The long noncoding RNA Caren protects against heart failure via suppressing the Hint1-ATM signaling pathway

Long noncoding RNAs (lncRNAs) have potential as novel therapeutic targets in cardiac disease, but their function in heart failure (HF) is not yet fully understood. Using a gene trapping approach in mouse embryonic stem cells, we identified a novel cytoplasmic lncRNA, dubbed Caren (cardiomyocyte-enriched noncoding transcript), which was predominantly expressed in cardiomyocytes. Caren was markedly downregulated in the mouse failing heart that was subjected to transverse aortic constriction (TAC). The ablation of Caren in the mouse heart accelerated HF-related phenotypes by TAC, whereas mice overexpressing Caren (CAG-Caren Tg mice) resisted TAC-induced HF. Proteomic analysis identified histidine triad nucleotide-binding protein 1 (Hint1) as a Caren target protein, while bioinformatic analysis of proteome revealed that Caren regulates the proteins involved in mitochondrial energetics in the heart. Furthermore, we found that Caren suppressed Hint1 expression at the translational level and that Hint1 overexpression reduced mitochondrial respiration capacity. Similar to CAG-Caren Tg mice, the reduced Hint1 expression in mice exerted cardioprotective effects on TAC-induced HF, which was associated with the decreased level of ATM serine/threonine kinase phosphorylation, known to activate DNA damage responses. Overall, we identify a novel cytoplasmic lncRNA that protects against the development of HF through suppressing the Hint1-ATM signaling, which presumably maintains mitochondrial energetics and prevents the DNA damage under pathological stress.

长链非编码RNA（long noncoding RNAs，lncRNAs）作为心脏疾病的新型治疗靶点具有潜在应用价值，但其在心力衰竭（heart failure，HF）中的功能尚未完全阐明。本研究通过小鼠胚胎干细胞中的基因捕获技术，发现了一种新型胞质长链非编码RNA，将其命名为Caren（心肌富集非编码转录本，cardiomyocyte-enriched noncoding transcript），该转录本主要在心肌细胞中表达。在经主动脉弓缩窄（transverse aortic constriction，TAC）构建的小鼠心力衰竭模型中，Caren的表达显著下调。在小鼠心脏中敲除Caren会加速TAC诱导的心力衰竭相关表型，而过表达Caren的CAG-Caren转基因小鼠（CAG-Caren Tg mice）则可抵抗TAC诱导的心力衰竭。蛋白质组学分析鉴定出组氨酸三联体核苷酸结合蛋白1（histidine triad nucleotide-binding protein 1，Hint1）为Caren的靶蛋白；同时蛋白质组生物信息学分析显示，Caren可调控心脏中参与线粒体能量代谢的蛋白质。进一步研究发现，Caren在翻译水平抑制Hint1的表达，而Hint1过表达会降低线粒体呼吸能力。与CAG-Caren转基因小鼠表型一致，小鼠体内Hint1表达下调可对TAC诱导的心力衰竭产生心脏保护作用，该作用与已知可激活DNA损伤应答（DNA damage responses）的ATM丝氨酸/苏氨酸激酶（ATM serine/threonine kinase）磷酸化水平降低相关。综上，本研究发现了一种新型胞质长链非编码RNA，其通过抑制Hint1-ATM信号通路发挥抗心力衰竭的保护作用，推测该通路可在病理应激状态下维持线粒体能量代谢并预防DNA损伤。