Zalba, G. (Guillermo)
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- Beneficial aspects of vascular apoptosis in hypertensive heart disease(Krause and Pachernegg, 2000) Fortuño, A. (Ana); Diez-Martinez, J. (Javier); Ravassa, S. (Susana); Gonzalez, A. (Arantxa); Zalba, G. (Guillermo)Arterial hypertension may be viewed as a generalized vascular disorder, with an imbalance between proliferation and apoptosis of vascular smooth muscle cells. As a consequence exaggerated accumulation of these cells may result leading to an encroachment of the tunica media into the lumen. This geometric abnormality of the vessel wall may play a critical role in the long-term maintenance of elevated blood pressure and development of hypertensive endorgan damage. In this short paper, we summarize data on alterations in the growth and death of vascular smooth muscle cells in the small coronary arteries in hypertension.
- NADPH oxidase-mediated oxidative stress(Mary Ann Liebert, 2005) Moreno, M.U. (María Ujué); Fortuño, A. (Ana); Diez-Martinez, J. (Javier); San-Jose, G. (Gorka); Zalba, G. (Guillermo)Increased vascular production of reactive oxygen species, especially superoxide anion, significantly contributes to the oxidative stress associated with hypertension. An enhanced superoxide production causes an increased inactivation of nitric oxide that diminishes nitric oxide bioavailability, thus contributing to endothelial dysfunction and hypertrophy of vascular cells. It has been shown that NADPH oxidases play a major role as the most important sources of superoxide anion in phagocytic and vascular cells. Several experimental observations have described an enhanced superoxide generation as a result of NADPH oxidase activation in hypertension. Although these enzymes respond to stimuli such as vasoactive factors, growth factors, and cytokines, recent data suggest a significant role of the genetic background in the modulation of the expression of its different components. Several polymorphisms have been identified in the promoter and in the coding region of CYBA, the gene that encodes the essential subunit of the NADPH oxidase p22phox, some of which seem to influence significantly the activity of these enzymes in the context of cardiovascular diseases. Among CYBA polymorphisms, genetic investigations have provided a novel marker, the -930(A/G) polymorphism, which determines the genetic susceptibility of hypertensive patients to oxidative stress.
- NADPH oxidase 5 (NOX5) overexpression promotes endothelial dysfunction via cell apoptosis, migration, and metabolic alterations in human brain microvascular endothelial cells (hCMEC/D3)(2022) Martínez-Azcona, M. (María); Ainzúa-Pérez, E. (Elena); Orbe, J. (Josune); Fernandez-Irigoyen, J. (Joaquín); Marqués-Cantero, J. (Javier); Cortés-Jiménez, A. (Adriana); Roncal, C. (Carmen); Zalba, G. (Guillermo); Santamaria, E. (Enrique)NADPH oxidases (NOX) constitute the main reactive oxygen species (ROS) source in blood vessels. An oxidative stress situation due to ROS overproduction can lead into endothelial dysfunction, a molecular mechanism that precedes cardiovascular diseases (CVDs) such as atherosclerosis, myocardial infarction, and stroke. NOX5 is the last discovered member of the NOX family, studied in a lesser extent due to its absence in the rodent genome. Our objective was to describe the phenotypic alterations produced by an oxidative stress situation derived from NOX5 overexpression in an endothelial in vitro model. The in vitro model consists of the hCMEC/D3 cell line, derived from brain microvascular endothelium, infected with a recombinant NOX5-beta adenovirus. After an initial proteomic analysis, three phenotypic alterations detected in silico were studied: cell proliferation and apoptosis, general and mitochondrial metabolism, and migration capacity. NOX5 infection of hCMEC/D3 generates a functional protein and an increase in ROS production. This model produced changes in the whole cell proteome. The in silico analysis together with in vitro validations demonstrated that NOX5 overexpression inhibits proliferation and promotes apoptosis, metabolic alterations and cell migration in hCMEC/D3 cells. NOX5 overexpression in endothelial cells leads to phenotypic changes that can lead to endothelial dysfunction, the onset of atherosclerosis, myocardial infarction, and stroke.
- Phagocytic NADPH Oxidase Overactivity Underlies Oxidative Stress in Metabolic Syndrome(American Diabetes Association, 2006) Moreno, M.U. (María Ujué); Beloqui, O. (Óscar); Fortuño, A. (Ana); Diez-Martinez, J. (Javier); San-Jose, G. (Gorka); Zalba, G. (Guillermo)Oxidative stress plays a critical role in the pathogenesis of atherosclerosis in patients with metabolic syndrome. This study aimed to investigate whether a relationship exists between phagocytic NADPH oxidase activity and oxidative stress and atherosclerosis in metabolic syndrome patients. The study was performed in 56 metabolic syndrome patients (metabolic syndrome group), 99 patients with one or two cardiovascular risk factors (cardiovascular risk factor group), and 28 healthy subjects (control group). NADPH oxidase expression and activity was augmented (P < 0.05) in metabolic syndrome compared with cardiovascular risk factor and control groups. Insulin was enhanced (P < 0.05) in metabolic syndrome patients compared with cardiovascular risk factor and control groups and correlated with NADPH oxidase activity in the overall population. Insulin stimulated NADPH oxidase activity; this effect was abolished by a specific protein kinase C inhibitor. Oxidized LDL and nitrotyrosine levels and carotid intima-media thickness were increased (P < 0.05) in the metabolic syndrome group compared with cardiovascular risk factor and control groups and correlated with NADPH oxidase activity in the overall population. These findings suggest that phagocytic NADPH oxidase overactivity is involved in oxidative stress and atherosclerosis in metabolic syndrome patients. Our findings also suggest that hyperinsulinemia may contribute to oxidative stress in metabolic syndrome patients through activation of NADPH oxidase.
