Hospital, Bratislava, Slovak Republic, Slovakia
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovak Republic, Slovakia
| | - Radka Opatrilova
- Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic
| | - Martin Caprnda
- 2nd Department of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Slavomira Filipova
- Department of Cardiology, National Institute of Cardiovascular Diseases, Bratislava, Slovakia
| | - Luis Rodrigo
- Faculty of Medicine, University of Oviedo, Central University of Asturias (HUCA), Oviedo, Spain
| | - Leone Malan
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom Campus, Potchefstroom, South Africa
| | - Ioana Mozos
- Department of Functional Sciences, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Miroslava Rabajdova
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia
| | - Vladimir Nosal
- Clinic of Neurology, Jessenius Faculty of Medicine, Comenius University and University Hospital in Martin, Martin, Slovak Republic
| | - Nazarii Kobyliak
- Department of Endocrinology, Bogomolets National Medical University, Kyiv, Ukraine
| | - Vanda Valentova
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovak Republic, Slovakia
| | - Daniel Petrovic
- Institute of Histology and Embryology, Faculty of Medicine, University of Ljublana, Ljublana, Slovenia
| | - Mariusz Adamek
- Department of Thoracic Surgery, Medical University of Silesia, Zabrze, Poland
| | - Peter Kruzliak
- Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic. .,2nd Department of Surgery, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
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González J, Valls N, Brito R, Rodrigo R. Essential hypertension and oxidative stress: New insights. World J Cardiol 2014; 6:353-366. [PMID: 24976907 PMCID: PMC4072825 DOI: 10.4330/wjc.v6.i6.353] [Citation(s) in RCA: 143] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Revised: 03/01/2014] [Accepted: 05/08/2014] [Indexed: 02/06/2023] Open
Abstract
Essential hypertension is a highly prevalent pathological condition that is considered as one of the most relevant cardiovascular risk factors and is an important cause of morbidity and mortality around the world. Despite the fact that mechanisms underlying hypertension are not yet fully elucidated, a large amount of evidence shows that oxidative stress plays a central role in its pathophysiology. Oxidative stress can be defined as an imbalance between oxidant agents, such as superoxide anion, and antioxidant molecules, and leads to a decrease in nitric oxide bioavailability, which is the main factor responsible for maintaining the vascular tone. Several vasoconstrictor peptides, such as angiotensin II, endothelin-1 and urotensin II, act through their receptors to stimulate the production of reactive oxygen species, by activating enzymes like NADPH oxidase and xanthine oxidase. The knowledge of the mechanism described above has allowed generating new therapeutic strategies against hypertension based on the use of antioxidants agents, including vitamin C and E, N-Acetylcysteine, polyphenols and selenium, among others. These substances have different therapeutic targets, but all represent antioxidant reinforcement. Several clinical trials using antioxidants have been made. The aim of the present review is to provide new insights about the key role of oxidative stress in the pathophysiology of essential hypertension and new clinical attempts to demonstrate the usefulness of antioxidant therapy in the treatment of hypertension.
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Rodrigo R, González J. Role of Oxidative Stress in Hypertension. ROLE OF OXIDATIVE STRESS IN CHRONIC DISEASES 2014:199-245. [DOI: 10.1201/b16653-14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Effect of vitamins a, C, and e supplementation in the treatment of metabolic syndrome in albino rats. Biochem Res Int 2012; 2012:678582. [PMID: 22953063 PMCID: PMC3431076 DOI: 10.1155/2012/678582] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Revised: 06/01/2012] [Accepted: 06/14/2012] [Indexed: 01/29/2023] Open
Abstract
Obesity and metabolic syndrome increase the risk of cardiovascular morbidity and mortality. Oxidative stress seems to be involved in the path physiology of cardiovascular complications of metabolic syndrome. In this study we investigated the effects of vitamins A, C, and E in the management of metabolic syndrome traits condition in albino rats fed with high salt diet. The rats were placed on 8% NaCl diet for 5 weeks and then supplemented with these vitamins for additional 4 weeks in the presence of salt diet. Supplementation with vitamins significantly (P < 0.01 ) decreased blood pressure of the rats as compared with the control. Supplementation also significantly (P < 0.05) reduced serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol and increased high-density lipoprotein cholesterol, and total antioxidant status as compared with untreated group. The percentage protection of the supplemented groups against atherogenesis indicated 55.50 ± 3.75%. Percentage weight gain indicated significant positive correlation with triglyceride, insulin resistance, and malondialdehyde while total antioxidant status and nitric oxide showed significant negative correlation. Salt diet significantly (P < 0.05) induced features of metabolic syndrome. The result, therefore, indicated strong relationship between obesity and metabolic syndrome and underscores the role of these vitamins in the management of metabolic syndrome.
