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Impact of cardiomyocyte cell cycle activity on atrial structural and functional remodeling following myocardial infarction

心肌细胞细胞周期活性对心肌梗死后心房结构和功能重塑的影响

基本信息

批准号：
10442795
负责人：
LOREN J FIELD
金额：
$ 64.12万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-22 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10442795
关键词：
Acute myocardial infarction Address Adult Anatomy Apoptosis Atrial Fibrillation Atrial Function Bacterial Artificial Chromosomes Blood capillaries CDKN2A gene Calcium Cardiac Myocytes Cell Cycle Cell Cycle Progression Cell Nucleus Cells Chronic Clinical Research Complex Coronary Coronary artery Cytokinesis Data Development Dilatation - action Electrophysiology (science)Exhibits Fibrosis Frequencies Functional disorder Genetic Models Harvest Heart Heart Atrium Human Hypertrophy Image Immune Individual Infarction Infiltration Injury Intervention Kinetics Laboratories Laser Scanning Microscopy Left Left Atrial Function Left atrial structure Ligation Location Mechanics Mediating Mitosis Modeling Molecular Mus Myocardial Myocardial Infarction Myocardium Optics Organ Pathologic Patients Phosphotransferases Play Predisposition Process Rattus Reporter Reporting Rodent Role S phase Secondary to Surface System Testing Therapeutic Intervention Tissues Transgenes Transgenic Mice Transgenic Organisms Vascularization Ventricular Whole Organism Wild Type Mouse anillin density event cycle experimental study heart function hemodynamics imaging system inhibitor insight interstitial cell mature animal mortality mouse model nerve supply new therapeutic target novel postnatal prevent response sham surgery transcriptome two-photon voltage

项目摘要

Both experimental and clinical studies have demonstrated that chronic myocardial infarction is associated with adverse remodeling of the left atrium, which in turn has an adverse impact on left atrial function. Left atrial dilatation is a powerful and independent predictor of mortality after myocardial infarction, but the mechanisms underlying the remodeling process are only poorly understood. Surprisingly, we have observed very high rates of cardiomyocyte cell cycle activity in the left atrium of infarcted mice. However, the role that cardiomyocyte cell cycle activity plays in mitigating or exacerbating structural and/or functional remodeling following myocardial infarction is not known. To directly address this question, we have generated a transgenic mouse model wherein infarct-induced left atrial cell cycle activity is silenced secondary to p16-Ink4a (p16) expression (p16 is a potent inhibitor of the proliferative kinase Cdk4 and transgenic expression in adult animals has previously been shown to be a potent cell cycle inhibitor). Here we propose to compare wild-type and p16 transgenic mice to determine the impact of atrial cardiomyocyte cell cycle activation on left atrial structural and functional remodeling following infarction. The experiments proposed in Aim 1 will determine the degree to which cardiomyocyte cell cycle activity impacts structural atrial remodeling following myocardial infarction. Left atrial structural analyses will be performed (a) at the tissue level to quantitate myocardial mass, cardiomyocyte number, fibrosis, immune cell infiltration, autonomic innervation and capillary density, (b) at the cardiomyocyte level to quantitate the extent of cell cycle progression and cellular hypertrophy as well as frequency of cardiomyocyte apoptosis, and (c) at the molecular level to quantitate transcriptome changes. The experiments proposed in Aim 2 will determine the degree to which cardiomyocyte cell cycle activity impacts atrial function following myocardial infarction. Atrial functional analyses will be performed (a) at whole organism level to quantitate echocardiographic and hemodynamic parameters, (b) at the intact heart level to quantitate calcium and voltage transient parameters in the left atrium (via optical mapping) and of cell clusters within the intact heart (via two-photon laser scanning microscopy), and (c) at the isolated cell level to quantitate fractional shortening and calcium handling kinetics. Importantly, cross-referencing the cell and molecular data from Aim 1 with the imaging and functional data from Aim 2 should enable us to better determine which cell cycle-mediated changes have a relevant impact on cardiac function. Such information may suggest interventions aimed at reversing compromised left atrial function in infarcted hearts.

实验和临床研究均表明慢性心肌梗死与