Tomasz J Guzik

Publications of Tomasz J Guzik

• Targeting NADPH oxidases in vascular pharmacology.

  Authors: Agata Schramm, Paweł Matusik, Grzegorz Osmenda, Tomasz J Guzik

  Vascular pharmacology. 03/2012;

  Oxidative stress is a molecular dysregulation in reactive oxygen species (ROS) metabolism, which plays a key role in the pathogenesis of atherosclerosis, vascular inflammation and endothelialOxidative stress is a molecular dysregulation in reactive oxygen species (ROS) metabolism, which plays a key role in the pathogenesis of atherosclerosis, vascular inflammation and endothelial dysfunction. It is characterized by a loss of nitric oxide (NO) bioavailability. Large clinical trials such as HOPE and HPS have not shown a clinical benefit of antioxidant vitamin C or vitamin E treatment, putting into question the role of oxidative stress in cardiovascular disease. A change in the understanding of the molecular nature of oxidative stress has been driven by the results of these trials. Oxidative stress is no longer perceived as a simple imbalance between the production and scavenging of ROS, but as a dysfunction of enzymes involved in ROS production. NADPH oxidases are at the center of these events, underlying the dysfunction of other oxidases including eNOS uncoupling, xanthine oxidase and mitochondrial dysfunction. Thus NADPH oxidases are important therapeutic targets. Indeed, HMG-CoA reductase inhibitors (statins) as well as drugs interfering with the renin-angiotensin-aldosterone system inhibit NADPH oxidase activation and expression. Angiotensin-converting enzyme (ACE) inhibitors, AT1 receptor antagonists (sartans) and aliskiren, as well as spironolactone or eplerenone, have been discussed. Molecular aspects of NADPH oxidase regulation must be considered, while thinking about novel pharmacological targeting of this family of enzymes consisting of several homologs Nox1, Nox2, Nox3, Nox4 and Nox5 in humans. In order to properly design trials of antioxidant therapies, we must develop reliable techniques for the assessment of local and systemic oxidative stress. Classical antioxidants could be combined with novel oxidase inhibitors. In this review, we discuss NADPH oxidase inhibitors such as VAS2870, VAS3947, GK-136901, S17834 or plumbagin. Therefore, our efforts must focus on generating small molecular weight inhibitors of NADPH oxidases, allowing the selective inhibition of dysfunctional NADPH oxidase homologs. This appears to be the most reasonable approach, potentially much more efficient than non-selective scavenging of all ROS by the administration of antioxidants.

• Novel therapeutic approaches in limiting oxidative stress and inflammation.

  Authors: Agnieszka Spychalowicz, Grzegorz Wilk, Tomasz Sliwa, Dominik Ludew, Tomasz J Guzik

  Current pharmaceutical biotechnology. 01/2012;

  The interaction between reactive oxygen species (ROS) and inflammation plays and important role in the pathogenesis of endothelial dysfunction and cardiovascular disease, cancer and other diseases.The interaction between reactive oxygen species (ROS) and inflammation plays and important role in the pathogenesis of endothelial dysfunction and cardiovascular disease, cancer and other diseases. Thus, antioxidant strategies may be very important in immune regulation and in limiting inflammation. Surprisingly, large clinical trials have shown that ROS scavenging by antioxidant vitamins is ineffective or even harmful in spite of the fact that reactive oxygen species themselves are pro-inflammatory, regulate immune system and enhance atherosclerosis. Therefore, there is a need of novel, more specific antioxidant and anti-inflammatory approaches aimed on prevention of ROS formation, by targeting specific molecular pathways involved in ROS generation and their activation of pro-inflammatory cascades. Potential targets include the NADPH oxidases (Nox enzymes), xanthine oxidase, endothelial nitric oxide synthase and mitochondrial oxidases. Nox enzymes play central role, as they can stimulate other enzymatic sources of ROS. The interplay between inflammation and oxidative stress is discussed in the context of adipose tissue, perivascular inflammation and role of central nervous system in immune regulation. All of the above participate in "brain-vessel axis" critical in the pathogenesis of numerous pathologies. Role of cytokines such as TNF-alpha, IL-17 or IL-6 and their links to superoxide and hydrogen peroxide production are discussed. Statins, angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists block upstream signaling of Nox activation, including MAP kinase signaling or G protein activation, which contributes to their clinical effectiveness. Here we discuss novel possibilities that drugs directly inhibiting Nox activation could successfully inhibit oxidative stress and inflammation related to cardiovascular disease. Moreover we describe potential gene therapy approaches in limiting oxidative stress in the vasculature. These approaches can become also useful in cancer immunomodulation.

