Journal article
Gene Therapy With the N-Terminus of Junctophilin-2 Improves Heart Failure in Mice
Circulation research, Vol.130(9), pp.1306-1317
04/29/2022
DOI: 10.1161/CIRCRESAHA.121.320680
PMCID: PMC9050933
PMID: 35317607
Abstract
Transcriptional remodeling is known to contribute to heart failure (HF). Targeting stress-dependent gene expression mechanisms may represent a clinically relevant gene therapy option. We recently uncovered a salutary mechanism in the heart whereby JP2 (junctophilin-2), an essential component of the excitation-contraction coupling apparatus, is site-specifically cleaved and releases an N-terminal fragment (JP2NT [N-terminal fragment of JP2]) that translocates into the nucleus and functions as a transcriptional repressor of HF-related genes. This study aims to determine whether JP2NT can be leveraged by gene therapy techniques for attenuating HF progression in a preclinical pressure overload model.
We intraventricularly injected adeno-associated virus (AAV) (2/9) vectors expressing eGFP (enhanced green fluorescent protein), JP2NT, or DNA-binding deficient JP2NT (JP2NT
) into neonatal mice and induced cardiac stress by transaortic constriction (TAC) 9 weeks later. We also treated mice with established moderate HF from TAC stress with either AAV-JP2NT or AAV-eGFP. RNA-sequencing analysis was used to reveal changes in hypertrophic and HF-related gene transcription by JP2NT gene therapy after TAC. Echocardiography, confocal imaging, and histology were performed to evaluate heart function and pathological myocardial remodeling following stress.
Mice preinjected with AAV-JP2NT exhibited ameliorated cardiac remodeling following TAC. The JP2NT DNA-binding domain is required for cardioprotection as its deletion within the AAV-JP2NT vector prevented improvement in TAC-induced cardiac dysfunction. Functional and histological data suggest that JP2NT gene therapy after the onset of cardiac dysfunction is effective at slowing the progression of HF. RNA-sequencing analysis further revealed a broad reversal of hypertrophic and HF-related gene transcription by JP2NT overexpression after TAC.
Our prevention- and intervention-based approaches here demonstrated that AAV-mediated delivery of JP2NT into the myocardium can attenuate stress-induced transcriptional remodeling and the development of HF when administered either before or after cardiac stress initiation. Our data indicate that JP2NT gene therapy holds great potential as a novel therapeutic for treating hypertrophy and HF.
Details
- Title: Subtitle
- Gene Therapy With the N-Terminus of Junctophilin-2 Improves Heart Failure in Mice
- Creators
- Jinxi Wang - University of IowaQian Shi - University of IowaYihui Wang - University of IowaLogan W Dawson - University of IowaGrace Ciampa - University of IowaWeiyang Zhao - University of IowaGuangqin Zhang - University of IowaBiyi Chen - University of IowaRobert M Weiss - University of IowaChad E Grueter - University of IowaDuane D Hall - University of IowaLong-Sheng Song - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.130(9), pp.1306-1317
- DOI
- 10.1161/CIRCRESAHA.121.320680
- PMID
- 35317607
- PMCID
- PMC9050933
- NLM abbreviation
- Circ Res
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Grant note
- S10 OD019941 / NIH HHS R01 HL130346 / NHLBI NIH HHS I01 BX002334 / BLRD VA
- Language
- English
- Date published
- 04/29/2022
- Academic Unit
- Cardiovascular Medicine; Craniofacial Anomalies Research Center; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984293084002771
Metrics
7 Record Views