Lysine Acetyltransferase 6A in Health and Cardiac Diseases

项目总结 病理性肥厚可发展为心力衰竭。在过渡过程中，脂肪酸的利用率会降低， 同时提高了对其他底物的利用，如酮体。多条证据表明 心肌酮体利用率增加是对心脏病理的适应性反应。此外， 尽管酮症酸中毒危及生命，但短期服用外源性酮体可增强 心肌耗氧量与酮体氧化和总三磷酸腺苷产量的增加 心脏。这种干预改善了人类和心力衰竭小鼠的心功能和重塑。 (Hf)。尽管酮体不仅是赖氨酸乙酰化的燃料来源，而且是赖氨酸乙酰化的调节剂。 酮体介导的乙酰化抗肥厚和心力衰竭仍然知之甚少。澄清 酮体作用于补给之外的分子机制，介导抗肥厚和促高血压。 在不引起不良影响的情况下，能量效应是建立酮体的最重要的问题 作为治疗心衰的一种选择。我们最近发现，赖氨酸乙酰转移酶6A(KAT6A)在 心脏由低碳水化合物(LC)饮食介导的酮体增加，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的乙酰化是否对 参与酮体对抗心脏病理的作用。我们的研究提供了证据，证明乙酰化 KAT6A抑制苯肾上腺素诱导的心肌细胞肥大及改善能量稳态 体外培养。然而，KAT6A乙酰化如何调节心脏的形态和功能仍不清楚。基座 在这些令人兴奋的观察中，我们提出了KAT6A乙酰化在病理性肥厚和 它向高频的过渡。再加上我们使用蛋白质组学和基因组学进行研究的令人惊讶的发现 分析，我们假设酮体促进KAT6A的乙酰化，从而刺激AMPK 心脏中抑制蛋白质合成和维持能量平衡的信号，从而抑制 病理性肥大和向心衰的过渡。为了解决这一假设，我们将进行以下操作 实验。在目标1中，我们将确定KAT6A乙酰化在压力超负荷诱导中的意义 利用新产生的KAT6A乙酰化抗性敲入小鼠和AAV-1在体内肥大和心衰 KAT6A乙酰化模拟突变体。在目标2中，我们将演示AMPK在KAT6A中的关键参与 通过药物和基因抑制AMPK的作用。我们将进一步阐明 AMPK是由KAT6A通过分子信号转导和生物检测来激活的。这样做的长期目标是 项目是确定特定调节酮体-KAT6A-AMPK通路的治疗靶点 与心肌肥厚和心力衰竭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.