THE ROLE OF CARDIOMYOCYTE AND CARDIOFIBROBLAST SENESCENCE IN THE AGING HEART

心肌细胞和心成纤维细胞衰老在心脏衰老中的作用

• 批准号: 8005820
• 负责人: Leroy Leon Cooper
• 金额: $ 4.14万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8005820
• 关键词: Abnormal Cell; Accounting; Age; Aging; Area; Arrhythmia; Biochemical; Calcium; Cardiac; Cardiac Death; Cardiac Myocytes; Cause of Death; Cell Aging; Cells; Cessation of life; Data; Fiber; Fibrosis; Flow Cytometry; Gene Expression; Heart; Heart Diseases; Immunofluorescence Immunologic; In Vitro; Incidence; Lead; Life Expectancy; Malignant - descriptor; Maps; Molecular; Muscle Cells; Myocardium; Optics; Oryctolagus cuniculus; Paraffin Embedding; Population; Quality of life; Risk; Role; Sudden Death; System; Techniques; Therapeutic; Trichrome stain; United States; Ventricular Fibrillation; age related; aged; base; cohort; hemodynamics; in vivo; novel; public health relevance; research study; senescence; sudden cardiac death

DESCRIPTION (provided by applicant): Accounting for approximately 50% of deaths related to heart disease, sudden cardiac death (SCD) is a leading cause of death in the United States; thus, understanding the mechanisms that underlie deadly arrhythmias that cause SCD could lead to preventative pharmacological and therapeutic strategies that would increase life expectancy and quality of life among a growing susceptible population. It is known that aging is associated with an increase of the incidence of SCD. Yet, much remains unknown about the mechanisms that underlie the age- related, proarrhythmic changes in the mammalian heart at the cellular and molecular level and how they are related to arrhythmogenesis and increased incidence of SCD. Thus far, we have conducted preliminary in vivo EP studies and optical mapping experiments that reveal an aging- related slowing of conduction through the His-Purkinje system and the ventricles. We have also shown an age-related increase in ventricular fibrillation inducibility, and I have performed Gomori trichrome staining on paraffin embedded sections, which revealed increased fibrosis in old hearts at the subepicardial region and between the fibers of the heart in the same area that showed slow conduction. Based on our preliminary data, I hypothesize that aging is not only associated with overall reduced cardiac function but also with the accumulation of senescent- like cardiomyocytes (CMs) and senescent cardiofibroblasts (CFs) in the cardiac muscle. Moreover, I postulate that the progressive senescence of CMs and CFs is associated with alterations in gene expression that will directly lead to abnormal myocyte contractility and abnormal cell excitation, as well as accelerated fibrosis. These alterations would lead to impaired cardiac contractility, a slowing of the conduction velocity, and a decrease in the threshold for induction of ventricular fibrillation. To that end, I am pursuing a multi-leveled approach to identify novel mechanisms that underlie malignant arrhythmias in the aging heart using comparisons between young and old rabbit cohorts, as well as comparisons among non- senescent, chronologically aged, and senescent cardiac cell populations. With a combination of in vivo and in vitro techniques (including invasive hemodynamics, immuoblotting/qPCR, immunofluorescence, flow cytometry, and single-cell calcium recordings), I hope to provide both biochemical and functional evidence revealing that cellular senescence underlies electrical and structural triggers and substrates for arrhythmias in the aging heart. PUBLIC HEALTH RELEVANCE: In the US, sudden cardiac death (SCD) accounts about 50% of deaths related to heart disease, so understanding what causes arrhythmias that lead to sudden death would allow for new ways to increase life expectancy and quality of life. We know that aging increases one's risk for SCD, so this study seeks to reveal the age-related changes in the heart that are related to increased incidence of SCD.

描述(申请人提供)：在美国，心脏性猝死(SCD)约占与心脏病有关的死亡的50%，是主要的死亡原因；因此，了解导致SCD的致命心律失常的机制可以导致预防性的药物和治疗策略，从而提高日益增长的易感人群的预期寿命和生活质量。众所周知，衰老与SCD发病率的增加有关。然而，关于哺乳动物心脏中与年龄相关的、在细胞和分子水平上导致心律失常的变化的机制，以及它们如何与心律失常的发生和SCD发病率的增加有关，目前仍不清楚。到目前为止，我们已经进行了初步的体内EP研究和光学标测实验，揭示了与衰老有关的通过His-Purkinje系统和脑室的传导减慢。我们还显示了与年龄相关的室颤诱发性的增加，我对石蜡切片进行了Gomori三色染色，显示在陈年心脏的心外膜下区域和同一区域显示传导缓慢的心脏纤维之间的纤维化增加。根据我们的初步数据，我假设衰老不仅与整体心功能下降有关，还与心肌中衰老的心肌细胞(CMS)和衰老的心脏成纤维细胞(CFs)的积累有关。此外，我推测CMS和CFS的进行性衰老与基因表达的改变有关，这些基因表达的改变将直接导致心肌细胞收缩异常和细胞兴奋异常，以及加速的纤维化。这些改变将导致心脏收缩能力受损，传导速度减慢，并降低诱发室颤的阈值。为此，我正在寻求一种多层次的方法，通过比较年轻和老年兔的队列，以及比较非衰老、按时间顺序老化和衰老的心脏细胞群体，来确定导致老化心脏恶性心律失常的新机制。通过体内和体外技术的结合(包括有创血流动力学、免疫印迹/qPCR、免疫荧光、流式细胞术和单细胞钙记录)，我希望提供生化和功能证据，揭示细胞衰老是老化心脏心律失常的电和结构触发因素和底物的基础。 公共卫生相关性：在美国，心脏性猝死(SCD)约占心脏病相关死亡的50%，因此了解导致猝死的心律失常的原因将为提高预期寿命和生活质量提供新的方法。我们知道衰老会增加一个人患SCD的风险，所以这项研究试图揭示心脏中与年龄相关的变化，这些变化与SCD的发病率增加有关。