Therapeutic Inhibition of LincRNA-p21 Protects Against Cardiac Hypertrophy

作者：Yi Wang, Mingming Zhang, Rong Wang, Jing Lin, Qing Ma, Haipeng Guo, Huihui Huang, Zhuomin Liang, Yangpo Cao, Xiaoran Zhang, Yao Wei Lu, Jianming Liu, Feng Xiao, Hualin Yan, Nadya Dimitrova, Zhan‐Peng Huang, John D. Mably, William T. Pu, Da‐Zhi Wang · 发表于：Circulation Research · 年份：2024 · DOI：10.1161/circresaha.123.323356 · 被引用次数：15 · 研究领域：Cancer-related molecular mechanisms research、Signaling Pathways in Disease、Cardiac Valve Diseases and Treatments

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 transcript...