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Förstermann U, Li H. Therapeutic effect of enhancing endothelial nitric oxide synthase (eNOS) expression and preventing eNOS uncoupling. Br J Pharmacol 2012; 164:213-23. [PMID: 21198553 DOI: 10.1111/j.1476-5381.2010.01196.x] [Citation(s) in RCA: 221] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Nitric oxide (NO) produced by the endothelium is an important protective molecule in the vasculature. It is generated by the enzyme endothelial NO synthase (eNOS). Similar to all NOS isoforms, functional eNOS transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH), via the flavins flavin adenine dinucleotide and flavin mononucleotide in the carboxy-terminal reductase domain, to the heme in the amino-terminal oxygenase domain. Here, the substrate L-arginine is oxidized to L-citrulline and NO. Cardiovascular risk factors such as diabetes mellitus, hypertension, hypercholesterolaemia or cigarette smoking reduce bioactive NO. These risk factors lead to an enhanced production of reactive oxygen species (ROS) in the vessel wall. NADPH oxidases represent major sources of this ROS and have been found upregulated in the presence of cardiovascular risk factors. NADPH-oxidase-derived superoxide avidly reacts with eNOS-derived NO to form peroxynitrite (ONOO(-)). The essential NOS cofactor (6R-)5,6,7,8-tetrahydrobiopterin (BH(4) ) is highly sensitive to oxidation by this ONOO(-). In BH(4) deficiency, oxygen reduction uncouples from NO synthesis, thereby converting NOS to a superoxide-producing enzyme. Among conventional drugs, compounds interfering with the renin-angiotensin-aldosterone system and statins can reduce vascular oxidative stress and increase bioactive NO. In recent years, we have identified a number of small molecules that have the potential to prevent eNOS uncoupling and, at the same time, enhance eNOS expression. These include the protein kinase C inhibitor midostaurin, the pentacyclic triterpenoids ursolic acid and betulinic acid, the eNOS enhancing compounds AVE9488 and AVE3085, and the polyphenolic phytoalexin trans-resveratrol. Such compounds enhance NO production from eNOS also under pathophysiological conditions and may thus have therapeutic potential.
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Affiliation(s)
- Ulrich Förstermann
- Department of Pharmacology, Johannes Gutenberg University Medical Center, Mainz, Germany.
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Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J 2012; 33:829-37, 837a-837d. [PMID: 21890489 PMCID: PMC3345541 DOI: 10.1093/eurheartj/ehr304] [Citation(s) in RCA: 2837] [Impact Index Per Article: 218.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2011] [Revised: 07/14/2011] [Accepted: 07/28/2011] [Indexed: 02/06/2023] Open
Abstract
Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS; EC 1.14.13.39). They all utilize l-arginine and molecular oxygen as substrates and require the cofactors reduced nicotinamide-adenine-dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and (6R-)5,6,7,8-tetrahydrobiopterin (BH(4)). All NOS bind calmodulin and contain haem. Neuronal NOS (nNOS, NOS I) is constitutively expressed in central and peripheral neurons and some other cell types. Its functions include synaptic plasticity in the central nervous system (CNS), central regulation of blood pressure, smooth muscle relaxation, and vasodilatation via peripheral nitrergic nerves. Nitrergic nerves are of particular importance in the relaxation of corpus cavernosum and penile erection. Phosphodiesterase 5 inhibitors (sildenafil, vardenafil, and tadalafil) require at least a residual nNOS activity for their action. Inducible NOS (NOS II) can be expressed in many cell types in response to lipopolysaccharide, cytokines, or other agents. Inducible NOS generates large amounts of NO that have cytostatic effects on parasitic target cells. Inducible NOS contributes to the pathophysiology of inflammatory diseases and septic shock. Endothelial NOS (eNOS, NOS III) is mostly expressed in endothelial cells. It keeps blood vessels dilated, controls blood pressure, and has numerous other vasoprotective and anti-atherosclerotic effects. Many cardiovascular risk factors lead to oxidative stress, eNOS uncoupling, and endothelial dysfunction in the vasculature. Pharmacologically, vascular oxidative stress can be reduced and eNOS functionality restored with renin- and angiotensin-converting enzyme-inhibitors, with angiotensin receptor blockers, and with statins.
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Affiliation(s)
- Ulrich Förstermann
- Department of Pharmacology, Johannes Gutenberg University Medical Center, 55101 Mainz, Germany.
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Rasoli S, Kakouros N, Harling L, Gukop P, Soni M, Athanasiou T, Kourliouros A. Antioxidant vitamins in the prevention of atrial fibrillation: what is the evidence? Cardiol Res Pract 2011; 2011:164078. [PMID: 21876823 PMCID: PMC3162973 DOI: 10.4061/2011/164078] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Accepted: 05/19/2011] [Indexed: 12/22/2022] Open
Abstract
Atrial fibrillation (AF) is the most common sustained arrhythmia that is associated with significant morbidity and mortality. Current available therapies remain inadequate in symptom control and secondary prevention and are often associated with significant side effects. The mechanisms underlying the pathogenesis of AF are poorly understood, although electrophysiological remodeling has been described as an important initiating step. Recently, increasing evidence implicates oxidative stress and inflammation in the pathogenesis of AF. We searched the literature for evidence to support the use of antioxidant vitamins C and E in the prevention of AF. These vitamins, through their reactive-oxygen-species- (ROS-) scavenging effect, have shown a role in AF prevention in both animal and small clinical studies. The available evidence, however, is currently insufficient to support recommendations for their use in the wider patient population. Larger-scale clinical studies are required to confirm these preliminary results. Research is also required to further the understanding of the processes involved in the pathogenesis of AF and the role of antioxidant therapies to prevent the arrhythmia.
