Gender Influence in Mice with Myocardial Infarction

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，绝经前的女性比同龄的男性更不容易患心血管疾病，这种优势在绝经后消失。最近，我们使用小鼠心肌梗死（MI）模型发现，MI后雌性小鼠的心脏破裂率比雄性小鼠低得多，左心室（LV）功能保存得更好。补充雌激素和/或去势降低了男性的破裂率，减缓了左心室重塑，而补充睾酮的女性增加了破裂的发生率，恶化了心脏功能和重塑，表明雌激素的保护作用和睾酮的有害作用后MI。在本提案中，我们将进一步验证以下假设：雌激素作用于α受体，保护心脏免于早期（梗死扩大和心脏破裂）和晚期重塑（心脏肥大、扩张和功能障碍），这种作用部分是通过促进急性MI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期间的氧化应激来介导的。相反，睾酮会加剧炎症反应。目的1：研究雌激素和睾酮对梗死愈合的影响，包括炎性细胞浸润、胶原酶活性、胶原沉积、梗死范围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，雌激素是否降低核因子-κ B和活性氧，从而改善炎症反应和改善男性的心脏功能，而睾酮是否减轻炎症和心功能障碍。在目标3中，我们将研究雌激素的心脏保护作用是否是通过激活其α受体介导的。在目标4中，我们将研究1）当小鼠经受MI时，卵巢切除术后不久给予的雌激素（模拟绝经早期状态）是否将比几周后给予的雌激素（模拟绝经晚期状态）提供更好的心脏保护;以及2）当与雌激素结合时，雌激素的心脏保护作用是否会减弱。

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.