• Mechanisms of increased vascular superoxide production in human varicose veins.

  Authors: Bartłomiej Guzik, Maciej Chwała, Paweł Matusik, Dominik Ludew, Dominik Skiba, Grzegorz Wilk, Wojciech Mrowiecki, Bogdan Batko, Andrzej Cencora, Bogusław Kapelak, Jerzy Sadowski, Ryszard Korbut, Tomasz J Guzik

  Polskie Archiwum Medycyny Wewnętrznej. 08/2011; 121(9):279-86.

  Varicose vein disease is one of the most common morbidities in the developed countries. Recent studies have shown that oxidative stress is increased in varicose veins (VV) and venous insufficiency.Varicose vein disease is one of the most common morbidities in the developed countries. Recent studies have shown that oxidative stress is increased in varicose veins (VV) and venous insufficiency. However, the exact mechanisms of oxidative stress in VV remain unknown. The aim of the study was to measure superoxide anion production and analyze its enzymatic sources in VV in comparison with control human saphenous veins (HSV). Superoxide production was also compared between the proximal and distal segments of the veins. Proximal and distal segments of varicose veins (14 patients, aged 52 ±3.5 years) and control veins (15 patients, aged 56 ±4 years) were obtained during VV removal or elective coronary artery bypass graft surgery, respectively. Subjects were matched for age, sex, and the major risk factors for atherosclerosis. Superoxide was measured by lucigenin-enhanced chemiluminescence (5 μmol/l) in the presence and absence of oxidase inhibitors. Superoxide production was increased in VV compared with control HSV. This increase was particularly evident in the distal segments of VV. There was a significant correlation between superoxide production in the proximal and distal segments of HSV but not of VV. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and uncoupled nitric oxide synthase (NOS) were the major sources of superoxide in VV, because their inhibitors greatly attenuated superoxide production in VV. NADPH oxidases and NOS could represent valuable drug targets for pharmacological treatment and prevention of varicose vein disease. Oxidative stress may provide a link between endothelial dysfunction, inflammation, and immune activation and the development of chronic venous dysfunction.

• Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterin-mediated endothelial nitric oxide synthase coupling.

  Authors: Charalambos Antoniades, Constantinos Bakogiannis, Paul Leeson, Tomasz J Guzik, Mei-Hua Zhang, Dimitris Tousoulis, Alexios S Antonopoulos, Michael Demosthenous, Kyriakoula Marinou, Ashley Hale, Andreas Paschalis, Costas Psarros, Costas Triantafyllou, Jennifer Bendall, Barbara Casadei, Christodoulos Stefanadis, Keith M Channon

  Circulation. 07/2011; 124(3):335-45.

  Treatment with statins improves clinical outcome, but the exact mechanisms of pleiotropic statin effects on vascular function in human atherosclerosis remain unclear. We examined the direct effectsTreatment with statins improves clinical outcome, but the exact mechanisms of pleiotropic statin effects on vascular function in human atherosclerosis remain unclear. We examined the direct effects of atorvastatin on tetrahydrobiopterin-mediated endothelial nitric oxide (NO) synthase coupling in patients with coronary artery disease. We first examined the association of statin treatment with vascular NO bioavailability and arterial superoxide (O(2)(·-)) in 492 patients undergoing coronary artery bypass graft surgery. Then, 42 statin-naïve patients undergoing elective coronary artery bypass graft surgery were randomized to atorvastatin 40 mg/d or placebo for 3 days before surgery to examine the impact of atorvastatin on endothelial function and O(2)(·-) generation in internal mammary arteries. Finally, segments of internal mammary arteries from 26 patients were used in ex vivo experiments to evaluate the statin-dependent mechanisms regulating the vascular redox state. Statin treatment was associated with improved vascular NO bioavailability and reduced O(2)(·-) generation in internal mammary arteries. Oral atorvastatin increased vascular tetrahydrobiopterin bioavailability and reduced basal and N-nitro-l-arginine methyl ester-inhibitable O(2)(·-) in internal mammary arteries independently of low-density lipoprotein lowering. In ex vivo experiments, atorvastatin rapidly improved vascular tetrahydrobiopterin bioavailability by upregulating GTP-cyclohydrolase I gene expression and activity, resulting in improved endothelial NO synthase coupling and reduced vascular O(2)(·-). These effects were reversed by mevalonate, indicating a direct effect of vascular hydroxymethylglutaryl-coenzyme A reductase inhibition. This study demonstrates for the first time in humans the direct effects of statin treatment on the vascular wall, supporting the notion that this effect is independent of low-density lipoprotein lowering. Atorvastatin directly improves vascular NO bioavailability and reduces vascular O(2)(·-) through tetrahydrobiopterin-mediated endothelial NO synthase coupling. These findings provide new insights into the mechanisms mediating the beneficial vascular effects of statins in humans. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01013103.

