Inflammasome-Mediated Cardiac Cell Death in the Aged Female Rat Heart

老年雌性大鼠心脏中炎症小体介导的心肌细胞死亡

基本信息

批准号：
10610214
负责人：
DONNA HOPE KORZICK
金额：
$ 5.48万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610214
关键词：
3-Dimensional Acute Acute myocardial infarction Adult Age Aging American Attenuated Award CASP1 gene Cardiac Cause of Death Cell Death Cells Cessation of life Chronic Clinical Coronary artery Data Development Dichloromethylene Diphosphonate Disease Progression Estrogens Face Female Future Goals Heart Heart Diseases Human IL18 gene Immune Immune Targeting Immune response Immune signaling Impairment Infarction Inflammasome Inflammation Inflammatory Interleukin-1 beta Intervention Knock-out Laboratories Ligation Link Liposomes Mediating Menopause Mitochondria Mitochondrial DNA Modeling Molecular Myocardial Infarction Myocarditis Natural History Oxidative Stress Pathogenesis Pattern Phenotype Population Postmenopause Production Quality Control Rattus Regulation Reperfusion Injury Reperfusion Therapy Resolution Respiration Rodent Model Role Scheme Severities Signal Transduction Testing Time Tumor-infiltrating immune cells Ventricular Remodeling Woman Work age effect aged cardioprotection cardiovascular disorder risk cytokine heart disease prevention immunological intervention immunoregulation improved inflammatory milieu inhibitor ischemic injury macrophage male marenostrin mitochondrial autophagy mortality novel novel therapeutics older women protective efficacy receptor reconstruction response small molecule small molecule inhibitor therapeutic target

项目摘要

Project Summary Acute myocardial infarction (AMI) is the leading cause of death in post-menopausal women, but how age- associated estrogen loss impacts the intersection of cardiac ischemic-reperfusion (I/R) injury, NLRP3 inflammasome signaling and subsequent AMI pathogenesis is untested. Promising feasibility data suggest that NLRP3 inflammasome hyperactivation and dysregulated cardiac mitochondrial quality control may create a toxic feed forward circuit to exacerbate proinflammatory responses and AMI progression in aged females. Age- associated chronic inflammation may amplify oxidative stress through impaired macrophage polarization. We will identify and characterize key age-associated changes in NLRP3 immune signaling that promote pyroptosis and infarct progression, and determine whether insufficient cardiac mitophagy is a driver of NLRP3 inflammasome hyperactivation following I/R injury in aged females (Aim 1). We will next determine if acute NLRP3 inflammasome suppression using a small molecule inhibitor, with and without macrophage depletion, confers cardioprotection through a mechanism involving reparative M2 macrophage phenotypic expression and protective cardiac mitochondrial quality control (Aim 2). We propose that targeted NLRP3 inflammasome inhibition will rescue the post-menopausal aged heart through unique and overlapping mechanisms involving cardiac macrophage polarization, mitophagy, and limiting mitochondrial-derived danger associated molecular patterns (DAMPs). The proposed studies are a logical extension of ongoing work in our laboratory, which seeks to define the effects of age-associated estrogen loss on cardiac I/R injury. F344 female rats will be ovariectomized at 15 mo and aged to 24 mo to better mimic human menopause, NLRP3 knock out rats for proof of concept, and adult and aged male rats for clinical comparison. Coronary artery ligation will be used to induce AMI with variable reperfusion over 7 days to test our specific aims in cardiac immune cell subsets and mitochondria. The findings from this study will be invaluable in establishing a role for NLRP3 inflammasome- mediated regulation of I/R injury in the aged female heart and strongly support the NLRP3 inflammasome as a therapeutic target for AMI reduction in older post-menopausal women. We will determine, for the first time, the contribution and mechanism by which NLRP3 inflammasome hyperactivation impacts vulnerability to AMI in aged female (and male) rats.

项目概要急性心肌梗塞（AMI）是绝经后女性死亡的主要原因，但年龄相关雌激素损失影响心脏缺血再灌注 (I/R) 损伤的交叉点，NLRP3 炎症小体信号传导和随后的 AMI 发病机制尚未经过测试。有希望的可行性数据表明 NLRP3 炎症小体过度激活和心肌线粒体质量控制失调可能会产生毒性前馈电路会加剧老年女性的促炎反应和 AMI 进展。年龄- 相关的慢性炎症可能通过受损的巨噬细胞极化而放大氧化应激。我们将识别并表征 NLRP3 免疫信号中与年龄相关的关键变化，这些变化会促进细胞焦亡和梗死进展，并确定心脏线粒体自噬不足是否是 NLRP3 的驱动因素老年女性 I/R 损伤后炎症小体过度激活（目标 1）。接下来我们将确定是否急性使用小分子抑制剂抑制 NLRP3 炎症小体，伴或不伴巨噬细胞耗竭，通过涉及修复性 M2 巨噬细胞表型表达的机制赋予心脏保护作用保护性心脏线粒体质量控制（目标 2）。我们建议靶向 NLRP3 炎性体抑制将通过独特和重叠的机制来拯救绝经后衰老的心脏，其中包括心脏巨噬细胞极化、线粒体自噬和限制线粒体衍生危险相关分子模式（DAMP）。拟议的研究是我们实验室正在进行的工作的逻辑延伸，旨在寻求确定与年龄相关的雌激素减少对心脏缺血再灌注损伤的影响。 F344雌性大鼠将为了更好地模拟人类更年期，在 15 个月时切除卵巢并延长至 24 个月，NLRP3 敲除大鼠作为证据概念，以及成年和老年雄性大鼠进行临床比较。冠状动脉结扎将用于诱导 AMI 具有 7 天的可变再灌注，以测试我们在心脏免疫细胞亚群中的特定目标和线粒体。这项研究的结果对于确定 NLRP3 炎症小体的作用非常有价值。介导老年女性心脏 I/R 损伤的调节，并强烈支持 NLRP3 炎性体作为减少老年绝经后妇女 AMI 的治疗目标。我们将首次确定 NLRP3炎症小体过度激活影响老年人AMI易感性的贡献和机制雌性（和雄性）大鼠。