title: Metabonomic profiling revealed an alteration in purine nucleotide metabolism associated with cardiac hypertrophy in rats treated with thiazolidinediones.
abstract: Thiazolidinediones (TZDs) including rosiglitazone (RSG) and pioglitazone (PIO) are synthetic agonists selective for peroxisome proliferator-activated receptor-γ (PPARγ) and have been clinically used to treat type-II diabetes as insulin sensitizers. Recent meta-analyses have shown that TZDs are associated with an increased risk for the development of heart failure. To elucidate the mechanism underlying such a cardiac adverse effect, we used a (1)H NMR-based approach to examine the metabonomic profiles in the cardiac tissues treated with RSG (15 mg/kg body weight/day) or PIO (45 mg/kg/day) for 4 weeks and found that the TZD treatments resulted in a significantly altered metabolic profile in hearts, which was associated with cardiac hypertrophy. Multivariate analysis demonstrated that TZDs led to an accumulation in adenosine monophosphate (AMP) and a depletion of inosine. Consistently, AMP kinase, a signal pathway sensitive to the change in the intracellular concentrations of AMP, was activated in the cardiac tissues from the TZDs-treated rats. Quantitative real-time reverse-transcriptase polymerase chain reaction showed a significant induction of the genes involved in the de novo synthesis of purine nucleotide but a reduction of those for the catabolism. Furthermore, the putative PPAR-responsive elements were identified in the 5'-flanking regions of the TZD-up-regulated genes such as adenylosuccinate synthase gene (Adss) and phosphoribosl pyrophosphate synthetase 1 (Prps1), and the binding of PPARγ to these motifs was confirmed by using chromatin immunoprecipitation assay. In conclusion, these results demonstrated that TZDs induced alterations in purine nucleotide metabolism in rat hearts via transcriptional regulation of the PPARγ-target genes, which may play an important role in the development of cardiac hypertrophy associated with TZDs.
authors.affiliation: Institute of Cardiovascular Science, Peking University Health Science Center , 38 Xueyuan Road, Beijing 100191, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Xing
authors.initials: X
authors.lastname: Yan
authors.forename: Guangmei
authors.initials: G
authors.lastname: Mao
authors.forename: Li
authors.initials: L
authors.lastname: Fang
authors.forename: Beilei
authors.initials: B
authors.lastname: Zhao
authors.forename: Yahan
authors.initials: Y
authors.lastname: Liu
authors.forename: Huiru
authors.initials: H
authors.lastname: Tang
authors.forename: Nanping
authors.initials: N
authors.lastname: Wang
mesh_terms: D024506:5' Flanking Region / Q000235:genetics; D000249:Adenosine Monophosphate / Q000378:metabolism*; D000265:Adenylosuccinate Synthase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D007288:Inosine / Q000378:metabolism*; D008297:Male; D055432:Metabolomics; D015999:Multivariate Analysis; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements; D012268:Ribose-Phosphate Pyrophosphokinase / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000009:adverse effects*
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000249:Adenosine Monophosphate; D007288:Inosine; D012268:Ribose-Phosphate Pyrophosphokinase; D000265:Adenylosuccinate Synthase; D000077205:Pioglitazone