BACKGROUND Cardiac hypertrophy is an adaptive response to pressure overload aimed at maintaining cardiac function. However, prolonged hypertrophy significantly increases the risk of maladaptive cardiac remodeling and heart failure. Recent studies have implicated long noncoding RNAs in cardiac hypertrophy and cardiomyopathy, but their significance and mechanism(s) of action are not well understood. METHODS We measured lincRNA-p21 RNA and H3K27ac levels in the hearts of dilated cardiomyopathy patients. We assessed the functional role of lincRNA-p21 in basal and surgical pressure-overload conditions using loss-of-function mice. Genome-wide transcriptome analysis revealed dysregulated genes and pathways. We labeled proteins in proximity to full-length lincRNA-p21 using a novel BioID2-based system. We immunoprecipitated lincRNA-p21-interacting proteins and performed cell fractionation, ChIP-seq (chromatin immunoprecipitation followed by sequencing), and co-immunoprecipitation to investigate molecular interactions and underlying mechanisms. We used GapmeR antisense oligonucleotides to evaluate the therapeutic potential of lincRNA-p21 inhibition in cardiac hypertrophy and associated heart failure. RESULTS lincRNA-p21 was induced in mice and humans with cardiomyopathy. Global and cardiac-specific lincRNA-p21 knockout significantly suppressed pressure overload-induced ventricular wall thickening, stress marker elevation, and deterioration of cardiac function. Genome-wide transcriptome analysis and transcriptional network analysis revealed that lincRNA-p21 acts in trans to stimulate the NFAT/MEF2 (nuclear factor of activated T cells/myocyte enhancer factor-2) pathway. Mechanistically, lincRNA-p21 is bound to the scaffold protein KAP1 (KRAB-associated protein-1). lincRNA-p21 cardiac-specific knockout suppressed stress-induced nuclear accumulation of KAP1, and KAP1 knockdown attenuated cardiac hypertrophy and NFAT activation. KAP1 positively regulates pathological hypertrophy by physically interacting with NFATC4 to promote the overactive status of NFAT/MEF2 signaling. GapmeR antisense oligonucleotide depletion of lincRNA-p21 similarly inhibited cardiac hypertrophy and adverse remodeling, highlighting the therapeutic potential of inhibiting lincRNA-p21. CONCLUSIONS These findings advance our understanding of the functional significance of stress-induced long noncoding RNA in cardiac hypertrophy and demonstrate the potential of lincRNA-p21 as a novel therapeutic target for cardiac hypertrophy and subsequent heart failure.

中文翻译：

---

LincRNA-p21 的治疗性抑制可防止心脏肥大。


背景 心脏肥大是对压力超负荷的适应性反应，旨在维持心脏功能。然而，长期肥大会显著增加适应不良心脏重塑和心力衰竭的风险。最近的研究表明长链非编码 RNA 与心脏肥大和心肌病有关，但它们的意义和作用机制尚不清楚。方法 我们测量了扩张型心肌病患者心脏中的 lincRNA-p21 RNA 和 H3K27ac 水平。我们使用功能丧失小鼠评估了 lincRNA-p21 在基础和手术压力过载情况下的功能作用。全基因组转录组分析揭示了失调的基因和通路。我们使用基于 BioID2 的新型系统标记了全长 lincRNA-p21 附近的蛋白质。我们免疫沉淀了 lincRNA-p21 相互作用蛋白并进行了细胞分级分离、ChIP-seq （染色质免疫沉淀后测序）和免疫共沉淀，以研究分子相互作用和潜在机制。我们使用 GapmeR 反义寡核苷酸来评估 lincRNA-p21 抑制在心脏肥大和相关心力衰竭中的治疗潜力。结果 lincRNA-p21 在患有心肌病的小鼠和人中被诱导。整体和心脏特异性 lincRNA-p21 敲除显着抑制压力超负荷诱导的心室壁增厚、应力标志物升高和心脏功能恶化。全基因组转录组分析和转录网络分析显示，lincRNA-p21 反式作用刺激 NFAT/MEF2 （活化 T 细胞核因子/肌细胞增强因子-2） 通路。从机制上讲，lincRNA-p21 与支架蛋白 KAP1 （KRAB 相关蛋白-1） 结合。 lincRNA-p21 心脏特异性敲除抑制应激诱导的 KAP1 核积累，KAP1 敲除减轻心脏肥大和 NFAT 激活。KAP1 通过与 NFATC4 的物理相互作用促进 NFAT/MEF2 信号转导的过度活跃状态，从而正向调节病理性肥大。lincRNA-p21 的 GapmeR 反义寡核苷酸耗竭同样抑制了心脏肥大和不良重塑，突出了抑制 lincRNA-p21 的治疗潜力。结论 这些发现促进了我们对应激诱导的长链非编码 RNA 在心脏肥大中的功能意义的理解，并证明了 lincRNA-p21 作为心脏肥大和后续心力衰竭的新型治疗靶点的潜力。