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Affiliation(s)
- Sonia Rasoli
- Department of Cardiothoracic Surgery, St George's Hospital, London SW17 0QT, UK
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Rodrigo R, González J, Paoletto F. The role of oxidative stress in the pathophysiology of hypertension. Hypertens Res 2011; 34:431-40. [PMID: 21228777 DOI: 10.1038/hr.2010.264] [Citation(s) in RCA: 284] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hypertension is considered to be the most important risk factor in the development of cardiovascular disease. An increasing body of evidence suggests that oxidative stress, which results in an excessive generation of reactive oxygen species (ROS), has a key role in the pathogenesis of hypertension. The modulation of the vasomotor system involves ROS as mediators of vasoconstriction induced by angiotensin II, endothelin-1 and urotensin-II, among others. The bioavailability of nitric oxide (NO), which is a major vasodilator, is highly dependent on the redox status. Under physiological conditions, low concentrations of intracellular ROS have an important role in the normal redox signaling maintaining vascular function and integrity. However, under pathophysiological conditions, increased levels of ROS contribute to vascular dysfunction and remodeling through oxidative damage. In human hypertension, an increase in the production of superoxide anions and hydrogen peroxide, a decrease in NO synthesis and a reduction in antioxidant bioavailability have been observed. In turn, antioxidants are reducing agents that can neutralize these oxidative and otherwise damaging biomolecules. The use of antioxidant vitamins, such as vitamins C and E, has gained considerable interest as protecting agents against vascular endothelial damage. Available data support the role of these vitamins as effective antioxidants that can counteract ROS effects. This review discusses the mechanisms involved in ROS generation, the role of oxidative stress in the pathogenesis of vascular damage in hypertension, and the possible therapeutic strategies that could prevent or treat this disorder.
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Affiliation(s)
- Ramón Rodrigo
- Renal Pathophysiology Laboratory, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
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van der Zwan LP, Teerlink T, Dekker JM, Henry RMA, Stehouwer CDA, Jakobs C, Heine RJ, Scheffer PG. Plasma myeloperoxidase is inversely associated with endothelium-dependent vasodilation in elderly subjects with abnormal glucose metabolism. Metabolism 2010; 59:1723-9. [PMID: 20580782 DOI: 10.1016/j.metabol.2010.04.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2009] [Revised: 04/13/2010] [Accepted: 04/14/2010] [Indexed: 02/07/2023]
Abstract
Myeloperoxidase (MPO), a biomarker related to inflammation, oxidative stress, and nitric oxide scavenging, has been shown to impair endothelium-dependent vasodilation. Because elevated hydrogen peroxide concentrations in diabetic vessels may enhance MPO activity, we hypothesized that a stronger association of MPO with flow-mediated dilation (FMD) may be found in subjects with abnormal glucose metabolism. Myeloperoxidase concentrations were measured in EDTA plasma samples from participants of a population-based cohort study, including 230 subjects with normal glucose metabolism and 386 with abnormal glucose metabolism. Vascular function was expressed as FMD and nitroglycerin-mediated dilation of the brachial artery. In subjects with abnormal glucose metabolism, MPO was negatively associated with FMD (-20.9 [95% confidence interval {CI}, -41.7 to -0.2] -μm change in FMD per SD increment of MPO). This association remained significant after adjustment for nitroglycerin-mediated dilation (-31.1 [95% CI, -50.0 to -12.3]) and was not attenuated after further adjustment for established risk factors. In subjects with normal glucose metabolism, MPO was not significantly associated with FMD (2.0 [95% CI, -16.0 to 20.0]). In conclusion, in subjects with abnormal glucose metabolism, plasma levels of MPO are inversely associated with endothelium-dependent vasodilation, possibly reflecting enhancement of MPO activity by vascular oxidative stress.
