Gender Influence in Mice with Myocardial Infarction

性别对心肌梗死小鼠的影响

• 批准号: 6992713
• 负责人: XIAO-PING YANG
• 金额: $ 28.12万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6992713
• 关键词: angiogenesis; collagen; collagenase; cytoprotection; disease /disorder model; estrogen receptors; estrogens; free radical oxygen; gender difference; genetically modified animals; heart ventricle; inflammation; laboratory mouse; myocardial infarction; nuclear factor kappa beta; ovariectomy; oxidative stress; testosterone

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality in the United States. There is evidence that premenopausal women are much less prone to suffer CVD than males of similar age, and that this advantage disappears after menopause. Using a mouse model of myocardial infarction (MI), we recently found that female mice had a much lower cardiac rupture rate and better preserved left ventricular (LV) function than males after MI. Supplementation of estrogen and/or castration in males reduced the rupture rate and slowed LV remodeling, while supplementation of testosterone in females increased the incidence of rupture and worsened cardiac function and remodeling, indicating a protective role of estrogen and detrimental role of testosterone post-MI. In this proposal, we will further test the hypotheses that estrogen, acting on the alpha-receptors, protects the heart from early (infarct expansion and cardiacrupture) and late remodeling (cardiac hypertrophy, dilatation and dysfunction) and this effect is partially mediated by facilitating the healing process during acute MI, and by inhibiting the inflammatory response and reducing oxidative stress during the development of heart failure. Conversely, testosterone exacerbates the inflammatory response. In Aim 1, we will study the effect of estrogen and testosterone on infarct healing, including inflammatory cell infiltration, collagenase activity, collagen deposition, infarct expansion and neovascularization. In Aim 2, we will study whether, during the chronic phase of MI, estrogen decreases nuclear factor-kappaB and reactive oxygen species, thereby ameliorating the inflammatory response and improving cardiac function in males, whereas testosterone aggravates inflammation and cardiac dysfunction. In Aim 3, we will study whether the cardioprotective effect of estrogen is mediated by activation of its alpha-receptor. In Aim 4, we will study whether 1) estrogen given soon after ovariectomy (mimics early postmenopausal status) will provide better cardiac protection than if it is given a few weeks later (mimics late postmenopausal status) when mice are subjected to MI; and 2) the cardioprotective effect of estrogen will be attenuated when combined with progestin.

描述(申请人提供)：心血管疾病(CVD)是美国发病率和死亡率的主要原因之一。有证据表明，绝经前的女性比同龄男性更不容易患心血管疾病，这一优势在绝经后消失。利用小鼠心肌梗死(MI)模型，我们最近发现，在MI后，雌性小鼠的心脏破裂发生率比雄性小鼠低得多，而且左心室(LV)功能保存得更好。男性补充雌激素和/或去势可降低心脏破裂发生率，延缓左室重构，而女性补充睾酮则增加破裂发生率，恶化心功能和重构，提示雌激素的保护作用和睾酮对心肌梗死后的不利作用。在这项提案中，我们将进一步测试雌激素作用于α受体，保护心脏免受早期(梗塞扩大和心脏破裂)和晚期重构(心脏肥大、扩张和功能障碍)的假设，这一作用部分是通过促进急性心肌梗死期间的愈合过程，以及通过抑制炎症反应和减少心力衰竭发展过程中的氧化应激来实现的。相反，睾丸素会加剧炎症反应。目的1研究雌激素和睾酮对心肌梗死愈合的影响，包括炎症细胞浸润、胶原酶活性、胶原沉积、梗塞扩大和新生血管形成。在目标2中，我们将研究在MI的慢性期，雌激素是否会减少核因子-kappaB和活性氧物种，从而改善男性的炎症反应和心功能，而睾酮则加剧炎症和心功能障碍。在目标3中，我们将研究雌激素的心脏保护作用是否通过激活其α受体而介导。在目标4中，我们将研究1)在卵巢切除后不久给予雌激素(模拟绝经后早期状态)是否比几周后在小鼠遭受MI时给予雌激素(模拟绝经后晚期状态)提供更好的心脏保护；以及2)当雌激素与孕激素联合使用时，其心脏保护作用将减弱。