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: 8318693
• 负责人: Leroy Leon Cooper
• 金额: $ 3.67万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318693
• 关键词: 17 year old; 4 year old; Abnormal Cell; Accidents; Accounting; Acquired Immunodeficiency Syndrome; Action Potentials; Address; Adolescent; Adult; Age; Aging; Area; Arrhythmia; Biochemical; Biological Markers; Biological Models; Calcium; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cause of Death; Cell Aging; Cell Size; Cells; Cessation of life; Colorectal Cancer; DNA Damage; Data; Female; Fiber; Fibrosis; Fire - disasters; Firearms; Flow Cytometry; Functional disorder; Gene Expression; Heart; Heart Diseases; Heart failure; Housing; Immunofluorescence Immunologic; In Vitro; Incidence; Investigation; Lead; Left Ventricular Function; Life Expectancy; Link; Malignant - descriptor; Malignant neoplasm of prostate; Maps; Modeling; Molecular; Muscle Cells; Myocardium; New Zealand; Older Population; Optics; Oryctolagus cuniculus; Paraffin Embedding; Pattern; Population; Quality of life; Risk; Role; Series; Sudden Death; System; Techniques; Therapeutic; Tissues; Trichrome stain; United States; Ventricular Fibrillation; age group; age related; aged; base; cohort; emerging adult; hemodynamics; in vivo; killings; malignant breast neoplasm; mortality; novel; research study; response; senescence; sudden cardiac death

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.

心源性猝死 (SCD) 约占与心脏病相关死亡的 50%，是美国的主要原因；因此，了解导致 SCD 的致命性心律失常的机制可能会导致预防性药理学和治疗策略，从而提高不断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，关于哺乳动物心脏在细胞和分子水平上与年龄相关的致心律失常变化的机制以及它们与心律失常发生和 SCD 发病率增加之间的关系，仍然有很多未知之处。到目前为止，我们已经进行了初步的体内 EP 研究和光学测绘实验，揭示了与衰老相关的希氏-浦肯野系统和心室传导减慢。我们还发现，心室颤动的诱发性与年龄有关，并且我对石蜡包埋切片进行了 Gomori 三色染色，结果显示老年心脏的心外膜下区域以及同一区域的心脏纤维之间的纤维化增加。传导缓慢。根据我们的初步数据，我假设衰老不仅与整体心脏功能下降有关，还与心肌中衰老样心肌细胞（CM）和衰老心肌成纤维细胞（CF）的积累有关。此外，我推测CM和CF的进行性衰老与基因表达的改变有关，这将直接导致异常的心肌细胞收缩力和异常的细胞兴奋，以及加速纤维化。这些改变会导致心脏收缩力受损、传导速度减慢以及诱发心室颤动的阈值降低。为此，我正在寻求一种多层次的方法，通过比较年轻和年老的兔子队列，以及非衰老、按时间顺序衰老和衰老的心肌细胞群之间的比较，来确定衰老心脏中恶性心律失常的新机制。 。通过结合体内和体外技术（包括侵入性血流动力学、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，揭示细胞衰老是电和结构触发因素的基础以及老化心脏中心律失常的基质。