title: Rosiglitazone induces cardiotoxicity by accelerated apoptosis.
abstract: Present investigation explores the cardiotoxicity of rosiglitazone (ROSI) using rat heart cardiomyocytes and db/db mice. In H9c2 cells, ROSI at 50 and 60 μM induced an increase in the percentage of apoptotic cells and superoxide generation, along with an increase in the expression of various subunits of NADPH oxidase and nitric oxide synthases, confirmed that ROSI-induced apoptosis in H9c2 cells is by ROS generation. The increase in the expression of the antioxidants like superoxide dismutase (SOD), catalase, glutathione reductase (GR), glutathione-S-transferase (GST), and glutathione peroxidase (GPx) further confirmed this notion. Heme oxygenase-1, having an important role in cell protection against oxidative stress, was found to be increased along with induction of nuclear translocation of NF-E2-related factor and increased protein kinase C δ expression. Moreover, in db/db mice, oral administration of ROSI (10 mg/kg) for 10 days induced an increase in serum creatinine kinase-MB, tissue antioxidants like SOD, catalase, GR, GST, GPx expression, cardiac troponin T, and inducible nitric oxide synthase protein expression strongly support the in vitro findings. Furthermore, global gene expression studies also showed the perturbation of oxidative phosphorylation, fat cell differentiation, and electron transport chain following ROSI treatment in vivo. These results suggested that ROSI-induced cardiac damage is due to accelerated apoptosis both in vitro and in vivo.
authors.affiliation: Genotoxicity Laboratory, Division of Toxicology, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
authors.forename: Pratibha
authors.initials: P
authors.lastname: Mishra
authors.forename: Sarvendra Vikram
authors.initials: SV
authors.lastname: Singh
authors.forename: Ajeet Kumar
authors.initials: AK
authors.lastname: Verma
authors.forename: Pallavi
authors.initials: P
authors.lastname: Srivastava
authors.forename: Sarwat
authors.initials: S
authors.lastname: Sultana
authors.forename: Srikanta Kumar
authors.initials: SK
authors.lastname: Rath
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006331:Heart Diseases / Q000097:blood / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000633:toxicity*; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000378:metabolism; D051381:Rats; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D045162:Thiazolidinediones / Q000633:toxicity*; D013997:Time Factors
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D007004:Hypoglycemic Agents; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D013481:Superoxides; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D019255:NADPH Oxidases; C497260:Prkcd protein, rat; D051745:Protein Kinase C-delta