• Inflammation, immunity, and hypertension.

  Authors: David G Harrison, Tomasz J Guzik, Heinrich E Lob, Meena S Madhur, Paul J Marvar, Salim R Thabet, Antony Vinh, Cornelia M Weyand

  Hypertension. 02/2011; 57(2):132-40.

• Inhibition and genetic ablation of the B7/CD28 T-cell costimulation axis prevents experimental hypertension.

  Authors: Antony Vinh, Wei Chen, Yelena Blinder, Daiana Weiss, W Robert Taylor, Jörg J Goronzy, Cornelia M Weyand, David G Harrison, Tomasz J Guzik

  Circulation. 12/2010; 122(24):2529-37.

  The pathogenesis of hypertension remains poorly understood, and treatment is often unsuccessful. Recent evidence suggests that the adaptive immune response plays an important role in this disease.The pathogenesis of hypertension remains poorly understood, and treatment is often unsuccessful. Recent evidence suggests that the adaptive immune response plays an important role in this disease. Various hypertensive stimuli cause T-cell activation and infiltration into target organs such as the vessel and the kidney, which promotes vascular dysfunction and blood pressure elevation. Classically, T-cell activation requires T-cell receptor ligation and costimulation. The latter often involves interaction between B7 ligands (CD80 and CD86) on antigen-presenting cells with the T-cell coreceptor CD28. This study was therefore performed to examine the role of this pathway in hypertension. Angiotensin II-induced hypertension increased the presence of activated (CD86(+)) dendritic cells in secondary lymphatic tissues. Blockade of B7-dependent costimulation with CTLA4-Ig reduced both angiotensin II- and deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Activation of circulating T cells, T-cell cytokine production, and vascular T-cell accumulation caused by these hypertensive stimuli were abrogated by CTLA4-Ig. Furthermore, in mice lacking B7 ligands, angiotensin II caused minimal blood pressure elevation and vascular inflammation, and these effects were restored by transplantation with wild-type bone marrow. T-cell costimulation via B7 ligands is essential for development of experimental hypertension, and inhibition of this process could have therapeutic benefit in the treatment of this disease.

• Central and peripheral mechanisms of T-lymphocyte activation and vascular inflammation produced by angiotensin II-induced hypertension.

  Authors: Paul J Marvar, Salim R Thabet, Tomasz J Guzik, Heinrich E Lob, Louise A McCann, Connie Weyand, Frank J Gordon, David G Harrison

  Circulation research. 07/2010; 107(2):263-70.

  We have previously found that T lymphocytes are essential for development of angiotensin II-induced hypertension; however, the mechanisms responsible for T-cell activation in hypertension remainWe have previously found that T lymphocytes are essential for development of angiotensin II-induced hypertension; however, the mechanisms responsible for T-cell activation in hypertension remain undefined. We sought to study the roles of the CNS and pressure elevation in T-cell activation and vascular inflammation caused by angiotensin II. To prevent the central actions of angiotensin II, we created anteroventral third cerebral ventricle (AV3V) lesions in mice. The elevation in blood pressure in response to angiotensin II was virtually eliminated by AV3V lesions, as was activation of circulating T cells and the vascular infiltration of leukocytes. In contrast, AV3V lesioning did not prevent the hypertension and T-cell activation caused by the peripheral acting agonist norepinephrine. To determine whether T-cell activation and vascular inflammation are attributable to central influences or are mediated by blood pressure elevation, we administered hydralazine (250 mg/L) in the drinking water. Hydralazine prevented the hypertension and abrogated the increase in circulating activated T cells and vascular infiltration of leukocytes caused by angiotensin II. We conclude that the central and pressor effects of angiotensin II are critical for T-cell activation and development of vascular inflammation. These findings also support a feed-forward mechanism in which modest degrees of blood pressure elevation lead to T-cell activation, which in turn promotes inflammation and further raises blood pressure, leading to severe hypertension.

• Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction.

  Authors: Meena S Madhur, Heinrich E Lob, Louise A McCann, Yoichiro Iwakura, Yelena Blinder, Tomasz J Guzik, David G Harrison

  Hypertension. 02/2010; 55(2):500-7.

