Genes and Metabolism: Targeting Mitochondrial Dysfunction in Atrial Fibrillation

项目2总结 各种心血管应激源会增加房颤(AF)的风险，包括肥胖、高血压、 冠状动脉或瓣膜疾病、心力衰竭、代谢综合征、睡眠呼吸暂停、过量饮酒和极端 体力消耗。房颤是一种进行性疾病，中风和其他并发症的风险随着房颤的增加而增加 负担。确定可以减缓或逆转房颤进展的药物或干预措施将具有 对临床有重大影响。在RNA测序研究中，我们发现线粒体功能障碍和 氧化磷酸化途径是与血管生成相关的最突出的途径之一 持续性房颤。项目2，基因和新陈代谢：针对心房颤动的线粒体功能障碍 (P2)，我们的中心假设是代谢应激源和衰老增加了线粒体氧化剂的产生， 促进心房线粒体DNA损伤、功能障碍和代谢异质性。我们假设 代谢的异质性是电学不稳定性的基础，而促进线粒体的干预 复原力和有限的代谢异质性将减少心房异位并减缓房颤进展。我们建议两个 明确的目标。目的1评价代谢应激源在工程心脏体外模型中的作用 人诱导多能干细胞分化的心房样心肌细胞来源的组织 细胞。我们将研究4种不同的代谢应激源对转录和功能的影响 房颤的病因对人心房EHT细胞组成及线粒体、收缩和电功能的影响 EHTS。应激源包括：长期接触异丙肾上腺素、棕榈酸酯、乙醇和内皮素-1；相同 应激源将用于测试代谢/线粒体靶向药物在EHTS中的保护作用。在目标2中， 我们将评估在杂合子CREM-IbCx中导致房颤进展的代谢机制 转基因小鼠的自发性房颤和房颤进展，采用高脂饮食作为代谢 我们可以用来研究肥胖对发育和转录的影响的压力 房颤的进展速度。我们假设在这个模型中房颤的进展也是由线粒体引起的 功能障碍，导致代谢、转录和电生理功能障碍。因此，我们建议 肥胖的小鼠将比瘦的转基因小鼠更快、更早地发生房颤，并且负担更重。 最后，使用肥胖的转基因小鼠，我们将评估保护EHTS的药物的影响。 线粒体功能障碍和下游效应，以确定这些药物是否可以减缓发育和 房颤的进展。我们预计心房高血压和肥胖的CREM-IbCx小鼠模型都将对 新的和现有的代谢性药物的临床前测试，可以改善房颤的治疗并减缓其进展。 该项目与其他PPG项目高度协作，将有助于实现本项目的总体目标 PPG用于推进可以减缓房颤进展和减轻其负担的治疗。

PROJECT 2 SUMMARY Atrial fibrillation (AF) risk is increased by a variety of cardiovascular stressors, including obesity, hypertension, coronary or valve disease, heart failure, metabolic syndrome, sleep apnea, excessive alcohol, and extreme exertion. AF is a progressive condition, and risk of stroke and other complications increases with increasing AF burden. Identification of drugs or interventions that can slow or reverse the progression of AF would have a significant clinical impact. In RNA sequencing studies, we have identified mitochondrial dysfunction and oxidative phosphorylation pathways among the most prominent pathways associated with development of persistent AF. In Project 2, Genes and Metabolism: Targeting Mitochondrial Dysfunction in Atrial Fibrillation (P2), our central hypothesis is that metabolic stressors and aging increase mitochondrial oxidant production, promoting atrial mitochondrial DNA damage, dysfunction and metabolic heterogeneity. We hypothesize that metabolic heterogeneity underlies electrical instability, and that interventions that promote mitochondrial resilience and limit metabolic heterogeneity will reduce atrial ectopy and slow AF progression. We propose two specific aims. Aim 1 seeks to evaluate the role of metabolic stressors on an in vitro model of engineered heart tissues (EHTs), derived from atrial-like cardiac myocytes differentiated from human induced pluripotent stem cells. We will study the transcriptional and functional impact of 4 distinct metabolic stressors relevant to the etiology of AF on EHT cellular composition and mitochondrial, contractile and electrical function of human atrial EHTs. Stressors include: chronic exposure to isoproterenol, palmitate, ethanol and endothelin-1; the same stressors will be used to test the protective effect of metabolic/mitochondrial targeted drugs in EHTs. In Aim 2, we will evaluate the metabolic mechanisms that underlie progression of AF in the heterozygous CREM-IbCX transgenic mouse model of spontaneous AF and AF progression, employing a high fat diet as a metabolic stress with which we can study the functional and transcriptomic impact of obesity on the development and rate of progression of AF. We hypothesize that progression of AF in this model is also caused by mitochondrial dysfunction, resulting in metabolic, transcriptional and electrophysiologic dysfunction. We thus propose that obese mice will develop AF more quickly, earlier, and with a greater burden than in lean transgenic mice. Finally, using obese transgenic mice, we will evaluate the impact of drugs that protected EHTs from mitochondrial dysfunction and downstream effects, to determine if these drugs can slow the development and progression of AF. We expect both the atrial EHT and obese CREM-IbCX mouse models will be useful for preclinical testing of new and existing metabolic drugs that can improve AF treatment and slow its progression. This project is highly collaborative with the other PPG projects, and will contribute to the overall goal of this PPG to advance therapies that can slow the progression and reduce the burden of atrial fibrillation.