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Affiliation(s)
- Leonard P van der Zwan
- Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, PO Box 7057, 1007MB Amsterdam, The Netherlands
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Förstermann U. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch 2010; 459:923-39. [PMID: 20306272 DOI: 10.1007/s00424-010-0808-2] [Citation(s) in RCA: 522] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2010] [Accepted: 02/16/2010] [Indexed: 02/07/2023]
Abstract
Endothelium-derived nitric oxide (NO) is a paracrine factor that controls vascular tone, inhibits platelet function, prevents adhesion of leukocytes, and reduces proliferation of the intima. An enhanced inactivation and/or reduced synthesis of NO is seen in conjunction with risk factors for cardiovascular disease. This condition, referred to as endothelial dysfunction, can promote vasospasm, thrombosis, vascular inflammation, and proliferation of vascular smooth muscle cells. Vascular oxidative stress with an increased production of reactive oxygen species (ROS) contributes to mechanisms of vascular dysfunction. Oxidative stress is mainly caused by an imbalance between the activity of endogenous pro-oxidative enzymes (such as NADPH oxidase, xanthine oxidase, or the mitochondrial respiratory chain) and anti-oxidative enzymes (such as superoxide dismutase, glutathione peroxidase, heme oxygenase, thioredoxin peroxidase/peroxiredoxin, catalase, and paraoxonase) in favor of the former. Also, small molecular weight antioxidants may play a role in the defense against oxidative stress. Increased ROS concentrations reduce the amount of bioactive NO by chemical inactivation to form toxic peroxynitrite. Peroxynitrite-in turn-can "uncouple" endothelial NO synthase to become a dysfunctional superoxide-generating enzyme that contributes to vascular oxidative stress. Oxidative stress and endothelial dysfunction can promote atherogenesis. Therapeutically, drugs in clinical use such as ACE inhibitors, AT(1) receptor blockers, and statins have pleiotropic actions that can improve endothelial function. Also, dietary polyphenolic antioxidants can reduce oxidative stress, whereas clinical trials with antioxidant vitamins C and E failed to show an improved cardiovascular outcome.
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Affiliation(s)
- Ulrich Förstermann
- Department of Pharmacology, Johannes Gutenberg University Medical Center, Obere Zahlbacher Strasse 67, 55101, Mainz, Germany.
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Sugiyama T, Michel T. Thiol-metabolizing proteins and endothelial redox state: differential modulation of eNOS and biopterin pathways. Am J Physiol Heart Circ Physiol 2010; 298:H194-201. [PMID: 19897710 PMCID: PMC2806140 DOI: 10.1152/ajpheart.00767.2009] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2009] [Accepted: 10/30/2009] [Indexed: 11/22/2022]
Abstract
The intracellular redox state is stringently maintained by thiol-based antioxidants to establish a balance for the physiological and pathophysiological roles of reactive oxygen species. The relative contributions of the thioredoxin (Trx) and glutathione/glutaredoxin systems to intracellular redox balance are incompletely understood, as are the consequences of altered thiol metabolism on endothelial nitric oxide (NO) synthase (eNOS) and NO-dependent pathways in the endothelium. We designed duplex small interfering RNA (siRNA) constructs to specifically "knock down" the expression of three key thiol-metabolizing enzymes in cultured aortic endothelial cells. Transfection of siRNA constructs targeting glutathione reductase (GR), cytosolic Trx reductase (TrxR1), or mitochondrial Trx reductase (TrxR2) significantly decreased the intracellular reduced glutathione-to-oxidized glutathione ratio. siRNA-mediated knockdown of either GR, TrxR1, or TrxR2 markedly suppressed VEGF-induced NO production (measured by an electrochemical NO sensor) and also blocked eNOS enzyme activity (using the [(3)H]arginine/[(3)H]citrulline assay). Pretreatment of endothelial cells with N,N'-bis(2-chloroethyl)-N-nitrosourea, an inhibitor of GR and TrxR, significantly decreased VEGF-induced NO production. siRNA-mediated TrxR2 knockdown led to a marked increase in hydrogen peroxide (H(2)O(2)) production in endothelial cells. In contrast, knockdown of GR or TrxR1 only slightly increased H(2)O(2) production. Supplementation of endothelial cells with tetrahydrobiopterin prevented the increase in H(2)O(2) generation seen with siRNA-mediated knockdown of GR. These studies show that the differential regulation of thiol-metabolizing proteins leads to critical changes in oxidative and nitrosative stress pathways. Greater understanding of the differential regulation of thiol-metabolizing proteins may lead to the development of new pharmacological targets for diseases associated with oxidative stress in the vascular wall.
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Affiliation(s)
- Toru Sugiyama
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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Spargias K, Adreanides E, Demerouti E, Gkouziouta A, Manginas A, Pavlides G, Voudris V, Cokkinos DV. Iloprost prevents contrast-induced nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention. Circulation 2009; 120:1793-9. [PMID: 19841299 DOI: 10.1161/circulationaha.109.863159] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The prevention of contrast-induced nephropathy, which accounts for considerable morbidity and mortality, remains a vexing problem. Contrast-induced renal vasoconstriction is believed to play a pivotal role in the pathogenesis of contrast-induced nephropathy. The aim of this study was to examine the efficacy of the prostacyclin analog iloprost in preventing contrast-induced nephropathy in patients with renal dysfunction undergoing a coronary procedure. METHODS AND RESULTS We conducted a randomized, double-blind, placebo-controlled trial of iloprost in 208 patients with a serum creatinine concentration >or=1.4 mg/dL who underwent coronary angiography and/or intervention. Iloprost 1 ng kg(-1) min(-1) or placebo was administered intravenously beginning 30 to 90 minutes before and ending 4 hours after the procedure. Contrast-induced nephropathy was defined by an absolute increase in serum creatinine >or=0.5 mg/dL or a relative increase >or=25% measured 2 to 5 days after the procedure. Contrast-induced nephropathy occurred in 23 of the 105 patients (22%) in the control group and in 8 of the 103 patients (8%) in the iloprost group (odds ratio, 0.29; 95% confidence interval, 0.12 to 0.69; P=0.005). In the control group, the estimated glomerular filtration rate declined from 49.7+/-15.5 to 46.6+/-16.6 mL min(-1) 1.73 m(-2) (P=0.01). In the iloprost group, the estimated glomerular filtration rate increased marginally from 47.5+/-14.5 to 48.6+/-16.1 mL min(-1) 1.73 m(-2) (P=0.26). The mean absolute estimated glomerular filtration rate decline in the control group was greater than its change in the iloprost group (difference, 4.2 mL min(-1) 1.73 m(-2); 95% confidence interval, 1.1 to 7.3; P=0.008). CONCLUSIONS Prophylactic administration of iloprost may protect against contrast-induced nephropathy in high-risk patients undergoing a coronary procedure.