  We have shown previously that T cells are required for the full development of angiotensin II-induced hypertension. However, the specific subsets of T cells that are important in this process areWe have shown previously that T cells are required for the full development of angiotensin II-induced hypertension. However, the specific subsets of T cells that are important in this process are unknown. T helper 17 cells represent a novel subset that produces the proinflammatory cytokine interleukin 17 (IL-17). We found that angiotensin II infusion increased IL-17 production from T cells and IL-17 protein in the aortic media. To determine the effect of IL-17 on blood pressure and vascular function, we studied IL-17(-/-) mice. The initial hypertensive response to angiotensin II infusion was similar in IL-17(-/-) and C57BL/6J mice. However, hypertension was not sustained in IL-17(-/-) mice, reaching levels 30-mm Hg lower than in wild-type mice by 4 weeks of angiotensin II infusion. Vessels from IL-17(-/-) mice displayed preserved vascular function, decreased superoxide production, and reduced T-cell infiltration in response to angiotensin II. Gene array analysis of cultured human aortic smooth muscle cells revealed that IL-17, in conjunction with tumor necrosis factor-alpha, modulated expression of >30 genes, including a number of inflammatory cytokines/chemokines. Examination of IL-17 in diabetic humans showed that serum levels of this cytokine were significantly increased in those with hypertension compared with normotensive subjects. We conclude that IL-17 is critical for the maintenance of angiotensin II-induced hypertension and vascular dysfunction and might be a therapeutic target for this widespread disease.

• Induction of Hypertension and Peripheral Inflammation by Reduction of Extracellular Superoxide Dismutase in the Central Nervous System.

  Authors: Heinrich E Lob, Paul J Marvar, Tomasz J Guzik, Shraya Sharma, Louise A McCann, Cornelia Weyand, Frank J Gordon, David G Harrison

  Hypertension. 12/2009;

  The circumventricular organs (CVOs) lack a well-formed blood-brain barrier and produce superoxide in response to angiotensin II and other hypertensive stimuli. This increase in central superoxide hasThe circumventricular organs (CVOs) lack a well-formed blood-brain barrier and produce superoxide in response to angiotensin II and other hypertensive stimuli. This increase in central superoxide has been implicated in the regulation of blood pressure. The extracellular superoxide dismutase (SOD3) is highly expressed in cells associated with CVOs and particularly with tanycytes lining this region. To understand the role of SOD3 in the CVOs in blood pressure regulation, we performed intracerebroventricular injection an adenovirus encoding Cre-recombinase (5x10(8) particles per milliliter) in mice with loxP sites flanking the SOD3 coding region (SOD3(loxp/loxp) mice). An adenovirus encoding red-fluorescent protein was injected as a control. Deletion of CVO SOD3 increased baseline blood pressure modestly and markedly augmented the hypertensive response to low-dose angiotensin II (140 ng/kg per day), whereas intracerebroventricular injection of adenovirus encoding red-fluorescent protein had minimal effects on these parameters. Adenovirus encoding Cre-recombinase-treated mice exhibited increased sympathetic modulation of heart rate and blood pressure variability, increased vascular superoxide production, and T-cell activation as characterized by increased circulating CD69(+)/CD3(+) cells. Deletion of CVO SOD3 also markedly increased vascular T-cell and leukocyte infiltration caused by angiotensin II. We conclude that SOD3 in the CVO plays a critical role in the regulation of blood pressure, and its loss promotes T-cell activation and vascular inflammation, in part by modulating sympathetic outflow. These findings provide insight into how central signals produce vascular inflammation in response to hypertensive stimuli, such as angiotensin II.

• NADPH oxidases - molecular understanding finally reaching the clinical level?

  Authors: Tomasz J Guzik, Kathy Griendling

  Antioxidants & redox signaling. 05/2009;

  NADPH oxidases (Nox) have been the subject of very intensive research over the past several years, which has led to in depth understanding of the function of these enzymes in health and disease.NADPH oxidases (Nox) have been the subject of very intensive research over the past several years, which has led to in depth understanding of the function of these enzymes in health and disease. Discovery of novel Nox enzymes and identification of a very wide range of tissue expression has increased our understanding of how NADPH oxidases may regulate so many distinct cellular functions, and how the dysfunction of these enzymes may lead to disease. The present Forum issue summarizes the most novel aspects of NADPH oxidase biology, focusing on linking the molecular basis of NADPH oxidase function, compartmentalization and differential expression patterns to diseases such as those of the pulmonary system, inflammation, central nervous system disorders, endothelial and vascular dysfunction, as well as disorders involving angiogenesis and stem cell and endothelial progenitor cell functions. Establishing these links may be the first step for future therapeutic use of NADPH oxidase inhibitors, which are discussed at length within this Forum issue.

