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.

衰老与心脏性猝死（SCD）发生率增加10倍以上相关。细胞

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