title: Tissue-specific Gene Expression in Rat Hearts and Aortas in a Model of Vascular Nitrate Tolerance.
abstract: Nitroglycerin exerts a direct myocardial anti-ischemic effect even in the state of vascular nitrate tolerance. To examine the potentially diverse molecular responses in vascular and cardiac tissues, we investigated the gene expression profile of the heart and the aorta by DNA microarray in male Wistar rats that were previously made tolerant to the vascular effects of nitroglycerin. The blood pressure-lowering effect of nitroglycerin (1-100 μg/kg) was markedly attenuated in rats pretreated for 3 days with 3 × 100 mg/kg nitroglycerin. Nitric oxide content was significantly elevated in the heart but not in the aorta of nitrate-tolerant animals, which indicated tissue-specific differences in nitroglycerin bioconversion. Of 7742 genes analyzed by DNA microarray, we found that although the expression of 25 genes changed significantly in the heart (increased: Tas2r119, Map6, Cd59, Kcnh2, Kcnh3, Senp6, Mcpt1, Tshb, Haus1, Vipr1, Lrn3, Lifr; decreased: Ihh, Fgfr1, Cryge, Krt9, Agrn, C4bpb, Fcer1a, Csf3, Hsd17b11, Hsd11b2, Ctnnbl1, Prpg1, Hsf1), only 14 genes were altered in the aorta (increased: Tas2r119, Ihh, Rrad, Npm1, Snai1; decreased: Tubb2b, Usp15, Sema6c, Wfdc2, Rps21, Ramp2, Galr1, Atxn1, Lhx1) in vascular nitrate tolerance. Quantitative reverse transcription polymerase chain reaction analysis of genes related to oxidative/nitrative/nitrosative stress also showed differential expression pattern in the heart and aorta. This is the first pharmacogenomic analysis showing that nitroglycerin treatment leading to vascular nitrate tolerance differentially impacts gene expression in vascular and cardiac tissues, which indicates different tissue-specific downstream signaling pathways.
authors: *Department of Biochemistry, University of Szeged, Szeged, Hungary; †Pharmahungary Group, Szeged, Hungary; ‡Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary; and §Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
authors: Tamás
authors: T
authors: Csont
authors: Zsolt
authors: Z
authors: Murlasits
authors: Dalma
authors: D
authors: Ménesi
authors: János Z
authors: JZ
authors: Kelemen
authors: Péter
authors: P
authors: Bencsik
authors: Márton
authors: M
authors: Pipicz
authors: Veronika
authors: V
authors: Fekete
authors: Ágnes
authors: Á
authors: Zvara
authors: László G
authors: LG
authors: Puskás
authors: Péter
authors: P
authors: Ferdinandy
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism*; D001013:Aorta, Thoracic / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D004334:Drug Administration Schedule; D004361:Drug Tolerance / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D007279:Injections, Subcutaneous; D008297:Male; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D005996:Nitroglycerin / Q000008:administration & dosage*; D020411:Oligonucleotide Array Sequence Analysis; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D009569:Nitric Oxide; D005996:Nitroglycerin