• Regulation of T cell function by endogenously produced angiotensin II.

  Authors: Nyssa E Hoch, Tomasz J Guzik, Wei Chen, Tenecia Deans, Samer A Maalouf, Petra Gratze, Cornelia Weyand, David G Harrison

  American journal of physiology. Regulatory, integrative and comparative physiology. 01/2009;

  The adaptive immune response, and in particular T cells have been shown to be important in the genesis of hypertension. In the present study, we sought to determine how angiotensin II, the NADPHThe adaptive immune response, and in particular T cells have been shown to be important in the genesis of hypertension. In the present study, we sought to determine how angiotensin II, the NADPH oxidase and reactive oxygen species interplay with T cells to modulate their activation and ultimately hypertension. We determined that T cells express angiotensinogen, the angiotensin I-converting enzyme and renin and produce physiological levels of angiotensin II. AT1 receptors were primarily expressed intracellularly and endogenously produced angiotensin II increased T cell activation, expression of tissue homing markers and production of the cytokine TNFalpha. Inhibition of T cell ACE reduced TNFalpha production; indicating endogenously produced angiotensin II has a regulatory role in this process. Studies with specific antagonists and T cells from AT1 and ATs mice indicated that both receptor subtypes contribute to TNFalpha production. We found that superoxide was a critical mediator of T cell TNFalpha production as this was significantly inhibited by PEG-SOD, but not PEG-catalase. Thus, T cells contain an endogenous renin-angiotensin system that modulates T cell function, NADPH oxidase activity and production of superoxide that in turn modulates TNFalpha production. These findings contribute to our understanding of how angiotensin II and T cells enhance inflammation in cardiovascular disease. Key words: NADPH oxidase, PEG-SOD, cytokine, superoxide.

• Is hypertension an immunologic disease?

  Authors: David G Harrison, Tomasz J Guzik, Jorg Goronzy, Cornelia Weyand

  Current cardiology reports. 12/2008; 10(6):464-9.

  Several studies published in the past three decades have suggested that the adaptive immune system contributes to hypertension. Recent studies have shown that T cells play a crucial role in the bloodSeveral studies published in the past three decades have suggested that the adaptive immune system contributes to hypertension. Recent studies have shown that T cells play a crucial role in the blood pressure elevation caused by angiotensin II and in response to sodium and volume challenge. Hypertensive stimuli cause effector T cells to enter visceral fat, in particular perivascular fat, where they release cytokines that promote vasoconstriction. Similarly, effector T cells accumulate in the kidney in hypertension and contribute to renal dysfunction, promoting sodium and volume retention. These findings provide some insight into the relationship between inflammation and hypertension and suggest that efforts to reduce T-cell activation may be useful in preventing or treating this disease.

• Calcium-Dependent NOX5 Nicotinamide Adenine Dinucleotide Phosphate Oxidase Contributes to Vascular Oxidative Stress in Human Coronary Artery Disease.

  Authors: Tomasz J Guzik, Wei Chen, Maria C Gongora, Bartlomiej Guzik, Heinrich E Lob, Deepa Mangalat, Nyssa Hoch, Sergey Dikalov, Pawel Rudzinski, Boguslaw Kapelak, Jerzy Sadowski, David G Harrison

  Journal of the American College of Cardiology. 12/2008; 52(22):1803-9.

  OBJECTIVES: This study sought to examine the expression and activity of the calcium-dependent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) in human atherosclerotic coronaryOBJECTIVES: This study sought to examine the expression and activity of the calcium-dependent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) in human atherosclerotic coronary arteries. BACKGROUND: The NOX-based NADPH oxidases are major sources of reactive oxygen species (ROS) in human vessels. Several NOX homologues have been identified, but their relative contribution to vascular ROS production in coronary artery disease (CAD) is unclear; NOX5 is a unique homolog in that it is calcium dependent and thus could be activated by vasoconstrictor hormones. Its presence has not yet been studied in human vessels. METHODS: Coronary arteries from patients undergoing cardiac transplantation with CAD or without CAD were studied; NOX5 was quantified and visualized using Western blotting, immunofluorescence, and quantitative real-time polymerase chain reaction. Calcium-dependent NADPH oxidase activity, corresponding greatly to NOX5 activity, was measured by electron paramagnetic resonance. RESULTS: Both Western blotting and quantitative real-time polymerase chain reaction indicated a marked increase in NOX5 protein and messenger ribonucleic acid (mRNA) in CAD versus non-CAD vessels. Calcium-dependent NADPH-driven production of ROS in vascular membranes, reflecting NOX5 activity, was increased 7-fold in CAD and correlated significantly with NOX5 mRNA levels among subjects. Immunofluorescence showed that NOX5 was expressed in the endothelium in the early lesions and in vascular smooth muscle cells in the advanced coronary lesions. CONCLUSIONS: These studies identify NOX5 as a novel, calcium-dependent source of ROS in atherosclerosis.

