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.

项目摘要急性心肌梗塞（AMI）是绝经后妇女死亡的主要原因，但年龄是如何相关的雌激素损失会影响心脏缺血性灌注（I/R）损伤的交点NLRP3 未经测试的炎性体信号传导和随后的AMI发病机理。有希望的可行性数据表明 NLRP3炎性体过度激活和心脏线粒体质量控制失调可能会产生有毒向前回路，以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会通过巨噬细胞极化受损来扩大氧化应激。我们将识别并表征NLRP3免疫信号传导中与年龄相关的关键相关变化，从而促进凋亡和梗塞进展，并确定心脏线粒体不足是NLRP3的驱动力老年女性I/R损伤后的炎性体过度激活（AIM 1）。接下来，我们将确定是否急性 NLRP3炎性体抑制使用小分子抑制剂，有或没有巨噬细胞耗尽，通过涉及修复性M2巨噬细胞表型表达和保护性心脏线粒体质量控制（AIM 2）。我们提出针对的NLRP3炎症体抑制作用将通过涉及的独特和重叠的机制来挽救绝经后老化的心脏心脏巨噬细胞极化，线粒体和线粒体衍生的危险相关分子图案（潮湿）。拟议的研究是我们实验室正在进行的工作的逻辑扩展，该研究正在寻求定义与年龄相关的雌激素损失对心脏I/R损伤的影响。 F344雌鼠将卵巢切除在15个月，年龄为24 mo，以更好地模仿人类更年期，NLRP3敲除大鼠以进行证明概念，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在7天内具有可变再灌注的AMI，以测试我们在心脏免疫细胞子集中的具体目标线粒体。这项研究的发现对于确立NLRP3炎性组的作用将是无价的老年女性心脏中I/R损伤的介导调节，并强烈支持NLRP3炎症小体作为一个年龄较大的绝经后妇女减少AMI的治疗靶标。我们将首次确定 NLRP3炎性体过度激活影响年龄的AMI脆弱性的贡献和机制雌性（和雄性）大鼠。