Rosiglitazone Causes Cardiotoxicity via Peroxisome Proliferator-Activated Receptor gamma-Independent Mitochondrial Oxidative Stress in Mouse Hearts
文献类型：期刊论文
| 作者 | He, Huamei; Tao, Hai; Xiong, Hui; Duan, ShengZhong（段胜仲） ; McGowan, Francis X., Jr.; Mortensen, Richard M.; Balschi, James A.
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| 刊名 | TOXICOLOGICAL SCIENCES
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| 出版日期 | 2014 |
| 卷号 | 138期号:2页码:468-481 |
| 关键词 | Rosiglitazone PPAR gamma energy metabolism cardiac function mitochondria oxidative stress |
| 英文摘要 | This study aims to test the hypothesis that thiazolidinedione rosiglitazone (RSG), a selective peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist, causes cardiotoxicity independently of PPAR gamma. Energy metabolism and mitochondrial function were measured in perfused hearts isolated from C57BL/6, cardiomyocyte-specific PPAR gamma-deficient mice, and their littermates. Cardiac function and mitochondrial oxidative stress were measured in both in vitro and in vivo settings. Treatment of isolated hearts with RSG at the supratherapeutic concentrations of 10 and 30 mu M caused myocardial energy deficiency as evidenced by the decreases in [PCr], [ATP], ATP/ADP ratio, energy charge with a concomitant cardiac dysfunction as indicated by the decreases in left ventricular systolic pressure, rates of tension development and relaxation, and by an increase in end-diastolic pressure. When incubated with tissue homogenate or isolated mitochondria at these same concentrations, RSG caused mitochondrial dysfunction as evidenced by the decreases in respiration rate, substrate oxidation rates, and activities of complexes I and IV. RSG also increased complexes I- and III-dependent O-2(-) production, decreased glutathione content, inhibited superoxide dismutase, and increased the levels of malondialdehyde, protein carbonyl, and 8-hydroxy-2-deoxyguanosine in mitochondria, consistent with oxidative stress. N-acetyl-L-cysteine (NAC) 20mM prevented RSG-induced above toxicity at those in vitro settings. Cardiomyocyte-specific PPAR gamma deletion and PPAR gamma antagonist GW9662 did not prevent the observed cardiotoxicity. Intravenous injection of 10 mg/kg RSG also caused cardiac dysfunction and oxidative stress, 600 mg/kg NAC antagonized these adverse effects. In conclusion, this study demonstrates that RSG at supratherapeutic concentrations causes cardiotoxicity via a PPAR gamma-independent mechanism involving oxidative stress-induced mitochondrial dysfunction in mouse hearts. |
| 类目[WOS] | Toxicology |
| 研究领域[WOS] | Toxicology |
| 关键词[WOS] | TYPE-2 DIABETIC-PATIENTS ; CARDIOVASCULAR OUTCOMES ; CARDIAC-HYPERTROPHY ; ENERGY-METABOLISM ; PROTEIN-KINASE ; IN-VITRO ; THIAZOLIDINEDIONES ; FAILURE ; MICE ; PIOGLITAZONE |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000333293500020 |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.144/handle/331004/140]  |
| 专题 | 中国科学院上海生命科学研究院营养科学研究所_核受体与代谢和疾病研究组 |
| 推荐引用方式 GB/T 7714 | He, Huamei,Tao, Hai,Xiong, Hui,et al. Rosiglitazone Causes Cardiotoxicity via Peroxisome Proliferator-Activated Receptor gamma-Independent Mitochondrial Oxidative Stress in Mouse Hearts[J]. TOXICOLOGICAL SCIENCES,2014,138(2):468-481. |
| APA | He, Huamei.,Tao, Hai.,Xiong, Hui.,Duan, ShengZhong.,McGowan, Francis X., Jr..,...&Balschi, James A..(2014).Rosiglitazone Causes Cardiotoxicity via Peroxisome Proliferator-Activated Receptor gamma-Independent Mitochondrial Oxidative Stress in Mouse Hearts.TOXICOLOGICAL SCIENCES,138(2),468-481. |
| MLA | He, Huamei,et al."Rosiglitazone Causes Cardiotoxicity via Peroxisome Proliferator-Activated Receptor gamma-Independent Mitochondrial Oxidative Stress in Mouse Hearts".TOXICOLOGICAL SCIENCES 138.2(2014):468-481. |
入库方式： OAI收割
来源：上海营养与健康研究所
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