• Loss of Extracellular Superoxide Dismutase Leads to Acute Lung Damage in the Presence of Ambient Air. A Potential Mechanism Underlying Adult Respiratory Distress Syndrome.

  Authors: Maria Carolina Gongora, Heinrich E Lob, Ulf Landmesser, Tomasz J Guzik, W David Martin, Kiyoski Ozumi, Susan M Wall, David Scott Wilson, Niren Murthy, Michael Gravanis, Tohru Fukai, David G Harrison

  The American journal of pathology. 10/2008;

  The extracellular superoxide dismutase 3 (SOD3) is highly expressed in both blood vessels and lungs. In different models of pulmonary injury, SOD3 is reduced; however, it is unclear whether thisThe extracellular superoxide dismutase 3 (SOD3) is highly expressed in both blood vessels and lungs. In different models of pulmonary injury, SOD3 is reduced; however, it is unclear whether this contributes to lung injury. To study the role of acute SOD3 reduction in lung injury, the SOD3 gene was deleted in adult mice by using the Cre-Lox technology. Acute reduction of SOD3 led to a fivefold increase in lung superoxide, marked inflammatory cell infiltration, a threefold increase in the arterial-alveolar gradient, respiratory acidosis, histological changes similar to those observed in adult respiratory distress syndrome, and 85% mortality. Treatment with the SOD mimetic MnTBAP and intranasal administration of SOD-containing polyketal microparticles reduced mortality, prevented the histological alterations, and reduced lung superoxide levels. To understand how mice with the SOD3 embryonic deletion survived without lung injury, gene array analysis was performed. These data demonstrated the up-regulation of 37 genes and down-regulation of nine genes, including those involved in cell signaling, inflammation, and gene transcription in SOD3(-/-) mice compared with either mice with acute SOD3 reduction or wild-type controls. These studies show that SOD3 is essential for survival in the presence of ambient oxygen and that acute loss of this enzyme can lead to severe lung damage. Strategies either to prevent SOD3 inactivation or to augment its levels might prove useful in the treatment of acute lung injury.

• GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease effects on vascular superoxide production and endothelial function.

  Authors: Charalambos Antoniades, Cheerag Shirodaria, Tim Van-Assche, Colin Cunnington, Irmgard Tegeder, Jörn Lötsch, Tomasz J Guzik, Paul Leeson, Jonathan Diesch, Dimitris Tousoulis, Christodoulos Stefanadis, Michael Costigan, Clifford J Woolf, Nicholas J Alp, Keith M Channon

  Journal of the American College of Cardiology. 07/2008; 52(2):158-65.

  OBJECTIVES: This study sought to determine the effects of endogenous tetrahydrobiopterin (BH4) bioavailability on endothelial nitric oxide synthase (eNOS) coupling, nitric oxide (NO) bioavailability,OBJECTIVES: This study sought to determine the effects of endogenous tetrahydrobiopterin (BH4) bioavailability on endothelial nitric oxide synthase (eNOS) coupling, nitric oxide (NO) bioavailability, and vascular superoxide production in patients with coronary artery disease (CAD). BACKGROUND: GTP-cyclohydrolase I, encoded by the GCH1 gene, is the rate-limiting enzyme in the biosynthesis of BH4, an eNOS cofactor important for maintaining enzymatic coupling. We examined the associations between haplotypes of the GCH1 gene, GCH1 expression and biopterin levels, and the effects on endothelial function and vascular superoxide production. METHODS: Blood samples and segments of internal mammary arteries and saphenous veins were obtained from patients with CAD undergoing coronary artery bypass grafting (n = 347). The GCH1 haplotypes were defined by 3 polymorphisms: rs8007267G<A, rs3783641A<T, and rs10483639C<G (X haplotype: A, T, G; O haplotype: any other combination). Vascular superoxide (+/- the eNOS inhibitor N(G)-nitro-L-arginine methyl ester [L-NAME]) was measured by lucigenin-enhanced chemiluminescence, whereas the vasorelaxations of saphenous veins to acetylcholine were evaluated ex vivo. RESULTS: Haplotype frequencies were OO 70.6%, XO 27.4%, and XX 2.0%. The X haplotype was associated with significantly lower vascular GCH1 messenger ribonucleic acid expression and substantial reductions in both plasma and vascular BH4 levels. In X haplotype carriers both vascular superoxide and L-NAME-inhibitable superoxide were significantly increased, and were associated with reduced vasorelaxations to acetylcholine. CONCLUSIONS: GCH1 gene expression, modulated by a particular GCH1 haplotype, is a major determinant of BH4 bioavailability both in plasma and in the vascular wall in patients with CAD. Genetic variation in GCH1 underlies important differences in endogenous BH4 availability and is a determinant of eNOS coupling, vascular redox state, and endothelial function in human vascular disease.

