Therapeutic Inhibition of <i>LincRNA-p21</i> Protects Against Cardiac Hypertrophy.

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

Therapeutic Inhibition of LincRNA-p21 Protects Against Cardiac Hypertrophy.

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.

Afiliación

Wang Y; Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA. (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.).
Zhang M; Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA. (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.).
Wang R; Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China (M.Z.).
Lin J; Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA. (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.).
Ma Q; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China (R.W.).
Guo H; Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA. (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.).
Huang H; School of Public Health, Xi'an Jiaotong University, China (J. Lin).
Liang Z; Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA. (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.).
Cao Y; Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA. (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.).
Zhang X; Department of Critical Care and Emergency Medicine, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China (H.G.).
Lu YW; Division of Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. (H.H.).
Liu J; Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA. (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.).
Xiao F; Department of Cardiology, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China. (Z.L.).
Yan H; Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA. (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.).
Dimitrova N; Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA. (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.).
Huang ZP; Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA. (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.).
Mably JD; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA. (Y.W.L.).
Pu WT; Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA. (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.).
Wang DZ; Vertex Pharmaceuticals, Vertex Cell and Genetic Therapy, Boston, MA (J. Liu).

Circ Res ; 2024 Jun 12.

Article en En | MEDLINE | ID: mdl-38864216

ABSTRACT

ABSTRACT

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 pathway. Mechanistically, lincRNA-p21 is bound to the scaffold protein KAP1. 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.

Palabras clave

RNA, long noncoding; gene expression profiling; heart failure; hypertrophy; ventricular remodeling

Texto completo

Imprimir

XML

PubMed Links

Buscar en Google