Tesis doctoral de Gemma Flores Mateo
Background selenium is an essential trace mineral involved in the protection against oxidative damage via selenium-dependent glutathione peroxidase (gsh-px) and other selenoproteins. Selenium supplementation increases enzymatic antioxidant activity and decreases lipid peroxidation. It has long been hypothesized that selenium may prevent cardiovascular and other chronic diseases due to its antioxidant properties. However, the effect of selenium on cardiovascular risk is uncertain. Results of observational studies assessing the association of low selenium levels with cardiovascular outcomes, as well as randomized trials focused on the ability of selenium supplements in the prevention of coronary heart disease (chd), have been inconclusive. Up to date the evidence has not been appraised systematically. selenium supplementation increases the expression and activity of gsh-px in vascular endothelial or smooth muscle cells and thus inhibites the oxidative stress, cell damage, and apoptosis from oxidized ldl. Oxidation of low density lipoproteins (ldl) is considered to be a key initial step in atherosclerosis and chd development and progression. Among the antioxidant enzymes, superoxide dismutase (sod), glutathione peroxidase, and catalase constitute a first line of defense against oxidative stress by removing key reactive oxygen species. Sod, which operates primarily within cells and in extracellular matrices, catalyzes the dismutation of the superoxide anion (o*2) into hydrogen peroxide (h2o2). Catalase and gsh-px remove h2o2, and gsh-px can also convert lipid peroxyl radicals to non toxic alcohols. Low activity levels of antioxidant enzymes have been associated with an increased risk of cardiovascular risk factors and chd. hypothesis hypothesis 1. Low levels of selenium are associated with an increase in coronary heart disease (chd). Due to this, selenium supplementation can be useful tool for chd prevention. hypothesis 2. Low activity levels of the antioxidant enzymes: superoxide dismutase, gltuathione peroxidase, and catalase are associated eith an increase of chd risk. hypothesis 3. An inverse association exists between plasma gsh-px activity and novel and classical chd risk factors. objectives objective 1 to perform meta-analyses of: a) the association of biomarkers of selenium levels with coronary heart disease endpoints in observational studies, and b) the efficacy of selenium supplements in preventing coronary heart disease events in randomized controlled trials. objective 2 to perform meta-analyses of the association of the gsh-px, sod or catalase activity levels with coronary heart disease endpoints in observational studies. objective 3 to assess the relationship between plasma gsh-px activity and novel and classical cardiovascular risk factors in elderly individuals at high risk for cardiovascular disease. material and methods we searched medline, embase and the cochrane library from 1966 through december 2009 with no language restrictions. Relative risk estimates were pooled using an inverse-variance weighted random-effect model. For observational studies reporting three or more categories of exposure we conducted a dose-response meta-analysis. we performed a cross-sectional study with baseline data from the predimed (prevención con dieta mediterránea) trial. The predimed trial is an intervention study directed at testing the efficacy of the mediterranean diet on the primary prevention of cardiovascular disease. Participants were 1,060 subjects selected in 8 spanish primary health care centres (phcc). Classical risk factors and plasma oxidized low density lipoproteins (oxldl) and gsh-px were assessed. Multilevel statistical procedures were performed. results selenium and chd twenty-six observational studies (15 cohort and 11 case-control studies) measuring blood or toenail selenium levels, and 7 randomized clinical trials testing single or combined selenium supplements met our inclusion criteria. The pooled relative risk, comparing the highest to the lowest categories of selenium levels, was 0.81 (95% confidence interval 0.69 to 0.96) in prospective cohort studies and 0.43 (0.29 to 0.66) in case-control studies. In dose-response models, a 50% increase in selenium levels was associated with a 24% (7 to 38%) reduced risk of coronary events. In randomized trials, the relative risk when comparing participants taking supplements containing selenium to those taking placebo was 0.90 (0.75 to 1.09). antioxidant enzymes and chd forty two case-control studies and 3 prospective studies were included. The pooled odds ratios for chd associated with a 1 standard deviation increase in gsh-px, sod, and catalase activity levels were 0.51 (95% ci: 0.35, 0.75), 0.48 (95% ci: 0.32, 0.72), and 0.32 (0.16, 0.61), respectively, with a high heterogeneity (i2 > 90% for the three enzymes). Meta-regression and subgroup analyses showed that the association between gsh-px and sod with chd did not vary significantly after adjustment for potential confounders. Catalase showed a strong association with acute outcomes (p = 0.02). These findings were remarkably robust in the sensitivity analyses. gsh-px activity and cardiovascular risk factors both glucose and oxidized ldl were positively associated with gsh-px activity after adjustment for possible confounder