Vitamin C and lifespan in model organisms.

The process of ageing has been repeatedly associated with increasing oxidative damage which has led to the hypothesis that reducing oxidative stress through antioxidant dietary factors may prolong lifespan. Ascorbic acid is an essential antioxidant in human diets and is widely used for supplementation. However, it is rather unclear if and to what extent ascorbic acid may affect lifespan in humans and model organisms. In our review of literature on vitamin C supplementation and its effect on lifespan in different model organisms we found that some studies suggest an increase in lifespan, other studies failed to observe any beneficial effect of vitamin C on longevity and some studies even reported a decrease in lifespan following vitamin C supplementation. Of the 14 studies included in our analysis, three were carried out in worms, four in flies and seven in rodents. The discrepancies between the studies may be related to species-specific differences, the concentration of vitamin C administered, the duration of supplementation and whether vitamin C was used alone or as part of a combined antioxidant diet. Potential underlying mechanisms through which vitamin C may influence lifespan and differences amongst species regarding the capacity to produce vitamin C endogenously are discussed.

Vitamin E supplementation and lifespan in model organisms.

We have conducted a comprehensive literature review regarding the effect of vitamin E on lifespan in model organisms including single-cell organisms, rotifers, Caenorhabditis elegans, Drosophila melanogaster and laboratory rodents. We searched Pubmed and ISI Web of knowledge for studies up to 2011 using the terms "tocopherols", "tocotrienols", "lifespan" and "longevity" in the above mentioned model organisms. Twenty-four studies were included in the final analysis. While some studies suggest an increase in lifespan due to vitamin E, other studies did not observe any vitamin E-mediated changes in lifespan in model organisms. Furthermore there are several studies reporting a decrease in lifespan in response to vitamin E supplementation. Different outcomes between studies may be partly related to species-specific differences, differences in vitamin E concentrations and the vitamin E congeners administered. The findings of our literature review suggest that there is no consistent beneficial effect of vitamin E on lifespan in model organisms which is consistent with reports in human intervention studies.

Relationships between nitric oxide-mediated endothelial function, eNOS coupling and blood pressure revealed by eNOS-GTP cyclohydrolase 1 double transgenic mice.

Endothelium-dependent relaxation in conduit vessels is mediated largely by nitric oxide (NO), produced by the enzyme endothelial nitric oxide synthase (eNOS) in the presence of the cofactor tetrahydrobiopterin (BH4) and mediated through a cGMP-dependent downstream signalling cascade. Endothelial NOS regulates blood pressure in vivo, and impaired endothelial NO bioactivity in vascular disease states may contribute to systemic hypertension. In the absence of sufficient levels of the cofactor BH4, NO becomes uncoupled from arginine oxidation and eNOS produces superoxide rather than NO. The enzymatic uncoupling of eNOS is an important feature of vascular disease states associated with increased oxidative stress. However, whether eNOS coupling, rather than overall eNOS activity, has specific effects on endothelium-dependent vasorelaxation in vitro, or on blood pressure regulation in vivo, remains unclear. In this study, we evaluate the relationships between blood pressure and endothelial function in models of eNOS uncoupling, using mice with endothelium-targeted transgenic eNOS overexpression (eNOS-Tg), in comparison with littermates in which eNOS coupling was rescued by additional endothelium-targeted overexpression of GTP cyclohydrolase 1 (eNOS/GCH-Tg) to increase endothelial BH4 levels. Despite the previously characterized differences in eNOS-dependent superoxide production between these animals, we find that blood pressure is equally reduced in both genotypes, compared with wild-type animals. Furthermore, both eNOS-Tg and eNOS/GCH-Tg mice exhibit similarly impaired endothelium-dependent vasorelaxation. We show that reduced vasorelaxation responses result from desensitization of cGMP-mediated signalling and are associated with increased NO production rather than changes in superoxide production.

Aldosterone-synthase overexpression in heart: a tool to explore aldosterone's effects.

Clinical observations indicate that elevated aldosterone impairs cardiovascular function. The mechanisms, however, are not totally understood although total and cardiovascular mortality are decreased by aldosterone antagonists. Experimentally, increased plasma aldosterone induces pericoronary inflammation and cardiac fibrosis. Our laboratory has discovered that aldosterone is synthesized in the rat heart, and has demonstrated that this cardiac aldosterone is involved in post-infarction cardiac remodeling. In man, activated cardiac aldosterone production has been described in patients with heart failure. In transgenic mice that overexpress aldosterone-synthase in the heart, we observe a normal cardiac function but a major coronary dysfunction, more pronounced in males. These observations converge to a potential physiological and pathological relevance of this system. Beneficial effects of anti-aldosterone treatment in heart failure may thus be secondary in part to blockade of cardiac aldosterone action.

Extracellular matrix and cardiac remodelling.

Cardiac remodelling associated with primitive and secondary cardiomyopathy is generally associated with changes in the expression in extracellular matrix (ECM) proteins as well as their transmembrane receptors, the integrins. It emerges now that the ECM provides a structural, chemical, and mechanical substrate that is essential in cardiac function and responses to pathophysiological signals. This review will describe the various elements of the ECM, its modifications that are associated with cardiac hypertrophy and heart failure, and the molecular basis bringing a better insight into the dynamics of the ECM.