Scarring and Arrhythmia in Infarcted Aged Hearts: Role of Senescent Fibroblasts

梗死老年心脏的疤痕和心律失常：衰老成纤维细胞的作用

• 批准号: 10335140
• 负责人: GIDEON KOREN
• 金额: $ 100.65万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-20 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335140
• 关键词: 3-Dimensional; 6 year old; Action Potentials; Affect; Age; Aging; Animal Model; Area; Arrhythmia; Biomimetics; Calcium; Cardiac; Cardiac Myocytes; Cause of Death; Cell Aging; Cells; Cessation of life; Characteristics; Cicatrix; Complement; Complex; Cre driver; Data; Developed Countries; Elderly; Engineering; Excision; Fibroblasts; Fibrosis; Frequencies; Genetic; Heart; Heart Atrium; Heart Injuries; Histocytochemistry; Homeostasis; Human; Image; Immune system; Immunohistochemistry; In Vitro; Incidence; Infarction; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Ischemia; Kinetics; Lead; Liver; Methodology; Modeling; Molecular; Molecular Analysis; Mus; Myocardial Infarction; Myocardial Ischemia; Myofibroblast; Natural Killer Cells; Optics; Oryctolagus cuniculus; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Physiological Processes; Play; Population; Procedures; Process; Property; Rattus; Research; Research Personnel; Risk; Role; Serial Magnetic Resonance Imaging; Skin wound healing; Spatial Distribution; TP53 gene; Testing; Time; Tissues; Tumor Suppression; Ventricular Arrhythmia; Work; age related; aged; base; biological adaptation to stress; cytokine; experimental study; healing; human old age (65+); immune clearance; in vivo; innovation; minimally invasive; mouse model; myocardial infarct sizing; novel; paracrine; periostin; promoter; response; senescence; sudden cardiac death; wound healing

Aging is associated with more than a 10-fold increase in the incidence of sudden cardiac death (SCD). Cellular senescence is a stress response that is characterized by an irreversible loss of proliferative capacity, accompanied by a complex senescence-associated secretory phenotype (SASP) that can have profound effects on neighboring cells in the tissue. Our research plan is based on the following main premises. First, that fibrosis is a consequence of heart injury (myocardial infarction) by being part of the natural wound healing response, and that inflammatory processes in the scar may predispose the heart to arrhythmias. Second, that cellular senescence of cardiac fibroblasts (CFs) plays an important role in post-MI wound healing. The overarching hypothesis of our proposal is that senescence is an important component of wound healing in the heart. Specifically, we postulate that in the aging human heart with a healed MI, the interplay between aging cardiomyocytes (CMs) that have a lower threshold for arrhythmogenic activity, and the a modified senescence response observed in the aging heart may lead to arrhythmogenesis. Furthermore, we hypothesize that aging also impacts the senescence of cardiac fibroblasts (CFs) by either affecting the kinetics of the senescence response, the intrinsic properties of the senescent cells, or their clearance by the immune system. This multi-PI proposal brings together several investigators with very different expertise to investigate mechanisms of SCD in the aging heart, using a novel age-appropriate large animal model (rabbit), CFs-specific genetically modified mice, and engineered 3D microtissues of CMs and CFs where their interactions can be studied in vitro. In Aim 1 the Koren group will investigate the infarct healing process in the aging rabbit heart, as compared to the young heart, and correlate the arrhythmogenesis with molecular and cellular analysis of CMs and CFs and myofibroblasts derived from the IBZ and infarct zone (IZ) as compared to the remote zone (RZ). In Aim 2 the Sedivy group will use mouse models to focus on the role CFs senescence in this process. Senescence will be manipulated in vivo using genetic and pharmacologic approaches, CFs will be cultured and investigated in vitro. Optical mapping of hearts ex vivo will be used to study arrhythmogenesis. In Aim 3 the Mende and Choi groups will study the effect of senescent CFs on excitation, conduction and calcium handling in biomimetic cardiac microtissues, in which CMs and senescent CFs can interact via direct cell-cell contact. In summary, we envision that by understanding the aging mechanisms that control cellular senescence we will be able to reduce fibrosis and the incidence of SCD.