- Oxidative stress and atherosclerosis in early chronic kidney disease(Oxford University Press, 2006) Fortuño, A. (Ana); Diez-Martinez, J. (Javier); Zalba, G. (Guillermo)
- A novel CYBA variant, the -675A/T polymorphism, is associated with essential hypertension(Lippincott, Williams & Wilkins, 2007) Moreno, M.U. (María Ujué); Beloqui, O. (Óscar); Fortuño, A. (Ana); Diez-Martinez, J. (Javier); San-Jose, G. (Gorka); Redon, J. (Josep); Chaves, F.J. (F.Javier.); Corella, D. (Dolores); Zalba, G. (Guillermo)OBJECTIVE: Oxidative stress is implicated in hypertension and the NADPH oxidase systems constitute the main source of superoxide in vascular wall. We searched for new polymorphisms within the CYBA promoter, the human gene that encodes the p22phox protein, and studied their potential association with essential hypertension. DESIGN: A case-control study in a random sample of the general population. METHODS: CYBA polymorphisms were determined by restriction fragment length polymorphism and allelic discrimination. NADPH oxidase activity was quantified in phagocytic cells by chemiluminescence. RESULTS: We identified three novel polymorphisms, at positions -852, -675 and -536 from the ATG codon. Only the -675(A/T) polymorphism associated with essential hypertension. The prevalence of the TT genotype and the T allele frequency were significantly higher (P < 0.05) in hypertensives than in normotensives. Furthermore, TT hypertensives exhibited higher (P < 0.05) systolic blood pressure values than TA/AA hypertensives. Increased phagocytic NADPH oxidase activity was observed in TT subjects compared to TA and AA individuals (P < 0.05). Enhanced carotid intima-media thickness, a surrogate marker of atherosclerosis, was found in TT subjects compared to TA and AA individuals (P < 0.05). Finally, mutagenesis experiments demonstrated a functional role of this polymorphism on the CYBA promoter activity. CONCLUSION: The -675 (A/T) CYBA polymorphism may be a novel genetic marker associated with essential hypertension. Furthermore, TT subjects exhibit features of NADPH oxidase-mediated oxidative stress and asymptomatic atherosclerosis.
- Vascular oxidant stress: molecular mechanisms and pathophysiological implications(Springer Verlag, 2000) Fortuño, A. (Ana); Diez-Martinez, J. (Javier); Fortuño, M.A. (María Antonia); San-Jose, G. (Gorka); Beaumont, J. (Javier); Zalba, G. (Guillermo)The term oxidative stress refers to a situation in which cells are exposed to excessive levels of either molecular oxygen or chemical derivatives of oxygen (ie, reactive oxygen species). Three enzyme systems produce reactive oxygen species in the vascular wall: NADH/NADPH oxidase, xanthine oxidoreductase, and endothelial nitric oxide synthase. Among vascular reactive oxygen species superoxide anion plays a critical role in vascular biology because it is the source for many other reactive oxygen species and various vascular cell functions. It is currently thought that increases in oxidant stress, namely excessive production of superoxide anion, are involved in the pathophysiology of endothelial dysfunction that accompanies a number of cardiovascular risk factors including hypercholesterolemia, hypertension and cigarette smoking. On the other hand, vascular oxidant stress plays a pivotal role in the evolution of clinical conditions such as atherosclerosis, diabetes and heart failure.
- Polymorphisms and promoter overactivity of the p22(phox) gene in vascular smooth muscle cells from spontaneously hypertensive rats(American Heart Association, 2001) Fortuño, A. (Ana); Diez-Martinez, J. (Javier); Fortuño, M.A. (María Antonia); San-Jose, G. (Gorka); Beaumont, J. (Javier); Zalba, G. (Guillermo)In a previous study, we found that the p22(phox) subunit of the NADH/NADPH oxidase is overexpressed in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHRs) with enhanced vascular production of superoxide anion ((.)O(2)(-)). Thus, we have investigated whether changes in the sequence or activity of the promoter region of p22(phox) gene are present in SHRs. To carry out this analysis, first of all, we characterized the rat gene structure and promoter region for the p22(phox) subunit. The p22(phox) gene spans approximately 10 kb and contains 6 exons and 5 introns. Primer extension analysis indicated the transcriptional start site 100 bp upstream from the translational start site. The immediate promoter region of the p22(phox) gene does not contain a TATA box, but there are a CCAC box and putative recognition sites for nuclear factors, such as SP1, gamma-interferon, and nuclear factor-kappaB. Using reporter-gene transfection analysis, we found that this promoter was functional in VSMCs. Furthermore, we observed that p22(phox) promoter activity was significantly higher in VSMCs from SHRs than from normotensive Wistar-Kyoto rats. In addition, we found that there were 5 polymorphisms in the sequence of p22(phox) promoter between Wistar-Kyoto rats and SHRs and that they were functional. The results obtained in this study provide a tool to explore the mechanisms that regulate the expression of p22(phox) gene in rat VSMCs. Furthermore, our findings show that changes in the sequence of p22(phox) gene promoter and in the degree of activation of VSMCs are responsible for upregulated expression of p22(phox) in SHRs.