• [Relapsing polychondritis--a challenge for modern diagnostics and treatment]

  Authors: Katarzyna Mihułka, Bogdan Batko, Antoni Skura, Piotr Krawiec, Marcin Krzanowski, Władysław Sułowicz, Tomasz J Guzik, Teresa Adamek-Guzik

  Przegla̧d lekarski. 02/2008; 65(2):77-81.

  Relapsing polychondritis is a rare autoimmune disease, which is due to sporadic occurrence, unexplained etiology and wide range of symptoms resulting in the difficulties in diagnosis. RecurrentRelapsing polychondritis is a rare autoimmune disease, which is due to sporadic occurrence, unexplained etiology and wide range of symptoms resulting in the difficulties in diagnosis. Recurrent inflammation leads to destruction of cartilaginous tissues, such as ear, nasal septum, larynx, trachea and bronchi, peripheral joints and vertebral structures. Blood vessels, the central nervous system, eyes, and the urinary tract can be involved as well. Clinical course of relapsing polychondritis is often modified by co-existing systemic diseases and remains misdiagnosed. In case of inappropriate or delayed treatment, serious and life-thretening complications may develop. In this article we present the most characteristic clinical features of the disease, differential diagnosis, focusing on current approaches to treatment.

• Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction.

  Authors: Tomasz J Guzik, Nyssa E Hoch, Kathryn A Brown, Louise A McCann, Ayaz Rahman, Sergey Dikalov, Jorg Goronzy, Cornelia Weyand, David G Harrison

  The Journal of experimental medicine. 11/2007; 204(10):2449-60.

  Hypertension promotes atherosclerosis and is a major source of morbidity and mortality. We show that mice lacking T and B cells (RAG-1-/- mice) have blunted hypertension and do not developHypertension promotes atherosclerosis and is a major source of morbidity and mortality. We show that mice lacking T and B cells (RAG-1-/- mice) have blunted hypertension and do not develop abnormalities of vascular function during angiotensin II infusion or desoxycorticosterone acetate (DOCA)-salt. Adoptive transfer of T, but not B, cells restored these abnormalities. Angiotensin II is known to stimulate reactive oxygen species production via the nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase in several cells, including some immune cells. Accordingly, adoptive transfer of T cells lacking the angiotensin type I receptor or a functional NADPH oxidase resulted in blunted angiotensin II-dependent hypertension and decreased aortic superoxide production. Angiotensin II increased T cell markers of activation and tissue homing in wild-type, but not NADPH oxidase-deficient, mice. Angiotensin II markedly increased T cells in the perivascular adipose tissue (periadventitial fat) and, to a lesser extent the adventitia. These cells expressed high levels of CC chemokine receptor 5 and were commonly double negative (CD3+CD4-CD8-). This infiltration was associated with an increase in intercellular adhesion molecule-1 and RANTES in the aorta. Hypertension also increased T lymphocyte production of tumor necrosis factor (TNF) alpha, and treatment with the TNFalpha antagonist etanercept prevented the hypertension and increase in vascular superoxide caused by angiotensin II. These studies identify a previously undefined role for T cells in the genesis of hypertension and support a role of inflammation in the basis of this prevalent disease. T cells might represent a novel therapeutic target for the treatment of high blood pressure.

• Endothelial NF-kappaB as a mediator of kidney damage: the missing link between systemic vascular and renal disease?

  Authors: Tomasz J Guzik, David G Harrison

  Circulation research. 09/2007; 101(3):227-9.

