Steroid As Cytoprotectants against Oxidative Toxicity

描述（由申请人提供）：已知压力会导致肾上腺皮质类固醇合成增加。尽管皮质类固醇已被证明有助于抑制免疫反应和许多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）是一种抗肿瘤药物，可产生慢性心脏毒性，表现为扩张性心肌病。这种形式的心肌病的一个重要特征是心肌细胞凋亡。我们的初步研究发现皮质酮（CT）预处理可以阻止Dox诱导心肌细胞凋亡。糖皮质激素受体拮抗剂米非司酮阻止CT诱导细胞存活反应。g!的几种形式糖皮质激素、醛固酮、孕酮和视黄酸能抑制心肌细胞凋亡，而雌激素、睾酮和l -甲状腺素不能。对ERK、Akt、SGK-1活性和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处理心肌细胞的条件培养基显示出部分的细胞保护作用。transsignal array方法发现，CT治疗可以潜在地激活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存活基因的转录激活。该资助的具体目的包括：1)测试CT结合是否会导致其受体与心肌细胞中的多种转录因子相互作用并激活；2)验证细胞存活基因的激活有助于ct诱导的细胞保护；3)证明CT通过诱导细胞存活基因的转录，在体内保护心脏免受Dox诱导的心肌病。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，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，该项目将提供新的信息，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，由于细胞凋亡已被证明有助于化疗药物Dox以及许多形式的心血管疾病引起的心力衰竭，我们的发现和提出的机制研究将为未来治疗心力衰竭的新疗法提供希望。

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.