{"doi":"10.1161/circresaha.121.320680","title":"Gene Therapy With the N-Terminus of Junctophilin-2 Improves Heart Failure in Mice","abstract":"Background: 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. Methods: We intraventricularly injected adeno-associated virus (AAV) (2/9) vectors expressing eGFP (enhanced green fluorescent protein), JP2NT, or DNA-binding deficient JP2NT (JP2NT ΔbNLS/ARR ) 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. Results: 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. Conclusions: 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.","journal":"Circulation Research","year":2022,"id":248875,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9622,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":329343,"name":"Qian Shi","orcid":"0000-0003-2634-9553","position":1,"is_corresponding":false},{"id":888476,"name":"Yihui Wang","orcid":"0000-0002-7348-5841","position":2,"is_corresponding":false},{"id":513624,"name":"Logan W. Dawson","orcid":"0000-0003-0777-8336","position":3,"is_corresponding":false},{"id":888477,"name":"Grace Ciampa","orcid":"0000-0001-5418-996X","position":4,"is_corresponding":false},{"id":888478,"name":"Weiyang Zhao","orcid":"0000-0001-5707-376X","position":5,"is_corresponding":false},{"id":888479,"name":"Guangqin Zhang","orcid":"0000-0002-0282-3807","position":6,"is_corresponding":false},{"id":300424,"name":"Biyi Chen","orcid":null,"position":7,"is_corresponding":false},{"id":261896,"name":"Robert M. Weiss","orcid":"0000-0003-1307-2647","position":8,"is_corresponding":false},{"id":301601,"name":"Chad E. Grueter","orcid":"0000-0001-8950-742X","position":9,"is_corresponding":false},{"id":397860,"name":"Duane D. Hall","orcid":"0000-0003-2228-0966","position":10,"is_corresponding":false},{"id":299279,"name":"Long‐Sheng Song","orcid":"0000-0002-6035-8106","position":11,"is_corresponding":false},{"id":579496,"name":"Jinxi Wang","orcid":"0000-0002-7349-6153","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T00:24:14.794521Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}