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Rodrigo R, Vinay J, Castillo R, Cereceda M, Asenjo R, Zamorano J, Araya J, Castillo-Koch R, Espinoza J, Larraín E. Use of vitamins C and E as a prophylactic therapy to prevent postoperative atrial fibrillation. Int J Cardiol 2009; 138:221-8. [PMID: 19446899 DOI: 10.1016/j.ijcard.2009.04.043] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2008] [Revised: 04/07/2009] [Accepted: 04/23/2009] [Indexed: 02/07/2023]
Abstract
Oxidative stress has been strongly involved in the underlying mechanism of atrial fibrillation, particularly in the arrhythmia occurring in patients undergoing cardiac surgery with extracorporeal circulation (postoperative atrial fibrillation). The ischemia/reperfusion injury thus occurring in the myocardial tissue contributes to the development of tissue remodeling, thought to be responsible for the functional heart impairment. Consequently, structural changes due to the cardiac tissue biomolecules attack by reactive oxygen and/or nitrogen species could account for functional changes in ion channels, transporters, membrane conductance, cytosolic transduction signals, and other events, all associated with the occurrence of arrhythmic consequences. The lack of success and significant side effects of anti-arrhythmic drugs have given rise to attempts aimed to develop alternative novel pharmacologic treatments. On this line, the biological properties of the antioxidant vitamins C and E suggest that they could decrease the vulnerability of the heart to the oxidative damage. Nevertheless, very few studies to assess their anti-arrhythmic effects have been reported in humans. The clinical and experimental evidence supporting the view that the pharmacological use of antioxidant vitamins could contribute to prevent postoperative atrial fibrillation is presented.
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Affiliation(s)
- Ramón Rodrigo
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Independencia 1027, Casilla 70058, Santiago 7, Chile.
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Sugiyama T, Levy BD, Michel T. Tetrahydrobiopterin recycling, a key determinant of endothelial nitric-oxide synthase-dependent signaling pathways in cultured vascular endothelial cells. J Biol Chem 2009; 284:12691-700. [PMID: 19286667 PMCID: PMC2675998 DOI: 10.1074/jbc.m809295200] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2008] [Revised: 03/09/2009] [Indexed: 02/06/2023] Open
Abstract
Tetrahydrobiopterin (BH4) is a key redox-active cofactor in endothelial isoform of NO synthase (eNOS) catalysis and is an important determinant of NO-dependent signaling pathways. BH4 oxidation is observed in vascular cells in the setting of the oxidative stress associated with diabetes. However, the relative roles of de novo BH4 synthesis and BH4 redox recycling in the regulation of eNOS bioactivity remain incompletely defined. We used small interference RNA (siRNA)-mediated "knockdown" GTP cyclohydrolase-1 (GTPCH1), the rate-limiting enzyme in BH4 biosynthesis, and dihydrofolate reductase (DHFR), an enzyme-recycling oxidized BH4 (7,8-dihydrobiopterin (BH2)), and studied the effects on eNOS regulation and biopterin metabolism in cultured aortic endothelial cells. Knockdown of either DHFR or GTPCH1 attenuated vascular endothelial growth factor (VEGF)-induced eNOS activity and NO production; these effects were recovered by supplementation with BH4. In contrast, supplementation with BH2 abolished VEGF-induced NO production. DHFR but not GTPCH1 knockdown increased reactive oxygen species (ROS) production. The increase in ROS production seen with siRNA-mediated DHFR knockdown was abolished either by simultaneous siRNA-mediated knockdown of eNOS or by supplementing with BH4. In contrast, addition of BH2 increased ROS production; this effect of BH2 was blocked by BH4 supplementation. DHFR but not GTPCH1 knockdown inhibited VEGF-induced dephosphorylation of eNOS at the inhibitory site serine 116; these effects were recovered by supplementation with BH4. These studies demonstrate a striking contrast in the pattern of eNOS regulation seen by the selective modulation of BH4 salvage/reduction versus de novo BH4 synthetic pathways. Our findings suggest that the depletion of BH4 is not sufficient to perturb NO signaling, but rather that concentration of intracellular BH2, as well as the relative concentrations of BH4 and BH2, together play a determining role in the redox regulation of eNOS-modulated endothelial responses.
