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.

心脏性猝死（SCD）约占与心脏病相关死亡人数的50%，是美国的主要死亡原因；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，在细胞和分子水平上，哺乳动物心脏中与年龄相关的促心律失常变化的机制以及它们与心律失常发生和SCD发病率增加的关系尚不清楚。到目前为止，我们已经进行了初步的体内电位研究和光学测绘实验，揭示了与衰老相关的通过His-Purkinje系统和心室的传导减慢。我们也显示了心室纤颤诱发性与年龄相关的增加，我在石蜡包埋切片上进行了Gomori三色染色，发现在心外膜下区域和同一区域的心脏纤维之间的纤维化增加，显示传导缓慢。根据我们的初步数据，我假设衰老不仅与心脏功能的整体下降有关，而且与心肌中衰老样心肌细胞（CMs）和衰老的心肌成纤维细胞（CFs）的积累有关。此外，我假设CMs和CFs的进行性衰老与基因表达的改变有关，基因表达的改变将直接导致肌细胞收缩性异常和细胞兴奋异常，以及纤维化加速。这些改变会导致心脏收缩力受损，传导速度减慢，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来确定衰老心脏中恶性心律失常的新机制，使用年轻和年老兔子队列之间的比较，以及在非衰老，按时间顺序衰老和衰老的心脏细胞群之间的比较。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，揭示细胞衰老是老化心脏中心律失常的电和结构触发和底物的基础。