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Functional role of IP3 receptors in the regulation of cardiac myofibroblasts

IP3受体在心肌成纤维细胞调节中的功能作用

基本信息

批准号：
10183310
负责人：
Gaetano Santulli
金额：
$ 41.75万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183310
关键词：
Ablation Adult Animal Model Arrhythmia Attenuated Autophagocytosis Autophagosome Biology Calcium Calcium Channel Cardiac Cardiac Myocytes Cardiovascular Diseases Cells Data Development Embryo Endoplasmic Reticulum Event Extracellular Matrix Fibroblasts Fibrosis Functional disorder Genes Genetic Recombination Goals Heart Heart Diseases Heart failure Human Hypertrophy ITPR1 gene In Vitro Inflammation Inflammatory Inflammatory Response Inositol Investigation Lead Link Mammals Measures Mediating Mission Mitochondria Modeling Molecular Mus Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Myofibroblast Pathogenicity Pathway interactions Pharmacology Phenotype Play Protein Isoforms Public Health Regulation Role Signal Transduction Pathway Site Stimulus Techniques Testing Therapeutic Time United States United States National Institutes of Health Up-Regulation coronary fibrosis endoplasmic reticulum stress experimental study genome wide association study healing heart function human disease in vivo innovation ischemic injury knock-down loss of function mitochondrial dysfunction mortality mouse model novel receptor release of sequestered calcium ion into cytoplasm response tool

项目摘要

Cardiovascular disorders remain the first cause of mortality in US, with myocardial infarction (MI) and subsequent heart failure as the major sequela underlying such lethality. Recent studies have reinforced the concept that cardiac fibroblasts (FBs), which are less investigated than cardiomyocytes, are much more than simple regulators of extracellular matrix turnover; indeed, these cells (and their activated phenotype, myoFBs) seem to be key players in heart failure progression. Although relatively understudied, myocardial fibrosis remains one of the major pathophysiologic features of ischemic cardiac disorders. Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular calcium release channels located on the endoplasmic reticulum (ER), the main calcium reservoir within the cell. While the role of IP3Rs in cardiomyocytes has been previously investigated, especially in the context of hypertrophy and arrhythmias, their exact function in the activation of cardiac FBs following an ischemic insult has not been explored hitherto. Human and murine FBs express all three isoforms of IP3Rs and their activity and levels are modulated by several stimuli. We hypothesize that IP3Rs play a key role in the activation of cardiac FBs in the infarcted heart and in the present proposal we will test this hypothesis in vivo, ex vivo, and in vitro. We have preliminary data showing that IP3R expression (all isoforms) is increased in cardiac FBs following MI. Moreover, genome-wide association studies revealed a significant association between IP3- mediated signal transduction pathways and ischemic heart disease. However, definitive functional studies examining the mechanistic role of IP3Rs in cardiac fibrosis in vivo are missing. Using a Cre/lox recombination technique, we generated a novel mouse model (IP3RKO) in which IP3Rs are ablated in activated cardiac myoFBs. This model provides an exquisite tool to evaluate the functional contribution of IP3R to cardiac fibrosis and allows us to overcome the difficulties encountered following the knockdown or KO of a single IP3R gene. Our preliminary studies show that following MI, IP3RKO mice display a significantly reduced fibrosis and attenuated myocardial dysfunction compared with control IP3RCre and IP3Rflox littermates. We will further assess the functional relationships between IP3Rs and cardiac fibrosis in primary isolated cardiac FBs at different time points and in response to established stimuli, in order to assess their proliferative, migratory, secretory, and contractile capacity. Additionally, we will examine IP3R-mediated responses in murine embryonic FBs and human cardiac FBs. To delineate the molecular mechanisms underlying the observed phenotype, we propose to explore the following calcium-mediated pathways: mitochondrial dysfunction, autophagy, ER stress, and inflammation. The proposed studies are highly significant and innovative as they will: (a) provide the first assessment of the functional role of IP3R in post-MI cardiac FBs using a specific Cre/lox KO model; (b) delineate previously unrecognized connections between IP3R and autophagy in the pathophysiology of cardiac fibrosis; (c) identify innovative therapeutic strategies that specifically target excessive post-ischemic cardiac fibrosis.

在美国，心血管疾病仍然是导致死亡的首要原因，其次是心肌梗死（MI）及其他疾病