Despite substantial evidence that nitric oxide (NO) and/or endogenous S-nitrosothiols (SNOs) exert protective effects in a variety of cardiovascular diseases, the molecular details are largely unknown. Here we show that following left coronary artery ligation, mice with a targeted deletion of the S-nitrosoglutathione reductase gene (GSNOR ؊/؊ ) have reduced myocardial infarct size, preserved ventricular systolic and diastolic function, and maintained tissue oxygenation. These profound physiological effects are associated with increases in myocardial capillary density and S-nitrosylation of the transcription factor hypoxia inducible factor-1␣ (HIF-1␣) under normoxic conditions. We further show that S-nitrosylated HIF-1␣ binds to the vascular endothelial growth factor (VEGF) gene, thus identifying a role for GSNO in angiogenesis and myocardial protection. These results suggest innovative approaches to modulate angiogenesis and preserve cardiac function.angiogenesis ͉ HIF-1␣ ͉ myocardial infarction ͉ nitric oxide ͉ S-nitrosylation

Seasonal variations in mood and behavior (seasonality) and seasonal affective disorder (SAD) have been attributed to seasonal fluctuations in brain serotonin (5-HT). 1 the short (s), as opposed to the long (l), allele of the 5-HT transporter linked polymorphism (5-HTTLPR) has been associated with neuroticism and depression. 2,3 We hypothesized that this short allele would also be associated with SAD and with higher levels of seasonality. Ninety-seven SAD patients and 71 non-seasonal healthy controls with low seasonality levels were genotyped for 5-HTTLPR and compared statistically. Patients with SAD were less likely to have the l/l genotype (27.8% vs 47.9%; P Ͻ 0.01) and more likely to have the s allele (44.8% vs 32.4%; P Ͻ 0.02) as compared to controls. The three 5-HTTLPR genotypes were also differentially distributed in patients and controls (P Ͻ 0.03). The SAD patients with the l/l genotype had a lower mean seasonality score than did patients with the other two genotypes (mean ± s.d. = 15.3 ± 2.8 vs 17.1 ± 3.4 respectively; P Ͻ 0.02). The 5-HTTLPR short allele contributes to the trait of seasonality and is a risk factor for SAD, providing further evidence for a relationship betwen genetic variation in the 5-HT transporter (5-HTT) and behavior.The tendency for the majority of individuals in temperate latitudes to experience changes in behavior across the seasons has been termed seasonality. 4 Seasonality, as measured retrospectively by self-report, is a heritable trait 5 which varies in severity across individuals. Seasonality is present to a marked degree in patients with seasonal affective disorder (SAD), a condition of regularly recurring winter depressions alternating with non-depressed periods in spring and summer. 6 Although depression is also heritable, it is unclear whether SAD is inherited as a distinct entity or whether it affects individuals who are genetically susceptible to both seasonality and depression.SAD has been hypothesized to result from disturbed brain serotonergic transmission 1 and patients with SAD have been shown to respond abnormally to drugs that act on serotonin (5-HT) receptors and favorably to antidepressants that block the 5-HTT. 1 Seasonal fluctuations in 5-HT hypothalamic concentration have been reported post-mortem in the general population, with lowest levels occurring in winter. 7 As the behaviors that vary with the seasons, including appetite, sleep, weight regulation and mood, are controlled in part by 5-HT pathways, seasonality may also be related to seasonal fluctuations in 5-HT function.Given the importance of the 5-HTT in modulating 5-HT transmission 2 in the 5-HT synapse, variations in 5-HTT regulation may account for variations in seasonality in the general population and may be a risk factor for SAD. A polymorphism of the promoter of the 5-HTT gene [SCL6A4 localization on chromosome 17q12] has recently been described. 2 The polymorphism is an insertion or deletion of a 44-bp sequence located approximately 1 kb upstream from the coding sequence. The l and s variants...

Atherosclerosis is promoted by a combination of hypercholesterolemia and vascular inflammation. The function of Angiopoietin (Ang)-2, a key regulator of angiogenesis, in the maintenance of large vessels is unknown. A single systemic administration of Ang-2 adenovirus (AdAng-2) to apoE ؊/؊ mice fed a Western diet significantly reduced atherosclerotic lesion size (Ϸ40%) and oxidized LDL and macrophage content of the plaques. These beneficial effects were abolished by the inhibition of nitric oxide synthase (NOS). In endothelial cells, endothelial NOS activation per se inhibited LDL oxidation and Ang-2 stimulated NO release in a Tie2-dependent manner to decrease LDL oxidation. These findings demonstrate a novel atheroprotective role for Ang-2 when endothelial cell function is compromised and suggest that growth factors, which stimulate NO release without inducing inflammation, could offer atheroprotection.