漆树酸通过调控组蛋白乙酰化修饰从而预防和改善心肌肥厚的机理

Cardiac hypertrophy is a critical medical complication of many cardiovascular diseases, and may eventually lead to heart failure and sudden cardiac death. Currently there no effective treatment is available for cardiac hypertrophy. Therefore, it is important to find effective drugs that can be used to reverse cardiac hypertrophy to prevent heart failure and sudden cardiac death. Growing evidence indicates that epigenetic modification involves in the occurrence and development of cardiac hypertrophy. In our previous studies, we found that anacardic acid, a histone acetylase inhibitor could attenuate cardiac hypertrophy. In this proposal, we will continue and extend our previous work to investigate the mechanisms of anacardic acid in the prevention and treatment of cardiac hypertrophy. We hypothesize that anacardic acid can attenuate cardiac hypertrophy by inhibiting the activation of transcription factors induced by histone acetylases. To test our hypothesis, we will establish animal models of cardiac hypertrophy including ligation of thoracic aorta and injection of epinephrine. Using these models, first we will study the relationship between histone modification and cardiac hypertrophy. Then we will investigate the roles of anacardic acid on the prevention and treatment of cardiac hypertrophy and explore the mechanisms underlying these roles. Finally, we will culture neonatal mouse cardiac myocytes to investigate how anacardic acid relates upstream signaling pathways in the attenuation of cardiac hypertrophy. The informtion from this study will greatly advance our understanding of the epigenetic mechanisms that contribute to the cardiac hypertrophy. This animal work is a necessary prerequisite to the design of a clinical trial of anacardic acid as a candidate drug for the prevention and treatment of cardiac hypertrophy.

心肌肥厚是多种心脏疾患的并发症，最终可导致心衰和心源性猝死，目前尚无有效治疗手段。因此，寻找抑制和逆转心肌肥厚的有效药物是预防心衰和心源性猝死的关键措施。表观遗传修饰是介导心肌肥厚发生、发展的重要调控因素之一。我们前期研究发现组蛋白乙酰化酶抑制剂漆树酸具有改善心肌肥厚的作用，但具体调控机制仍不清楚。因此，在本项目中我们将以表观遗传学为切入点来证实“漆树酸通过抑制组蛋白乙酰化酶介导的转录活化从而预防和改善心肌肥厚”的科研假说。我们将通过构建不同病因的小鼠心肌肥厚模型，来明确组蛋白乙酰化修饰失衡与心肌肥厚之间的关系；并通过外源性给予漆树酸干预心肌肥厚模型小鼠体内组蛋白乙酰化修饰状态，来探讨漆树酸对心肌肥厚的防治作用及具体调控机制；同时将在体外对培养的乳鼠心肌细胞进行干预实验，来探讨漆树酸改善心肌肥厚的上游信号通路。通过本研究，有望从表观遗传的全新角度为心肌肥厚的防治提供新的干预靶点和候选药物。

本项目旨在研究组蛋白乙酰化酶抑制剂漆树酸对心肌肥厚的保护作用及机制。本研究在不同病因所致小鼠心肌肥厚模型研究中发现：通过苯肾上腺素和部分结扎胸主动脉成功构建小鼠心肌肥厚模型，并发现组蛋白乙酰化修饰失衡参与了心脏发育核心转录因子MEF2A、MEF2C及GATA4及心肌肥厚相关标志物ANP、BNP及β-MHC的过表达，而组蛋白乙酰化酶抑制剂漆树酸能够通过抑制p300及PCAF介导的组蛋白H3K9ac高乙酰化来调控心肌肥厚相关基因的表达水平进而改善苯肾上腺素和压力过载诱导的小鼠心肌肥厚。进一步研究发现，MAPKs信号通路中的p-JNK、p-ERK及p-P38在漆树酸改善小鼠心肌肥厚中具有重要的调控作用。该研究充分证实了组蛋白乙酰化酶P300和PCAF以及MAPKs（P38、ERK、JNK）信号通路是防控心肌肥厚的两个关键节点。这一研究成果将为治疗心肌肥厚提供新的理论基础和研究思路，具有十分重要的临床意义和广泛的应用前景。项目资助发表SCI论文4篇，国内期刊论文5篇，获得实用新型专利1项，荣获贵州省创新型“千”层次人才，荣获中组部“西部之光”访问学者，培养硕士研究生4名。