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Affiliation(s)
- Toru Sugiyama
- Cardiovascular and Pulmonary Divisions, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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Block G, Jensen CD, Norkus EP, Hudes M, Crawford PB. Vitamin C in plasma is inversely related to blood pressure and change in blood pressure during the previous year in young Black and White women. Nutr J 2008; 7:35. [PMID: 19091068 PMCID: PMC2621233 DOI: 10.1186/1475-2891-7-35] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2007] [Accepted: 12/17/2008] [Indexed: 01/03/2023] Open
Abstract
Background The prevalence of hypertension and its contribution to cardiovascular disease risk makes it imperative to identify factors that may help prevent this disorder. Extensive biological and biochemical data suggest that plasma ascorbic acid may be such a factor. In this study we examined the association between plasma ascorbic acid concentration and blood pressure (BP) in young-adult women. Methods Participants were 242 Black and White women aged 18–21 yr from the Richmond, CA, cohort of the National Heart, Lung and Blood Institute Growth and Health Study. We examined the associations of plasma ascorbic acid with BP at follow-up year 10, and with change in BP during the previous year. Results In cross-sectional analysis, plasma ascorbic acid at year 10 was inversely associated with systolic BP and diastolic BP after adjusting for race, body mass index, education, and dietary intake of fat and sodium. Persons in the highest one-fourth of the plasma ascorbic acid distribution had 4.66 mmHg lower systolic BP (95% CI 1.10 to 8.22 mmHg, p = 0.005) and 6.04 mmHg lower diastolic BP (95% CI 2.70 to 9.38 mmHg, p = 0.0002) than those in the lowest one-fourth of the distribution. In analysis of the change in BP, plasma ascorbic acid was also inversely associated with change in systolic BP and diastolic BP during the previous year. While diastolic blood pressure among persons in the lowest quartile of plasma ascorbic acid increased by 5.97 mmHg (95% CI 3.82 to 8.13 mmHg) from year 9 to year 10, those in the highest quartile of plasma vitamin C increased by only 0.23 mmHg (95% CI -1.90 to +2.36 mmHg) (test for linear trend: p < 0.0001). A similar effect was seen for change in systolic BP, p = 0.005. Conclusion Plasma ascorbic acid was found to be inversely associated with BP and change in BP during the prior year. The findings suggest the possibility that vitamin C may influence BP in healthy young adults. Since lower BP in young adulthood may lead to lower BP and decreased incidence of age-associated vascular events in older adults, further investigation of treatment effects of vitamin C on BP regulation in young adults is warranted.
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Affiliation(s)
- Gladys Block
- School of Public Health, 50 University Hall, University of California, Berkeley, CA 94720, USA.
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Herspring KF, Ferreira LF, Copp SW, Snyder BS, Poole DC, Musch TI. Effects of antioxidants on contracting spinotrapezius muscle microvascular oxygenation and blood flow in aged rats. J Appl Physiol (1985) 2008; 105:1889-96. [PMID: 18845782 DOI: 10.1152/japplphysiol.90642.2008] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Aged rats exhibit a decreased muscle microvascular O(2) partial pressure (Pmv(O(2))) at rest and during contractions compared with young rats. Age-related reductions in nitric oxide bioavailability due, in part, to elevated reactive O(2) species, constrain muscle blood flow (Qm). Antioxidants may restore nitric oxide bioavailability, Qm, and ameliorate the reduced Pmv(O(2)). We tested the hypothesis that antioxidants would elevate Qm and, therefore, Pmv(O(2)) in aged rats. Spinotrapezius muscle Pmv(O(2)) and Qm were measured, and oxygen consumption (Vm(O(2))) was estimated in anesthetized male Fisher 344 x Brown Norway hybrid rats at rest and during 1-Hz contractions, before and after antioxidant intravenous infusion (76 mg/kg vitamin C and 52 mg/kg tempol). Before infusion, contractions evoked a biphasic Pmv(O(2)) that fell from 30.6 +/- 0.9 Torr to a nadir of 16.8 +/- 1.2 Torr with an "undershoot" of 2.8 +/- 0.7 Torr below the subsequent steady-state (19.7 +/- 1.2 Torr). The principal effect of antioxidants was to elevate baseline Pmv(O(2)) from 30.6 +/- 0.9 to 35.7 +/- 0.8 Torr (P < 0.05) and reduce or abolish the undershoot (P < 0.05). Antioxidants reduced Qm and Vm(O(2)) during contractions (P < 0.05), while decreasing force production 16.5% (P < 0.05) and elevating the force production-to-Vm(O(2)) ratio (0.92 +/- 0.03 to 1.06 +/- 0.6, P < 0.05). Thus antioxidants increased Pmv(O(2)) by altering the balance between muscle O(2) delivery and Vm(O(2)) at rest and during contractions. It is likely that this effect arose from antioxidants reducing myocyte redox below the level optimal for contractile performance and directly (decreased tension) or indirectly (altered balance of vasoactive mediators) influencing O(2) delivery and Vm(O(2)).
