Therapeutic Inhibition of <i>LincRNA-p21</i> Protects Against Cardiac Hypertrophy-Reference-Cited by-同舟云学术

Therapeutic Inhibition of LincRNA-p21 Protects Against Cardiac Hypertrophy

Published:2024-07-19 Issue:3 Volume:135 Page:434-449
ISSN:0009-7330
Container-title:Circulation Research
language:en
Short-container-title:Circulation Research

Author:

Wang Yi¹^ORCID,Zhang Mingming¹²^ORCID,Wang Rong¹³,Lin Jing¹^ORCID,Ma Qing⁴^ORCID,Guo Haipeng¹⁵,Huang Huihui⁶^ORCID,Liang Zhuomin¹⁷^ORCID,Cao Yangpo¹,Zhang Xiaoran¹^ORCID,Lu Yao Wei¹⁸^ORCID,Liu Jianming¹⁹,Xiao Feng¹^ORCID,Yan Hualin¹¹⁰^ORCID,Dimitrova Nadya¹¹^ORCID,Huang Zhan-Peng¹¹²^ORCID,Mably John D.¹³^ORCID,Pu William T.¹¹⁴^ORCID,Wang Da-Zhi¹¹³^ORCID

Affiliation:

1. 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.

2. Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi’an, China (M.Z.).

3. 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.).

4. School of Public Health, Xi’an Jiaotong University, China (J. Lin).

5. 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.).

6. Division of Nephrology, Beth Israel Deaconess Medical Center (H.H.), Harvard Medical School, Boston, MA.

7. Department of Cardiology (Z.L.), Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.

8. Vascular Biology Program, Boston Children’s Hospital (Y.W.L.), Harvard Medical School, Boston, MA.

9. Vertex Pharmaceuticals, Vertex Cell and Genetic Therapy, Boston, MA (J. Liu).

10. Department of Medical Ultrasound, Laboratory of Ultrasound Imaging Drug, West China Hospital, Sichuan University, Chengdu, China (H.Y.).

11. Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT (N.D.).

12. Department of Cardiology, Center for Translational Medicine (Z.-P.H.), Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.

13. Center for Regenerative Medicine and USF Health Heart Institute, Department of Internal Medicine, University of South Florida, Tampa (J.D.M., D.-Z.W.).

14. Harvard Stem Cell Institute, Harvard University, Cambridge, MA (W.T.P.).

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 (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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Reference29 articles.

1. Prognostic Implications of Echocardiographically Determined Left Ventricular Mass in the Framingham Heart Study

2. Cardiac Hypertrophy: The Good, the Bad, and the Ugly

3. Non-coding RNAs in cardiac regeneration: Mechanism of action and therapeutic potential

4. Deep RNA Sequencing Reveals Dynamic Regulation of Myocardial Noncoding RNAs in Failing Human Heart and Remodeling With Mechanical Circulatory Support

5. A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response

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