Gender Influence in Mice with Myocardial Infarction

性别对心肌梗死小鼠的影响

• 批准号: 7535212
• 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
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7535212
• 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; Phase; Postmenopause; Premenopause; Prevalence; Process; Progestins; 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; Woman; Wound Healing; collagenase; healing; improved; macrophage; male; migration; mortality; mouse model; neovascularization; receptor

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）是美国发病率和死亡率的主要原因之一。有证据表明，绝经前妇女比年龄相似的男性容易患CVD，而更年期后这种优势消失了。使用心肌梗塞（MI）的小鼠模型，我们最近发现雌性小鼠的心脏破裂率要低得多，并且在MI后的左心室（LV）功能更好得多。补充雄性雌激素和/或去势降低了破裂率并减慢LV重塑，而女性中睾丸激素补充剂的补充增加了破裂的发生率，并使心脏功能恶化和重塑，这表明雌激素的保护作用和睾丸激素后MI的有害作用。在这项提案中，我们将进一步测试雌激素作用于α受体的雌激素，可保护心脏免受早期（梗塞扩张和心脏爆发）和晚期重塑的早期（心脏肥大，扩张，扩张和功能障碍）（这种效应）在促进良好过程中促进急性的抗疗法，并通过促进急性促进的敏锐的反应，并通过促进急性MI的疗效，并通过促进急性促进，并通过促进急性mi的疗效来促进急性MI，从而保护心脏免受早期（梗塞和心脏爆发）和晚期重塑的影响。 心脏衰竭。相反，睾丸激素加剧了炎症反应。在AIM 1中，我们将研究雌激素和睾丸激素对梗死愈合的影响，包括炎性细胞浸润，胶原酶活性，胶原蛋白沉积，梗塞扩张和新血管形成。在AIM 2中，我们将研究雌激素的慢性阶段是否会降低核因子 - 卡帕布和活性氧，从而改善雄性炎症反应并改善雄性心脏功能，而睾丸激素加剧炎症和心脏功能障碍。在AIM 3中，我们将研究雌激素的心脏保护作用是否是通过其α受体激活介导的。在AIM 4中，我们将研究1）卵巢切除术后不久（模仿绝经后状态的早期）是否会提供更好的心脏保护，而几周后（模仿小鼠后期小鼠）接受MI时给予的雌激素。 2）与孕激素结合时，雌激素的心脏保护作用将减弱。

项目成果

Dose-dependent cardiac effect of oestrogen replacement in mice post-myocardial infarction.

心肌梗塞后小鼠雌激素替代的剂量依赖性心脏效应。

• DOI: 10.1113/expphysiol.2008.042788
• 发表时间: 2008
• 期刊: Experimental physiology
• 影响因子: 2.7
• 作者: Zhan,Enbo;Keimig,Thomas;Xu,Jiang;Peterson,Edward;Ding,Jennifer;Wang,Fangfei;Yang,Xiao-Ping
• 通讯作者: Yang,Xiao-Ping

Augmented healing process in female mice with acute myocardial infarction.

增强急性心肌梗死雌性小鼠的愈合过程。

• DOI: 10.1016/s1550-8579(07)80043-x
• 发表时间: 2007
• 期刊: Gender medicine. official journal of the Partnership for Gender-Specific Medicine at Columbia University
• 作者: Wang,Fangfei;Keimig,Thomas;He,Quan;Ding,Jennifer;Zhang,Zhenggang;Pourabdollah-Nejad,Siamak;Yang,Xiao-Ping
• 通讯作者: Yang,Xiao-Ping