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Affiliation(s)
- Kyle F Herspring
- Department of Kinesiology, Kansas State University, Manhattan, Kansas 66506-5802, USA
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Decrease in oxidative stress through supplementation of vitamins C and E is associated with a reduction in blood pressure in patients with essential hypertension. Clin Sci (Lond) 2008; 114:625-34. [PMID: 17999638 DOI: 10.1042/cs20070343] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Oxidative stress has been associated with mechanisms of EH (essential hypertension). The aim of the present study was to test the hypothesis that the antioxidant properties of vitamins C and E are associated with a decrease in BP (blood pressure) in patients with EH. A randomized double-blind placebo-controlled clinical trial was conducted in 110 men with grade 1 EH (35-60 years of age without obesity, dyslipidaemia and diabetes mellitus, non-smokers, not undergoing vigorous physical exercise, without the use of any medication and/or high consumption of fruit and vegetables). Participants were randomly assigned to receive either vitamins C+E [vitamin C (1 g/day) plus vitamin E (400 international units/day)] or placebo for 8 weeks. Measurements included 24 h ambulatory BP and blood analysis of oxidative-stress-related parameters in erythrocytes (GSH/GSSH ratio, antioxidant enzymes and malondialdehyde) and plasma [FRAP (ferric reducing ability of plasma)], and levels of 8-isoprostane, vitamins C and E were measured at baseline and after treatment. Following administration of vitamins C+E, patients with EH had significantly lower systolic BP, diastolic BP and mean arterial BP and higher erythrocyte and serum antioxidant capacity compared with either placebo-treated patients with EH or the patients with EH at baseline prior to treatment. BP correlated positively with plasma 8-isoprostane levels and negatively with plasma FRAP levels in the vitamins C+E- and placebo-treated groups. In conclusion, the present study supports the view that oxidative stress is involved in the pathogenesis of EH, and that enhancement of antioxidant status by supplementation with vitamins C and E in patients with EH is associated with lower BP. This suggests intervention with antioxidants as an adjunct therapy for hypertension.
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Kumar S, Wedgwood S, Black SM. Nordihydroguaiaretic acid increases endothelial nitric oxide synthase expression via the transcription factor AP-1. DNA Cell Biol 2008; 26:853-62. [PMID: 17919072 DOI: 10.1089/dna.2007.0614] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
It has been previously reported that the antioxidant compound nordihydroguaiaretic acid (NDGA) increases endothelial nitric oxide synthase (eNOS) expression in cultured bovine aortic endothelial cells. However, the exact mechanism for this effect was unresolved. Thus, the purpose of this study was to further elucidate the effect of NDGA on eNOS protein expression and enzymatic activity in fetal pulmonary arterial endothelial cells (FPAECs), and to identify the transcription factors involved in this regulation. Following overnight exposure to 0-32 microM NDGA, we observed a 2- to 2.5-fold increase in eNOS protein expression in FPAECs, with a similar increase observed in eNOS activity. For eNOS gene promoter analysis, we initially used two promoter-reporter constructs: a 1.6 kb promoter fragment and an 840 bp construct, both of which include an AP-1-specific binding site. NDGA exposure induced a significant increase in eNOS promoter activity in both constructs. However, the NDGA-mediated increase was abolished when we used either a truncated promoter construct lacking the AP-1 element or a construct in which the AP-1 binding site was mutated. AP-1 binding efficiency was also determined by electrophoretic mobility shift assay, where we observed an increase in AP-1 binding in FPAECs treated with NDGA while the binding of AP-1 was found to be decreased when a mutated AP-1 consensus sequence was used. Further, supershift analyses indicated that the AP-1 complex consisted of c-Jun and FosB. We therefore conclude that NDGA antioxidant activity regulates eNOS expression via AP-1 and that antioxidant therapy could potentially be used to increase eNOS expression in diseases, such as persistent pulmonary hypertension of the newborn, where eNOS expression and activity are known to be reduced.