- The inhibitory effect of leptin on angiotensin II-induced vasoconstriction is blunted in spontaneously hypertensive rats(Lippincott, Williams & Wilkins, 2006) Fortuño, A. (Ana); Catalan, V. (Victoria); Diez-Martinez, J. (Javier); Frühbeck, G. (Gema); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia); Zalba, G. (Guillermo); Sainz, N. (Neira)OBJECTIVE: Leptin attenuates the angiotensin II-induced increase of cytosolic calcium ([Ca2+]i) and vasoconstriction in the aorta of normotensive Wistar rats. To determine whether these effects may be altered in hypertension, we assessed the effect of leptin on angiotensin II-induced vascular response in the aorta of 10-week-old spontaneously hypertensive rats (SHR). METHODS: Contractile responses to angiotensin II (100 nmol/l) in the presence of different concentrations of leptin (0.1, 1, 10, 100 nmol/l) were evaluated in isolated aortic rings by the organ bath system. [Ca2+]i was measured in vascular smooth muscle cells (VSMCs) using Fura-2 fluorescence. The expression of the short (OB-Ra) and long (OB-Rb) isoforms of the leptin receptor in VSMCs was evaluated by real-time reverse transcriptase-polymerase chain reaction and western-blot analysis. RESULTS: Circulating leptin concentrations were increased in SHR. Serum metabolic parameters, including glucose, insulin, total cholesterol and triglyceride levels, were also elevated in SHR. Leptin did not modify the angiotensin II-induced vasoconstriction in SHR either in intact or endothelium-denuded aortic rings. In addition, leptin was not able either to diminish the angiotensin II-induced the peak rise of [Ca2+]i or to accelerate the recovery rate to basal calcium levels in VSMCs from SHR. However, OB-Ra and OB-Rb mRNA and protein expression were increased in SHR VSMCs. CONCLUSIONS: The lack of effect of leptin on angiotensin II-induced contraction in the aorta of SHR is due to an impaired handling of [Ca2+]i in VSMCs. Hyperleptinemia and overexpression of OB-R in VSMCs could be compensatory mechanisms against VSMC leptin resistance in genetically hypertensive rats.
- Functional Effect of the p22phox -930A/G Polymorphism on p22phox Expression and NADPH Oxidase Activity in Hypertension(American Heart Association, 2004-08) Moreno, M.U. (María Ujué); Beloqui, O. (Óscar); Fortuño, A. (Ana); Diez-Martinez, J. (Javier); San-Jose, G. (Gorka); Zalba, G. (Guillermo); Olivan, S. (Sara)Oxidative stress induced by superoxide is implicated in hypertension. NADPH oxidase is the main source of superoxide in phagocytic and vascular cells, and the p22phox subunit is involved in NADPH oxidase activation. Recently we reported an association of 930A/G polymorphism in the human p22phox gene promoter with hypertension. This study was designed to investigate the functional role of this polymorphism in hypertension. We thus investigated the relationships between the 930A/G polymorphism and p22phox expression and NADPH oxidase–mediated superoxide production in phagocytic cells from 70 patients with essential hypertension and 70 normotensive controls. Genotyping of the polymorphism was performed by restriction fragment length polymorphism. NADPH oxidase activity was determined by chemiluminescence assays, and p22phox mRNA and protein expression was measured by Northern and Western blotting, respectively. Compared with hypertensive subjects with the AA/AG genotype, hypertensive subjects with the GG genotype exhibited increased (P 0.05) phagocytic p22phox mRNA (1.26 0.06 arbitrary unit [AU] versus 0.99 0.03 AU) and protein levels (0.58 0.05 AU versus 0.34 0.04 AU) and enhanced NADPH oxidase activity (1998 181 counts/s versus 1322 112 counts/s). No differences in these parameters were observed among genotypes in normotensive cells. Transfection experiments on vascular smooth muscle cells showed that the A-to-G substitution of this polymorphism produced an increased reporter gene expression in hypertensive cells. Nitric oxide production, as assessed by measurement of serum nitric oxide metabolites, was lower in GG hypertensive subjects than in AA/AG hypertensive subjects. In conclusion, these results suggest that hypertensive subjects carrying the GG genotype of the p22phox 930A/G polymorphism are highly exposed to NADPH oxidase-mediated oxidative stress.