Steroid As Cytoprotectants against Oxidative Toxicity

类固醇作为抗氧化毒性的细胞保护剂

• 批准号: 7030934
• 负责人: QIN M CHEN
• 金额: $ 36.83万
• 依托单位: UNIVERSITY OF ARIZONA
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7030934
• 关键词: SDS polyacrylamide gel electrophoresis; adrenal glands; apoptosis; biological signal transduction; cardiac myocytes; corticosteroid receptors; corticosteroids; cytoprotection; doxorubicin; gel mobility shift assay; gene expression; immune response; laboratory rat; myocardium disorder; oxidative stress; proteomics; transcription factor; western blottings

DESCRIPTION (provided by applicant): Stress is known to cause an increase in the synthesis of corticosteroids by the adrenal glands. Although corticosteroids have been shown to contribute to the pathophysiology of suppressed Immune response and a number of psychiatric disorders, the effect of CT on the heart remains unclear. Doxorubicin (Dox) is an anti-neoplastic drug that can produce chronic cardiac toxicity which is manifested as dilated cardiomyopathy. An important feature of this form of cardiomyopathy is the apoptosis of cardiomyocytes. Our preliminary studies found that corticosterone (CT) pretreatment prevented Dox from inducing apoptosis of cardiomyocytes. The glucocorticoid receptor antagonist mifepristone prevented CT from inducing a cell survival response. Several forms of g!ucocorticoids, aldosterone, progesterone and retinoic acid but not estrogen, testosterone or L-thyroxin can inhibit apoptosis of cardiomyocytes. Analyses of ERK, Akt and SGK-1 activities or bcl-2 expression indicated that CT neither activated the known survival kinases nor elevated the expression of the anti-apoptotic gene bcl- 2. The conditioned medium of CT-treated cardiomyocytes shows partially cytoprotective effective. The TranSignal array approach found that CT treatment could potentially activate 21 transcription factors. We hypothesize that activation of the glucocorticoid receptor initiates transcriptional activation of survival genes in cardiomyocytes in vitro and in vivo. Specific aims of this grant include: 1) To test if CT binding causes its receptor to interact with and to activate multiple transcription factors in cardiomyocytes; 2) To test that the activation of cell survival genes contributes to CT-induced cytoprotection; and 3) To demonstrate that CT protects the heart from cardiomyopathy induced by Dox in vivo via inducing the transcription of cell survival genes. This project will combine our expertise in genomics, transcriptomics and proteomics to systematically study the linkage between the glucocorticoid receptor and cell survival mechanisms. Given the fact that stress is unavoidable in our daily life, this project will provide novel information to advance our understanding in the biological effect of corticosteroids on the heart. More importantly, since apoptosis has been shown to contribute to heart failure induced by the chemotherapy agent Dox as well as by many forms of cardiovascular disease, our finding and proposed mechanistic study will provide a hope for novel therapy against heart failure in the future.

描述（由申请人提供）：已知应力会导致肾上腺对皮质类固醇的合成增加。尽管已证明皮质类固醇有助于抑制免疫反应和多种精神疾病的病理生理，但CT对心脏的影响尚不清楚。阿霉素（DOX）是一种抗塑性药物，可以产生慢性心脏毒性，表现为扩张的心肌病。这种形式的心肌病的重要特征是心肌细胞的凋亡。我们的初步研究发现，皮质酮（CT）预处理阻止DOX诱导心肌细胞凋亡。糖皮质激素受体拮抗剂米非酮阻止CT诱导细胞存活反应。几种形式的G型皮质激素，醛固酮，孕酮和视黄酸，但不能雌激素，睾丸激素或L-甲状腺素可以抑制心肌细胞的凋亡。 ERK，AKT和SGK-1活性或Bcl-2表达的分析表明，CT既没有激活已知的存活激酶，也没有升高抗凋亡基因BCl-2的表达。CT治疗的心肌细胞的条件培养基显示部分细胞增多剂有效。跨点阵列方法发现CT处理可能会激活21个转录因子。我们假设糖皮质激素受体的激活启动了体外和体内心肌细胞中生存基因的转录激活。该赠款的具体目的包括：1）测试CT结合是否导致其受体与心肌细胞中的多个转录因子相互作用并激活； 2）测试细胞存活基因的激活有助于CT诱导的细胞保护作用； 3）证明CT通过诱导细胞存活基因的转录来保护Dox在体内诱导的心肌病免受心肌病的伤害。该项目将结合我们在基因组学，转录组学和蛋白质组学方面的专业知识，以系统地研究糖皮质激素受体与细胞存活机制之间的联系。鉴于压力在我们的日常生活中是不可避免的，因此该项目将提供新颖的信息，以促进我们对皮质类固醇对心脏的生物学作用的理解。更重要的是，由于凋亡已被证明会导致化学疗法剂DOX以及许多形式的心血管疾病引起的心力衰竭，因此我们的发现和提议的机械研究将为未来的心力衰竭提供新的治疗。