衰老与心脏猝死（SCD）的发生率增加了10倍以上。细胞 衰老是一种压力反应，其特征是不可逆转的增殖能力丧失， 伴随着复杂的衰老相关分泌表型（SASP），可以具有深刻的 对组织中相邻细胞的影响。我们的研究计划基于以下主要前提。首先，那 纤维化是心脏损伤（心肌梗塞）的结果 反应，疤痕中的炎症过程可能会使心律不齐。第二，那 心脏成纤维细胞（CFS）的细胞衰老在MI后伤口愈合中起重要作用。这 我们提议的总体假设是衰老是伤口愈合的重要组成部分 心。具体而言，我们假设在衰老的人心脏中，MI疗法之间的相互作用 心律不齐活性阈值较低的心肌细胞（CMS），修饰的衰老 在衰老心脏中观察到的反应可能导致心律失常。此外，我们假设衰老 还通过影响衰老动力学来影响心脏成纤维细胞（CFS）的衰老 反应，衰老细胞的内在特性或免疫系统清除。这个多pi 提案汇集了一些具有截然不同专业知识的调查员来研究SCD的机制 在衰老的心脏中，使用新颖的年龄大型动物模型（兔子），CFS特异性基因修饰 可以在体外研究其相互作用的CMS和CFS的小鼠以及工程的3D微动物。目标 1 Koren组将研究衰老兔心脏的梗塞愈合过程，与 年轻的心脏，并将心律失常与CM和CFS的分子和细胞分析相关联 与远程区域（RZ）相比，源自IBZ和梗塞区（IZ）的肌纤维细胞（IZ）。在目标2中 Sedivy Group将使用小鼠模型专注于此过程中CFS衰老的角色。衰老会 使用遗传和药理方法在体内操纵，CFS将在体外进行培养和研究。 心脏的光学映射将用于研究心律失常。在目标3中，门德和崔 小组将研究衰老CFS对仿生型激发，传导和钙处理的影响 心脏微动物，其中CMS和衰老CF可以通过直接细胞接触相互作用。总而言之，我们 设想，通过了解控制细胞衰老的衰老机制，我们将能够 降低纤维化和SCD的发生率。

项目成果

The endosomal trafficking regulator LITAF controls the cardiac Nav1.5 channel via the ubiquitin ligase NEDD4-2.

• DOI: 10.1074/jbc.ra120.015216
• 发表时间: 2020-12-25
• 期刊: The Journal of biological chemistry
• 作者: Turan NN;Moshal KS;Roder K;Baggett BC;Kabakov AY;Dhakal S;Teramoto R;Chiang DY;Zhong M;Xie A;Lu Y;Dudley SC Jr;MacRae CA;Karma A;Koren G
• 通讯作者: Koren G

Three-Week-Old Rabbit Ventricular Cardiomyocytes as a Novel System to Study Cardiac Excitation and EC Coupling.

• DOI: 10.3389/fphys.2021.672360
• 发表时间: 2021
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Kabakov AY;Sengun E;Lu Y;Roder K;Bronk P;Baggett B;Turan NN;Moshal KS;Koren G
• 通讯作者: Koren G

Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart.

• DOI: 10.7554/elife.84088
• 发表时间: 2023-05-19
• 期刊: eLife
• 影响因子: 7.7
• 作者: Baggett BC;Murphy KR;Sengun E;Mi E;Cao Y;Turan NN;Lu Y;Schofield L;Kim TY;Kabakov AY;Bronk P;Qu Z;Camelliti P;Dubielecka P;Terentyev D;Del Monte F;Choi BR;Sedivy J;Koren G
• 通讯作者: Koren G