Induction of Cellular Antioxidants and Cardioprotection

细胞抗氧化剂的诱导和心脏保护

• 批准号: 6772153
• 负责人: YUNBO LI
• 金额: $ 27.25万
• 依托单位: ST. JOHN'S UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6772153
• 关键词: NAD(P)H oxidoreductase; aconitate hydratase; antioxidants; cardiac myocytes; cardiotoxin; cardiovascular injury; cell line; cellular pathology; cellular respiration; citrate synthase; cytoprotection; doxorubicin; echocardiography; electron microscopy; enzyme activity; glutathione peroxidase; glutathione transferase; heart function; laboratory mouse; light microscopy; mitochondria; mitogen activated protein kinase; myocardium; oxidative stress; superoxide dismutase; thiones; thiophenes

DESCRIPTION (provided by applicant): The survival rate of cancer patients has been dramatically improved over the last two decades, largely due to the development of effective cancer therapeutic agents, such as doxorubicin. However, the clinical use of doxorubicin is limited by the development of cardiomyopathy upon chronic treatment. Extensive evidence suggests that doxorubicin-induced cardiotoxicity occurs through an oxidative mechanism. In this regard, administration of a variety of exogenous antioxidants has been shown to protect against doxorubicin-induced cardiotoxicity in both cultured cells and animals. However, whether induction of endogenous cellular antioxidants by chemical agents (drugs) in cardiomyocytes also affords protection against doxorubicin-induced cardiotoxicity has not been carefully studied. The long-term objective of this research project is to develop rational protective or therapeutic strategies to prevent and/or retard the oxidative degenerative process underlying various cardiac diseases. These strategies rely on the understanding of the inducibility of cellular antioxidants in cardiac tissue. The hypothesis we are currently investigating is that the endogenous cellular antioxidants in cardiomyocytes can be induced by the unique chemoprotectant, 3H-1, 2-dithiole-3-thione (D3T) and that the increased endogenous antioxidant defenses protect against doxorubicin-induced cardiotoxicity in cultured cells and in experimental animals without interfering with its desired antitumor activity. Accordingly, the specific aims of this application are designed to: (1) characterize the cellular antioxidants and their inducibility by D3T in mouse cardiac HL-1 cells, a recently established cardiac cell line with phenotypic characteristics of differentiated cardiomyocytes; (2) determine the protective effects of D3T-induced cellular antioxidants against doxorubicin-mediated toxicity in HL-1 cells; (3) characterize the cardiac cellular antioxidants and their inducibility by D3T in mice in vivo; and (4) investigate the effects of D3T administration to mice on doxorubicin cardiotoxicity and antitumor activity in vivo. Fulfillment of the above aims will result in a greater understanding of the inducibility of cardiac antioxidants by D3T and the protective role of the D3T-induced cellular antioxidant defenses in oxidative cardiac injury _caused not only by doxorubicin but also by other pathophysiological processes, such as ischemia-reperfusion

描述（由申请人提供）：在过去二十年中，癌症患者的存活率已经显著提高，这主要是由于有效的癌症治疗剂如多柔比星的开发。然而，阿霉素的临床使用受到慢性治疗后心肌病发展的限制。大量证据表明，阿霉素诱导的心脏毒性是通过氧化机制发生的。在这方面，各种外源性抗氧化剂的管理已被证明可以防止多柔比星诱导的心脏毒性在培养细胞和动物。然而，是否诱导内源性细胞抗氧化剂的化学试剂（药物）在心肌细胞也提供保护，对阿霉素诱导的心脏毒性尚未仔细研究。本研究项目的长期目标是开发合理的保护或治疗策略，以预防和/或延缓各种心脏疾病的氧化变性过程。这些策略依赖于对心脏组织中细胞抗氧化剂的诱导的理解。我们目前正在研究的假设是，心肌细胞中的内源性细胞抗氧化剂可以由独特的化学保护剂3 H-1，2-二硫杂环戊烯-3-基（D3 T）诱导，并且增加的内源性抗氧化剂防御在培养细胞和实验动物中保护免受阿霉素诱导的心脏毒性，而不干扰其所需的抗肿瘤活性。因此，本申请的具体目的被设计为：（1）表征小鼠心脏HL-1细胞中的细胞抗氧化剂及其由D3 T诱导的作用，所述细胞HL-1细胞是最近建立的具有分化的心肌细胞的表型特征的心脏细胞系;（2）确定D3 T诱导的细胞抗氧化剂对HL-1细胞中阿霉素介导的毒性的保护作用;（3）研究D3 T对小鼠心肌细胞抗氧化活性的影响，（4）研究D3 T对阿霉素心脏毒性和抗肿瘤活性的影响。实现上述目标将使我们更好地了解D3 T对心脏抗氧化剂的诱导能力，以及D3 T诱导的细胞抗氧化防御在氧化性心脏损伤中的保护作用--氧化性心脏损伤不仅由阿霉素引起，还由其他病理生理过程引起，例如缺血再灌注