Lysine Acetyltransferase 6A in Health and Cardiac Diseases

赖氨酸乙酰转移酶 6A 在健康和心脏病中的作用

基本信息

批准号：
10442359
负责人：
Michinari Nakamura
金额：
$ 39.25万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10442359
关键词：
Acetylation Acetyltransferase Address Anabolism Attenuated Binding Biological Assay Biological Process Calories Carbohydrates Cardiac Cardiac Myocytes Cell Nucleus Clinical Diet Dietary Component Epigenetic Process Fasting Fatty Acids Future Gene Delivery Genomics Glucose Goals Health Heart Heart Diseases Heart Hypertrophy Heart failure Histones Homeostasis Human Hydroxybutyrates Hypertrophy In Vitro Intake Intervention Ketone Bodies Knock-in Mouse Life Ligation Lysine Mammals Mediating Molecular Molecular Conformation Morphology Mus Myocardial Nutrient Oral Ingestion Oxygen Consumption Pathologic Pathology Pathway interactions Patients Pharmacologic Actions Pharmacology Phenylephrine Phosphorylation Post-Translational Protein Processing Primary Prevention Production Protein Biosynthesis Proteomics Regulation Resistance Role Secondary Prevention Signal Transduction Source System Testing Therapeutic Up-Regulation base cardioprotection deprivation experimental study heart function improved in vivo mTOR inhibition mutant novel novel therapeutic intervention oxidation pressure protein protein interaction response therapeutic target treatment strategy

项目摘要

PROJECT SUMMARY Pathological hypertrophy can progress to failing heart. During the transition, fatty acid utilization is decreased, while utilization of other substrates, such as ketone body, is increased. Multiple lines of evidence indicate that increased myocardial ketone body utilization is an adaptive response against cardiac pathology. Furthermore, although ketoacidosis is life-threatening, short-term administration of exogenous ketone body enhances myocardial oxygen consumption with increases in both ketone body oxidation and overall ATP production in the heart. This intervention improves cardiac function and remodeling in humans and mice with heart failure (HF). Although ketone body serves as not only a fuel source but a modulator of lysine acetylation, the effect of ketone body-mediated acetylation against hypertrophy and HF remains poorly understood. Elucidating the molecular mechanisms of ketone body action beyond fueling, which mediates anti-hypertrophic and pro- energetic effects without provoking detrimental effects, is the most important issue in establishing ketone body as a therapeutic option for HF. We recently found that lysine acetyltransferase 6A (KAT6A) is acetylated in the heart by a low-carbohydrate (LC) diet-mediated increase in ketone body, which is negatively associated with hypertrophy and HF after pressure overload. Thus, we here ask whether acetylation of KAT6A is critically involved in ketone body action against cardiac pathology. Our study provided evidence that acetylation of KAT6A inhibits phenylephrine-induced hypertrophy and improves energy homeostasis in cardiomyocytes in vitro. However, it remains unknown how KAT6A acetylation regulates cardiac morphology and function. Based on these exciting observations we propose a novel role of KAT6A acetylation in pathological hypertrophy and its transition to HF. Together with the surprising findings from our studies using proteomics and genomics analyses, we hypothesize that ketone body promotes acetylation of KAT6A, which stimulates the AMPK signaling in the heart to suppress protein synthesis and maintain energy homeostasis, thereby inhibiting pathological hypertrophy and a transition to HF. To address this hypothesis, we will conduct the following experiments. In Aim 1, we will determine the significance of KAT6A acetylation in pressure overload-induced hypertrophy and HF in vivo by using newly generated KAT6A acetylation-resistant knock-in mice and an AAV- KAT6A acetylation-mimicking mutant. In Aim 2, we will demonstrate the critical involvement of AMPK in KAT6A action by pharmacologically and genetically inhibiting AMPK. We will further elucidate the mechanism by which AMPK is activated by KAT6A by using molecular signaling and biological assays. The long-term goal of this project is to identify the therapeutic targets to specifically modulate the ketone body-KAT6A-AMPK pathway relevant to the strategies for the primary and secondary prevention of cardiac hypertrophy and HF.

项目概要病理性肥大可进展为心脏衰竭。在转变过程中，脂肪酸的利用率降低，同时增加了其他底物（例如酮体）的利用率。多项证据表明心肌酮体利用率增加是针对心脏病理学的适应性反应。此外，虽然酮症酸中毒危及生命，但短期给予外源性酮体可增强心肌耗氧量随着酮体氧化和总 ATP 产生的增加而增加心脏。这种干预措施可改善患有心力衰竭的人类和小鼠的心脏功能和重塑（高频）。虽然酮体不仅是一种燃料来源，而且是赖氨酸乙酰化的调节剂，但酮体的作用酮体介导的乙酰化对抗肥大和心力衰竭的作用仍然知之甚少。阐明酮体作用的分子机制超越燃料，介导抗肥厚和促在不引起有害影响的情况下产生能量效应，是建立酮体的最重要问题作为 HF 的治疗选择。我们最近发现赖氨酸乙酰转移酶 6A (KAT6A) 在低碳水化合物（LC）饮食介导的酮体增加对心脏有影响，这与压力超负荷后出现肥厚和心力衰竭。因此，我们在这里询问 KAT6A 的乙酰化是否至关重要参与酮体对抗心脏病的作用。我们的研究提供了乙酰化的证据 KAT6A 抑制去氧肾上腺素诱导的肥大并改善心肌细胞的能量稳态体外。然而，KAT6A 乙酰化如何调节心脏形态和功能仍不清楚。基于基于这些令人兴奋的观察结果，我们提出了 KAT6A 乙酰化在病理性肥大中的新作用，向高频的过渡。以及我们使用蛋白质组学和基因组学进行的研究的令人惊讶的发现通过分析，我们假设酮体促进 KAT6A 的乙酰化，从而刺激 AMPK 心脏信号传导抑制蛋白质合成并维持能量稳态，从而抑制病理性肥大并转变为心力衰竭。为了解决这个假设，我们将进行以下操作实验。在目标 1 中，我们将确定 KAT6A 乙酰化在压力过载引起的中的重要性通过使用新生成的 KAT6A 乙酰化抗性敲入小鼠和 AAV- 体内肥大和心力衰竭 KAT6A 乙酰化模拟突变体。在目标 2 中，我们将展示 AMPK 在 KAT6A 中的关键参与通过药理学和基因抑制 AMPK 发挥作用。我们将进一步阐明其机制 AMPK 通过分子信号传导和生物测定被 KAT6A 激活。本次活动的长远目标该项目旨在确定特异性调节酮体-KAT6A-AMPK通路的治疗靶点与心脏肥大和心力衰竭的一级和二级预防策略相关。