Regulation der Genexpression durch organische Nitrate

Nitric oxide (NO) has been described to have multiple effects on gene expression. NO regulates gene expression by modulating the activity of transcription factors and thereby the activity of the promoters of NO-regulated genes. In addition, also posttranscriptional effects of NO (mRNA-stability, -translatability, -localization) and also post-translational effects (Protein-stability, -localization) have been described. Organic nitrates like nitroglycerin (NTG) and pentaerithrityl tetranitrate (PETN) are used in the treatment of angina pectoris, myocardial infarction, and congestive heart failure. Organic nitrates are believed to be donors for nitric oxide (NO) and their cardiovascular effects are attributed to this NO. There are also reports showing effects of organic nitrates (mostly NTG) on gene expression. However, recent data show marked differences in the effects of NTG and PETN on expression of genes. For example, in endothelial cells PETN but not NTG enhances the expression of the antioxidative protein heme oxygenase-I (HO-1) or the heavy chain of ferritin (FeHc). Analyses of the effects of NTG or PETN on the total genomic expression profiles in rat hearts indicate marked differences in the expressional effects of these organic nitrates. A close analysis of the expression profiles induced by NTG or PETN indicate that NTG-treatment results in the induction of cardiotoxic gene expression networks leading to an activation of mechanisms, which result in pathologic changes in cardiomyocytes. In contrast, PETN-treatment seems to activate gene expression networks, which result in cardioprotective effects. These data may explain the described adverse cardiovascular effect associated with long-term NTG-treatment.