Metabolic modulation is a promising therapeutic approach to prevent adverse remodeling of the ischemic heart. Because little is known about the involvement of long non-coding RNAs (lncRNAs) in regulating cardiac metabolism, we used unbiased transcriptome profiling in a mouse model of myocardial infarction (MI). We identified a novel cardiomyocyte-enriched lncRNA, called LncHrt, which regulates metabolism and the pathophysiological processes that lead to heart failure. AAV-based LncHrt overexpression protects the heart from MI as demonstrated by improved contractile function, preserved metabolic homeostasis, and attenuated maladaptive remodeling responses. RNA-pull down followed by mass spectrometry and RNA immunoprecipitation (RIP) identified SIRT2 as a LncHrt-interacting protein involved in cardiac metabolic regulation. Mechanistically, we established that LncHrt interacts with SIRT2 to preserve SIRT2 deacetylase activity by interfering with the CDK5 and SIRT2 interaction. This increases downstream LKB1-AMPK kinase signaling, which ameliorates functional and metabolic deficits. Importantly, we found the expression of the human homolog of mouse LncHrt was decreased in patients with dilated cardiomyopathy. Together, these studies identify LncHrt as a cardiac metabolic regulator that plays an essential role in preserving heart function by regulating downstream metabolic signaling pathways. Consequently, LncHrt is a potentially novel RNA-based therapeutic target for ischemic heart disease.

代谢调节是预防缺血性心脏不良重塑的一种有前景的治疗方法。由于人们对长非编码 RNA (lncRNA) 在调节心脏代谢中的作用知之甚少，因此我们在心肌梗死 (MI) 小鼠模型中使用了无偏转录组分析。我们发现了一种新型的富含心肌细胞的lncRNA，称为LncHrt ，它调节新陈代谢和导致心力衰竭的病理生理过程。基于 AAV 的LncHrt过度表达可以保护心脏免受心肌梗死的影响，这通过改善收缩功能、保持代谢稳态和减弱适应不良重塑反应来证明。 RNA 下拉后进行质谱分析和 RNA 免疫沉淀 (RIP) 鉴定 SIRT2 是参与心脏代谢调节的LncHrt相互作用蛋白。从机制上讲，我们确定LncHrt与 SIRT2 相互作用，通过干扰 CDK5 和 SIRT2 相互作用来保留 SIRT2 脱乙酰酶活性。这增加了下游 LKB1-AMPK 激酶信号传导，从而改善功能和代谢缺陷。重要的是，我们发现扩张型心肌病患者中小鼠LncHrt的人类同源物表达降低。总之，这些研究确定LncHrt是一种心脏代谢调节剂，通过调节下游代谢信号通路在保护心脏功能方面发挥着重要作用。因此， LncHrt是一种潜在的新型基于 RNA 的缺血性心脏病治疗靶点。