Gender Influence in Mice with Myocardial Infarction

性别对心肌梗死小鼠的影响

基本信息

批准号：
7149194
负责人：
XIAO-PING YANG
金额：
$ 27.31万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-15 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7149194
关键词：
Acute Acute myocardial infarction Adult Adverse effects Affect Age Animals Anti-Inflammatory Agents Anti-inflammatory Attenuated Cardiac Cardiovascular Diseases Castration Cell Adhesion Molecules Cells Cessation of life Chronic Phase Cicatrix Collagen Conflict (Psychology)Congestive Heart Failure Cutaneous Deposition Development Dilatation - action Doctor of Medicine Endometrial Estrogen Receptors Estrogens Event Female Functional disorder Gelatinase B Gender Healed Heart Heart Hypertrophy Heart failure Hormones Human Incidence Infarction Infiltration Inflammation Inflammatory Inflammatory Response Interleukin-6 Ischemia Knockout Mice Lead Left Left Ventricular Function Left Ventricular Remodeling Leukocytes Matrix Metalloproteinases Mediating Menopause Metalloproteases Monocyte Chemoattractant Protein-1 Morbidity - disease rate Mus Myocardial Infarction Myocardial rupture Myofibroblast Necrosis Nuclear Ovariectomy Oxidative Stress Pathogenesis Pathological Dilatation Personal Satisfaction Phase Postmenopause Premenopause Prevalence Process Progestins Rate Reactive Oxygen Species Risk Risk Factors Role Rupture Severities Sex Characteristics Stress Stroke Supplementation Testing Testosterone Time Tissue Inhibitor of Metalloproteinase-1 Tissues United States Ventricular Week Woman Wound Healing collagenase day healing improved macrophage male migration mortality mouse model neovascularization receptor size

项目摘要

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（由申请人提供）：心血管疾病（CVD）是美国发病和死亡的主要原因之一。有证据表明，绝经前女性比同龄男性更不容易患心血管疾病，而且这种优势在绝经后消失。我们最近使用小鼠心肌梗死（MI）模型发现，与雄性小鼠相比，雌性小鼠在心肌梗死后心脏破裂率要低得多，并且左心室（LV）功能保存得更好。男性补充雌激素和/或去势可降低破裂率并减慢左心室重塑，而女性补充睾酮则增加破裂发生率并恶化心功能和重塑，表明心肌梗死后雌激素的保护作用和睾酮的有害作用。在本提案中，我们将进一步测试以下假设：雌激素作用于α受体，保护心脏免受早期（梗塞扩张和心脏破裂）和晚期重塑（心脏肥大、扩张和功能障碍）的影响，并且这种作用部分是通过促进急性心肌梗死期间的愈合过程，以及心力衰竭发展过程中抑制炎症反应和减少氧化应激。相反，睾酮会加剧炎症反应。在目标1中，我们将研究雌激素和睾酮对梗塞愈合的影响，包括炎症细胞浸润、胶原酶活性、胶原沉积、梗塞扩张和新生血管形成。在目标2中，我们将研究在MI的慢性期，雌激素是否会降低核因子-κB和活性氧，从而改善炎症反应并改善男性的心脏功能，而睾酮是否会加重炎症和心脏功能障碍。在目标 3 中，我们将研究雌激素的心脏保护作用是否是通过激活其 α 受体来介导的。在目标 4 中，我们将研究：1）当小鼠遭受 MI 时，卵巢切除术后不久给予雌激素（模拟绝经后早期状态）是否会比几周后给予雌激素（模拟绝经后晚期状态）提供更好的心脏保护； 2）雌激素与孕激素合用时，其心脏保护作用会减弱。