variables (p = 0.03, p = 0.01 respectively). No relationship was obtained between gsh-px and other cardiovascular risk factors. discussion the first hipothesis of this thesis was that selenium may prevent coronary heart disease (chd). In our meta-analysis, we identified a moderate, but statistically significant, inverse association between selenium concentrations in several tissues and chd outcomes in observational studies. A 50% increase in selenium concentrations was associated with a 24% reduced risk of coronary events. The validity of this association, however, is uncertain, because observational studies have been unreliable in determining the cardiovascular effects of other antioxidants and vitamins, such as íY-carotene, vitamin e, and folate . Few randomized controlled trials have addressed the effect of selenium supplementation on clinical endpoints. In these trials, participants taking supplements containing selenium had a nonsignificant 11% reduction in coronary events, but the trials were small and selenium was given in combination with other vitamins or minerals in all but 2 trials. the second hypothesis of this thesis was that low activity levels of antioxidant enzymes are associated with an increased risk of chd. We performed meta-analyses to systematically review the issue. In the present meta-analyses, we identified strong and statistically significant inverse associations of gsh-px, sod, and catalase activities with chd outcomes. The quality of the study base was limited, however, and, for gsh-px and sod, the associations were attenuated when the analyses were restricted to studies that adjusted for at least 3 potential confounders. Etiologic inferences about the role of oxidative stress on chd are thus complicated by limitations in the design of the original studies and by the complexity of the relationship between oxidative stress and antioxidant enzyme activity. While our analyses provide evidence that chd cases have reduced antioxidant enzyme activity levels, lower enzyme activity could be a consequence of the increased oxidative stress induced by the coronary events, or by subclinical disease, rather than a causal mechanism in chd etiology. the third hypothesis of this thesis was that there is a negative association between plasma gsh-px activity and cardiovascular risk factors. Contrary to our hypothesis we identified a positive and linear association between plasma gsh-px activity and glucose and oxldl levels. This association remained after ajudstment by age, sex, and other possible confounder variables (definir cuales). A high gsh-px activity may result from a preservation of the enzyme by a high antioxidant status (with a low reactive oxygen species (ros) generation) or from a gsh-px increased production stimulated by ros. In our study, the fact that a high gsh-px activity is observed when an oxidative stress situation, such as hyperglycemia and lipid oxidative damage, occurs would be compatible with an increase of the antioxidant defences response against the oxidative injury in our cardiovascular risk population conclusions 1. Selenium concentrations were inversely associated with coronary heart disease risk in observational studies. Because observational studies have provided misleading evidence for other antioxidants, the validity of this association is uncertain. Few randomized controlled trials have addressed the effect of selenium supplementation on clinical endpoints. In these trials, participants taking supplements containing selenium had a nonsignificant 11% reduction in coronary events. Currently, selenium supplements should not be recommended for cardiovascular disease prevention. 2.Our meta-analyses has identified a strong inverse association between gsh-px, sod, and catalase activity levels and chd. These analyses provide one the strongest pieces of evidence up to date supporting the fact that chd patients experience a state of increased oxidative stress. Unfortunately, this association is difficult to interpret in mechanistic or etiologic terms because of methodological limitations of the available studies. High-quality prospective studies evaluating the association between low antioxidant enzyme activity levels and cardiovascular endpoints are warranted. 3.In a high cardiovascular risk population, a positive linear association between plasma gsh-px activity and glucose and ox-ldl levels was found. The fact that a high gsh-px activity is observed when an oxidative stress situation, such as hyperglycemia and lipid oxidative damage, occurs would be compatible with an increase of the antioxidant defences response against the oxidative injury in our cardiovascular risk population. Further studies are needed to assess the cause-effect relationships between hyperglycemia, oxidative status, and gsh-px in elderly populations at high cardiovascular risk.
Datos académicos de la tesis doctoral «Sistemas enzimáticos antioxidantes y enfermedad coronaria«
- Título de la tesis: Sistemas enzimáticos antioxidantes y enfermedad coronaria
- Autor: Gemma Flores Mateo
- Universidad: Autónoma de barcelona
- Fecha de lectura de la tesis: 23/03/2011
Dirección y tribunal
- Director de la tesis
- Roberto Elosua Llanos
- Tribunal
- Presidente del tribunal: María victoria Arija val
- montserrat (secretario) Martín baranera (vocal)
- (vocal)
- (vocal)