• Role of the multidrug resistance protein-1 in hypertension and vascular dysfunction caused by angiotensin II.

  Authors: Julian D Widder, Tomasz J Guzik, Cornelius F H Mueller, Roza E Clempus, Harald H H W Schmidt, Sergey I Dikalov, Kathy K Griendling, Dean P Jones, David G Harrison

  Arteriosclerosis, thrombosis, and vascular biology. 05/2007; 27(4):762-8.

  OBJECTIVE: Human endothelial cells use the multidrug resistance protein-1 (MRP1) to export glutathione disulfide (GSSG). This can promotes thiol loss during states of increased glutathione oxidation.OBJECTIVE: Human endothelial cells use the multidrug resistance protein-1 (MRP1) to export glutathione disulfide (GSSG). This can promotes thiol loss during states of increased glutathione oxidation. We investigated how MRP1 modulates blood pressure and vascular function during angiotensin II-induced hypertension. METHODS AND RESULTS: Angiotensin II-induced hypertension altered vascular glutathione flux by increasing GSSG export and decreasing vascular levels of glutathione in wild-type (FVB) but not in MRP1-/- mice. Aortic endothelium-dependent vasodilatation was reduced in FVB after angiotensin II infusion, but unchanged in MRP1-/- mice. Aortic superoxide (O2*-) production and expression of several NADPH oxidase subunits were increased by angiotensin II in FVB. These effects were markedly blunted in MRP1-/- vessels. The increase in O2*- production in FVB vessels caused by angiotensin II was largely inhibited by L-NAME, suggesting eNOS uncoupling. Accordingly, aortic tetrahydrobiopterin and levels of NO were decreased by angiotensin II in FVB but were unchanged in MRP1-/-. Finally, the hypertension caused by angiotensin II was markedly blunted in MRP1-/- mice (137+/-4 versus 158+/-6 mm Hg). CONCLUSION: MRP1 plays a crucial role in the genesis of multiple vascular abnormalities that accompany hypertension and its presence is essential for the hypertensive response to angiotensin II.

• Implications of oral Helicobacter pylori for the outcome of its gastric eradication therapy.

  Authors: Marta Czesnikiewicz-Guzik, Bartłomiej Loster, Wladyslaw Bielanski, Tomasz J Guzik, Peter C Konturek, Jan Zapala, Stanisław J Konturek

  Journal of clinical gastroenterology. 03/2007; 41(2):145-51.

  BACKGROUND AND AIMS: Helicobacter pylori (H. pylori) is an important pathogen in gastritis, peptic ulcer and possibly gastric cancer, but several questions remain unanswered. Particularly how theBACKGROUND AND AIMS: Helicobacter pylori (H. pylori) is an important pathogen in gastritis, peptic ulcer and possibly gastric cancer, but several questions remain unanswered. Particularly how the organism is transmitted and what is the relationship between oral presence of H. pylori and the gastric infection. Accordingly, we aimed to characterize the H. pylori in oral cavity and to evaluate its relationship to gastric H. pylori infection. MATERIALS AND METHODS: Out of total 100 screened for H. pylori infection female subjects (40 to 85 y), 49 patients (pts), who had positive C-urea breath test (UBT) and dyspeptic symptoms, agreed for 1 week regimen of triple anti-H. pylori therapy. The presence of H. pylori in oral cavity was assessed using bacterial culture from saliva and gingival pockets. Gastric H. pylori infection was estimated using capsulated C-urea breath test and plasma anti-H. pylori IgG and saliva IgA antibodies. In addition, plasma gastrin, ghrelin, and pepsinogen I were measured by radioimmunoassay. In selected patients, gastroscopy was additionally performed and gastric biopsy samples were taken for H. pylori random amplification of polymorphic DNA genetic profiling. RESULTS: The triple therapy resulted in gastric H. pylori eradication in 79% pts, along with significant decrease of plasma gastrin combined with an increase in plasma ghrelin and pepsinogen I (PgI) levels and a marked alleviation of dyspeptic symptoms. In contrast to gastric effects, the eradication therapy failed to cause any changes in the presence of H. pylori in oral cavity. Moreover no relationship was observed between the presence of H. pylori in oral cavity and the gastric H. pylori eradication. In line with these findings, no relationship between gastric and oral H. pylori was found using genetic profiling by random amplification of polymorphic DNA. CONCLUSIONS: H. pylori was detected both in the oral cavity and the stomach but oral H. pylori had no relation to gastric H. pylori and remained unaffected by eradication of gastric H. pylori.