Submitted on February 25, 2009
Revised on April 16, 2009
Accepted on May 4, 2009
Effects of nitroglycerin- or pentaerithrityl tetranitrate treatment on the gene expression in rat hearts - evidence for cardiotoxic and cardioprotective effects
Andrea Pautz1, Peter Rauschkolb1, Nadine Schmidt1, Julia Art1, Matthias Oelze1, Philip Wenzel1, Ulrich Forstermann1, Andreas Daiber1, and Hartmut Kleinert1*
1 University Medical Center of the Johannes Gutenberg University Mainz
* To whom correspondence should be addressed. E-mail: Kleinert{at}mail.uni-mainz.de.
Nitroglycerin (NTG) and pentaerithrityl tetranitrate (PETN) are organic nitrates used in the treatment of angina pectoris, myocardial infarction, and congestive heart failure. Recent data show marked differences in the effects of NTG and PETN on the generation of reactive oxygen species. These differences are attributed to different effects of NTG and PETN on the expression of antioxidative proteins like the heme oxygenase-I. To analyze the expressional effects of NTG and PETN in a more comprehensive manner we performed whole genome expression profiling experiments using cardiac total RNA from NTG- or PETN-treated rats and DNA microarrays containing oligonucleotides representing 27,044 rat gene transcripts. The data obtained show that NTG and PETN together significantly modify the expression of more than 1600 genes (NTG 532; PETN 1212). However, only the expression of a small group of these genes (68) was modified by both treatments, indicating marked differences in the expressional effects of NTG and PETN. NTG-treatment resulted in the enhanced expression of genes that are believed to be markers for cardiotoxic processes. In addition, NTG-treatment reduced the expression of genes described to code for cardioprotective proteins. In sharp contrast, PETN-treatment enhanced the expression of cardioprotective genes and reduced the expression of genes believed to perform cardiotoxic effects. In conclusion, our data suggest 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.
