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

• 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
• 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

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.

实验和临床研究都表明，慢性心肌梗塞与 左心房的不良重塑，进而对左心房功能产生不利影响。离开心房 扩张是心肌梗死后死亡率的强大而独立的预测指标，但是机制 重塑过程的基础仅是对重塑过程的理解。令人惊讶的是，我们已经观察到非常高的比率 梗塞小鼠左心房中心肌细胞周期活性。但是，心肌细胞细胞的作用 循环活性在减轻或加剧心肌后的结构和/或功能重塑时发挥作用 梗塞尚不清楚。为了直接解决这个问题，我们已经生成了一个转基因鼠标模型 梗塞引起的左心房细胞周期活性继发于p16-ink4a（p16）表达（p16是有效的 以前已经显示出成年动物中增殖激酶CDK4和转基因表达的抑制剂 成为有效的细胞周期抑制剂）。在这里，我们建议比较野生型和p16转基因小鼠以确定 心房心肌细胞周期激活对左心房结构和功能重塑的影响 梗塞。 AIM 1中提出的实验将确定心肌细胞周期活性的程度 影响心肌梗死后结构心房重塑。左心房结构分析将是 在组织水平上进行（a）以定量心肌质量，心肌细胞数，纤维化，免疫细胞 浸润，自主神经和毛细血管密度，（b）在心肌细胞水平上，以量化 细胞周期进展和细胞肥大以及心肌细胞凋亡的频率，（c） 分子水平来定量转录组变化。 AIM 2中提出的实验将确定 心肌梗塞后心肌细胞周期活性影响心房功能的程度。心房 将在整个生物层进行功能分析（a），以定量超声心动图和 血液动力学参数，（b）在完整的心脏水平上，以定量钙和电压瞬态参数 左心房（通过光学映射）和完整心脏内的细胞簇（通过双光子激光扫描 显微镜）和（c）在分离的细胞水平上，以定量分数缩短和钙处理动力学。 重要的是，将AIM 1的细胞和分子数据交叉引用与来自成像和功能数据的分子数据 AIM 2应该使我们能够更好地确定哪些细胞周期介导的变化对心脏有相关的影响 功能。此类信息可能表明旨在逆转妥协的干预措施，左心房功能 梗塞的心。