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Affiliation(s)
- Sanjiv Kumar
- Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912, USA
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Rodrigo R, Cereceda M, Castillo R, Asenjo R, Zamorano J, Araya J, Castillo-Koch R, Espinoza J, Larraín E. Prevention of atrial fibrillation following cardiac surgery: basis for a novel therapeutic strategy based on non-hypoxic myocardial preconditioning. Pharmacol Ther 2008; 118:104-27. [PMID: 18346791 DOI: 10.1016/j.pharmthera.2008.01.005] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2008] [Accepted: 01/24/2008] [Indexed: 02/06/2023]
Abstract
Atrial fibrillation is the most common complication of cardiac surgical procedures performed with cardiopulmonary bypass. It contributes to increased hospital length of stay and treatment costs. At present, preventive strategies offer only suboptimal benefits, despite improvements in anesthesia, surgical technique, and medical therapy. The pathogenesis of postoperative atrial fibrillation is considered to be multifactorial. However oxidative stress is a major contributory factor representing the unavoidable consequences of ischemia/reperfusion cycle occurring in this setting. Considerable evidence suggests the involvement of reactive oxygen species (ROS) in the pathogenic mechanism of this arrhythmia. Interestingly, the deleterious consequences of high ROS exposure, such as inflammation, cell death (apoptosis/necrosis) or fibrosis, may be abrogated by a myocardial preconditioning process caused by previous exposure to moderate ROS concentration known to trigger survival response mechanisms. The latter condition may be created by n-3 PUFA supplementation that could give rise to an adaptive response characterized by increased expression of myocardial antioxidant enzymes and/or anti-apoptotic pathways. In addition, a further reinforcement of myocardial antioxidant defenses could be obtained through vitamins C and E supplementation, an intervention also known to diminish enzymatic ROS production. Based on this paradigm, this review presents clinical and experimental evidence supporting the pathophysiological and molecular basis for a novel therapeutic approach aimed to diminish the incidence of postoperative atrial fibrillation through a non-hypoxic preconditioning plus a reinforcement of the antioxidant defense system in the myocardial tissue.
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Affiliation(s)
- Ramón Rodrigo
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
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Rodrigo R, Guichard C, Charles R. Clinical pharmacology and therapeutic use of antioxidant vitamins. Fundam Clin Pharmacol 2007; 21:111-27. [PMID: 17391284 DOI: 10.1111/j.1472-8206.2006.00466.x] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The clinical use of antioxidants has gained considerable interest during the last decade. It was suggested from epidemiological studies that diets high in fruits and vegetables might help decrease the risk of cardiovascular disease. Therefore, supplements of vitamins C and E were applied through protocols aimed to prevent diseases such as atherosclerosis, preeclampsia or hypertension, thought to be mediated by oxidative stress. Despite the biological properties of these vitamins could account for an effective protection, as shown by several clinical and experimental studies, their efficacy remains controversial in the light of some recent clinical trials and meta-analyses. However, the methodology of these studies, criteria for selection of patients, the uncertain extent of progression of the disease when initiating supplementation, the lack of mechanistic studies containing basic scientific aspects, such as the bioavailability, pharmacokinetic properties, and the nature of the antioxidant sources of vitamins, could account for the inconsistency of the various clinical trials and meta-analyses assessing the efficacy of these vitamins to prevent human diseases. This review presents a survey of the clinical use of antioxidant vitamins E and C, proposing study models based on the biological effects of these compounds likely to counteract the pathophysiological mechanisms able to explain the structural and functional organ damage.
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Affiliation(s)
- Ramón Rodrigo
- Laboratory of Renal Pathophysiology, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, Casilla, Santiago, Chile.
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Förstermann U. Janus-faced role of endothelial NO synthase in vascular disease: uncoupling of oxygen reduction from NO synthesis and its pharmacological reversal. Biol Chem 2007; 387:1521-33. [PMID: 17132097 DOI: 10.1515/bc.2006.190] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Endothelial NO synthase (eNOS) is the predominant enzyme responsible for vascular NO synthesis. A functional eNOS transfers electrons from NADPH to its heme center, where L-arginine is oxidized to L-citrulline and NO. Common conditions predisposing to atherosclerosis, such as hypertension, hypercholesterolemia, diabetes mellitus and smoking, are associated with enhanced production of reactive oxygen species (ROS) and reduced amounts of bioactive NO in the vessel wall. NADPH oxidases represent major sources of ROS in cardiovascular pathophysiology. NADPH oxidase-derived superoxide avidly interacts with eNOS-derived NO to form peroxynitrite (ONOO(-)), which oxidizes the essential NOS cofactor (6R-)5,6,7,8-tetrahydrobiopterin (BH(4)). As a consequence, oxygen reduction uncouples from NO synthesis, thereby rendering NOS to a superoxide-producing pro-atherosclerotic enzyme. Supplementation with BH(4) corrects eNOS dysfunction in several animal models and in patients. Administration of high local doses of the antioxidant L-ascorbic acid (vitamin C) improves endothelial function, whereas large-scale clinical trials do not support a strong role for oral vitamin C and/or E in reducing cardiovascular disease. Statins, angiotensin-converting enzyme inhibitors and AT1 receptor blockers have the potential of reducing vascular oxidative stress. Finally, novel approaches are being tested to block pathways leading to oxidative stress (e.g. protein kinase C) or to upregulate antioxidant enzymes.
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Affiliation(s)
- Ulrich Förstermann
- Department of Pharmacology, Johannes Gutenberg University, D-55101 Mainz, Germany.
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Affiliation(s)
- Ngoc-Anh Le
- Emory University School of Medicine, Emory Lipid Research Laboratory, Atlanta, Georgia 30033, USA.
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