Lysine Acetyltransferase 6A in Health and Cardiac Diseases

项目摘要 病理性肥大可发展为心力衰竭。在过渡期间，脂肪酸利用率降低， 同时增加了其它底物如酮体的利用。多条证据表明， 增加的心肌酮体利用是对心脏病理的适应性反应。此外，委员会还认为， 虽然酮症酸中毒是危及生命的，但短期给予外源性酮体可增强 心肌耗氧量增加，酮体氧化和总ATP产生增加， 心脏这种干预改善了患有心力衰竭的人类和小鼠的心脏功能和重塑 （HF）.虽然酮体不仅作为燃料源，而且作为赖氨酸乙酰化的调节剂，但 酮体介导的乙酰化对肥大和HF的作用仍知之甚少。阐明 酮体作用的分子机制超出了燃料，介导抗肥大和促 能量效应而不引起有害效应，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（KAT 6A）在细胞内被乙酰化， 低碳水化合物（LC）饮食介导的酮体增加导致心脏病， 压力超负荷后心肌肥厚和心力衰竭。因此，我们在此询问KAT 6A的乙酰化是否是关键性的。 参与酮体对心脏病理的作用。我们的研究提供了证据， KAT 6A抑制苯肾上腺素诱导的心肌细胞肥大并改善心肌细胞的能量稳态 体外然而，KAT 6A乙酰化如何调节心脏形态和功能仍然是未知的。基于 基于这些令人兴奋的观察，我们提出了KAT 6A乙酰化在病理性肥大中的新作用， 过渡到HF。再加上我们利用蛋白质组学和基因组学研究的惊人发现， 分析，我们假设酮体促进KAT 6A的乙酰化，这刺激AMPK 心脏中的信号传导以抑制蛋白质合成并维持能量稳态，从而抑制 病理性肥大和向HF的转变。为了解决这个假设，我们将进行以下操作 实验在目的1中，我们将确定KAT 6A乙酰化在压力过载诱导的细胞凋亡中的意义。 通过使用新产生的KAT 6A乙酰化抗性敲入小鼠和AAV- KAT 6A乙酰化模拟突变体。在目标2中，我们将证明AMPK在KAT 6A中的关键参与 作用通过腺苷酸和遗传抑制AMPK。我们将进一步阐明 通过使用分子信号传导和生物测定，AMPK被KAT 6A激活。长期目标是 该项目旨在确定特异性调节酮体-KAT 6A-AMPK通路的治疗靶点 与心脏肥大和HF的一级和二级预防策略相关。

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.