Estrogen and Mechanisms of Cardiomyocyte Protection

雌激素与心肌细胞保护机制

• 批准号: 7418689
• 负责人: RICHARD H KARAS
• 金额: $ 34.77万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7418689
• 关键词: Acute; Age; Anthracycline Antibiotics; Anthracyclines; Apoptosis; Apoptotic; Attention; Cardiac; Cardiac Myocytes; Cells; Chronic; Clinical; Complex; Data; Dominant-Negative Mutation; Elderly; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Failure; Female; Gender; Gonadal Steroid Hormones; Health; Heart; Heart failure; Hormones; Hospitalization; Hour; In Vitro; Incidence; Infarction; Inhibition of Apoptosis; Knowledge; Ligands; Mediating; Membrane; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Neonatal; Pathway interactions; Patients; Phosphatidylinositols; Phosphotransferases; Physiological; Postmenopause; Premenopause; Prevalence; Protein Overexpression; Protein-Serine-Threonine Kinases; Public Health; Rate; Rattus; Receptor Protein-Tyrosine Kinases; Recruitment Activity; Reporting; Research Personnel; Role; SRC gene; Scaffolding Protein; Sex Characteristics; Signal Pathway; Signal Transduction; Signaling Molecule; Societies; Structure; Testing; Vasodilation; Woman; base; day; improved; in vivo; lipid metabolism; member; mortality; mouse model; mutant; normal aging; novel; outcome forecast; programs; protein-tyrosine kinase c-src; receptor; research study; response; size; src-Family Kinases; steroid hormone receptor; transcription factor

DESCRIPTION (provided by applicant): Heart failure continues to be a major public health problem in our society. Clinical and experimental studies have shown that female gender is associated with improved prognosis in heart failure, but the mechanisms underlying the gender based differences in heart failure survival are not known. Recent data show that female gender is associated with decreased cardiomyocyte apoptosis in normal and failing hearts, providing a plausible explanation for gender differences in heart failure progression. Whether sex hormones influence cardiomyocyte survival in failing hearts ha not been studied. Over the past several years, our lab has explored the effects of 17beta-estradiol (E2), the primary circulating form of estrogen, in cardiomyocyte signaling. In a mouse model of myocardial infarction, we reported that physiologic E2 replacement administered to ovariectomized females reduced infarct size and cardiomyocyte apoptosis in the peri-infarct zone, in association with heightened myocardial activation of the serine-threonine kinase Akt that has important anti-apoptotic effects in cells. In cultured cardiomyocytes, physiologic levels of E2 inhibit anthracycline-induced apoptosis by estrogen receptor (ER) - and phosphoinositide-3 (PI3) kinase/Akt-dependent mechanisms. Moreover, within cardiomyocytes, E2 induces the formation of a signaling complex that contains Estrogen Receptor a, cSrc-kinase, the p85 regulatory subunit of PI3 kinase, and Striatin, a membrane-associated scaffold protein. Based on these exciting new data, we hypothesize that estrogen-mediated cardiomyocyte protection occurs via ER-dependent activation of the PIS kinase-Akt signaling pathway that leads to inhibition of cardiomyocyte apoptosis. This hypothesis will be tested with three Specific Aims: SA#1: Explore the contribution of both estrogen receptors alpha and beta, and the PI3 kinase signaling pathway in estrogen-mediated cardiomyocyte protection in vivo, SA#2: Examine the mechanisms of estrogen-mediated cardiomyocyte protection in vitro by analyzing the specific contributions of ERalpha, ERbeta, and components of the PI3 kinase-Akt signaling pathway. SA#3: Investigate the molecular mechanisms of estrogen receptor-dependent PI3 kinase and Akt activation in cardiomyocytes. These experiments will help elucidate the molecular basis for estrogen/estrogen receptor-dependent cardiomyocyte protection. Completion of these studies will add to our understanding of the gender-based differences in cardiomyocyte apoptosis and heart failure progression, and the role of sex hormones in ischemic heart disease and heart failure which are major causes of morbidity and mortality in our society.

描述（由申请人提供）：心力衰竭仍然是我们社会的主要公共卫生问题。临床和实验研究表明，女性性别与心力衰竭的预后改善有关，但是基于性别的心力衰竭生存差异的机制尚不清楚。最近的数据表明，女性性别与心脏正常和失败的心肌细胞凋亡减少有关，为心力衰竭进展的性别差异提供了合理的解释。性激素是否影响心脏失败心脏的心肌细胞生存。在过去的几年中，我们的实验室探索了17beta-雌二醇（E2）（雌激素的主要循环形式）在心肌细胞信号传导中的影响。在心肌梗死的小鼠模型中，我们报道说，对卵巢的女性施用的生理E2替换降低了牙周周围区域的梗塞大小和心肌细胞凋亡，并与丝氨酸 - 胸蛋白激酶Akt的心肌激活相关，对静脉 - 抗蛋白酶酶Akt的增强具有重要的抗激态效应。在培养的心肌细胞中，E2的生理水平抑制了蒽环类药物诱导的雌激素受体（ER）和磷酸肌醇3（PI3）激酶/AKT依赖性机制的凋亡。此外，在心肌细胞中，E2诱导了含有雌激素受体A，CSRC-激酶，PI3激酶的p85调节亚基和纹状体蛋白（膜相关的支架蛋白）的信号传导复合物的形成。基于这些令人兴奋的新数据，我们假设雌激素介导的心肌细胞保护通过ER依赖性激活PIS激酶-AKT信号传导途径，从而导致抑制心肌细胞凋亡。该假设将以三个具体的目的进行测试：SA＃1：探索雌激素受体α和β的贡献，以及雌激素介导的体内雌激素介导的心肌细胞保护中的PI3激酶信号传导途径，SA＃2：检查通过在体内进行特异性促进的肌肉促进的贡献，并检查雌激素介导的贡献，并通过对雌激素介导的贡献进行了特定的贡献。 PI3激酶-akt信号通路。 SA＃3：研究心肌细胞中雌激素受体依赖性PI3激酶和Akt激活的分子机制。这些实验将有助于阐明雌激素/雌激素受体依赖性心肌细胞保护的分子基础。这些研究的完成将增加我们对心肌细胞凋亡和心力衰竭进展的基于性别的差异的理解，以及性激素在缺血性心脏病和心力衰竭中的作用，这是我们社会中发病率和死亡率的主要原因。