Effects of nitroglycerin or pentaerithrityl tetranitrate treatment on the gene expression in rat hearts: evidence for cardiotoxic and cardioprotective effects.
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 >1,600 genes (NTG 532, PETN 1212). However, the expression of only 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 that result in pathological changes in cardiomyocytes. In contrast, PETN treatment seems to activate gene expression networks that result in cardioprotective effects.
Department of Pharmacology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Andrea
A
Pautz
Peter
P
Rauschkolb
Nadine
N
Schmidt
Julia
J
Art
Matthias
M
Oelze
Philip
P
Wenzel
Ulrich
U
Förstermann
Andreas
A
Daiber
Hartmut
H
Kleinert
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D054715:Cardiotoxins / Q000494:pharmacology*; D017931:DNA Primers / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D005996:Nitroglycerin / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D010417:Pentaerythritol Tetranitrate / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002316:Cardiotonic Agents; D054715:Cardiotoxins; D017931:DNA Primers; D010417:Pentaerythritol Tetranitrate; D005996:Nitroglycerin