The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor-regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant-dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.

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Complex cellular and inflammatory interactions are involved in the progress of vascular diseases. Endothelial cells, upon exposure to cytokines, undergo profound alterations of function that involve gene expression and de novo protein synthesis. The functional reprogramming of endothelial cells by cytokines is of importance especially in patients with chronic vascular inflammation. The intercellular network of dendritic cells, T-lymphocytes, macrophages and smooth muscle cells generates a variety of stimulatory cytokines [e.g. TNF-alpha (tumour necrosis factor-alpha), IL (interleukin)-1, IL-6 and IFN-gamma (interferon-gamma)] and growth factors that promote the development of functional and structural vascular changes. High concentrations of proinflammatory cytokines increase oxidative stress, down-regulate eNOS (endothelial nitric oxide synthase) bioactivity and induce endothelial cell apoptosis. Chemoattractant cytokines [e.g. VEGF (vascular endothelial growth factor), TGF-beta1 (transforming growth factor-beta1) and IL-8] are important regulators of inflammation-induced angiogenesis and are directly modulated by nitric oxide. This review will focus on the vascular mechanisms orchestrated by cytokines and summarizes the current knowledge concerning the contribution of cytokines to cardiovascular diseases.

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