Wang Yi, Zhang Mingming, Wang Rong, Lin Jing, Ma Qing, Guo Haipeng, Huang Huihui, Liang Zhuomin, Cao Yangpo, Zhang Xiaoran, Lu Yao Wei, Liu Jianming, Xiao Feng, Yan Hualin, Dimitrova Nadya, Huang Zhan-Peng, Mably John D, Pu William T, Wang Da-Zhi
Department of Cardiology, Boston Children's Hospital (Y.W., M.Z., R.W., J. Lin, Q.M., H.G., Z.L., Y.C., X.Z., Y.W.L., J. Liu, F.X., H.Y., Z.-P.H., W.T.P., D.-Z.W.), Harvard Medical School, Boston, MA.
Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China (M.Z.).
Circ Res. 2024 Jul 19;135(3):434-449. doi: 10.1161/CIRCRESAHA.123.323356. Epub 2024 Jun 12.
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.
We measured RNA and H3K27ac levels in the hearts of dilated cardiomyopathy patients. We assessed the functional role of 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 inhibition in cardiac hypertrophy and associated heart failure.
was induced in mice and humans with cardiomyopathy. Global and cardiac-specific 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 acts 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). 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 .
These findings advance our understanding of the functional significance of stress-induced long noncoding RNA in cardiac hypertrophy and demonstrate the potential of as a novel therapeutic target for cardiac hypertrophy and subsequent heart failure.
心脏肥大是对压力超负荷的一种适应性反应，旨在维持心脏功能。然而，长期肥大显著增加了适应性不良的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，但其作用的意义和机制尚未完全了解。
我们测量了扩张型心肌病患者心脏中的RNA和H3K27ac水平。我们使用功能丧失小鼠评估了在基础和手术压力超负荷条件下的功能作用。全基因组转录组分析揭示了失调的基因和通路。我们使用基于新型BioID2系统标记与全长lincRNA-p21邻近的蛋白质。我们免疫沉淀与lincRNA-p21相互作用的蛋白质，并进行细胞分级分离、ChIP-seq（染色质免疫沉淀测序）和共免疫沉淀，以研究分子相互作用和潜在机制。我们使用GapmeR反义寡核苷酸评估抑制在心脏肥大和相关心力衰竭中的治疗潜力。
在患有心肌病的小鼠和人类中被诱导产生。整体和心脏特异性基因敲除显著抑制压力超负荷诱导的心室壁增厚、应激标志物升高以及心脏功能恶化。全基因组转录组分析和转录网络分析表明，通过刺激NFAT/MEF2（活化T细胞核因子/心肌细胞增强因子2）通路发挥作用。从机制上讲，lincRNA-p21与支架蛋白KAP1（KRAB相关蛋白1）结合。心脏特异性基因敲除抑制了应激诱导的KAP1核积累，而KAP1敲低减弱了心脏肥大和NFAT激活。KAP1通过与NFATC4物理相互作用促进NFAT/MEF2信号过度激活状态，从而正向调节病理性肥大。lincRNA-p21的GapmeR反义寡核苷酸缺失同样抑制了心脏肥大和不良重塑，突出了抑制的治疗潜力。
这些发现增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，并证明了作为心脏肥大及后续心力衰竭的新型治疗靶点的潜力。
