{"doi":"10.1161/jaha.122.027004","title":"SENP1 Protects Against Pressure Overload‐Induced Cardiac Remodeling and Dysfunction Via Inhibiting STAT3 Signaling","abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background</jats:title>\n            <jats:p xml:lang=\"en\">SENP1 (sentrin/small ubiquitin‐like modifier‐specific protease 1) has emerged as a significant modulator involved in the pathogenesis of a variety of human diseases, especially cancer. However, the regulatory roles of SENP1 in cardiovascular biology and diseases remain controversial. Our current study aims to clarify the function and regulation of SENP1 in pressure overload‐induced cardiac remodeling and dysfunction.</jats:p>\n          </jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results</jats:title>\n            <jats:p xml:lang=\"en\">We used a preclinical mouse model of transverse aortic constriction coupled with in vitro studies in neonatal rat cardiomyocytes to study the role of SENP1 in cardiac hypertrophy. Gene delivery system was used to knockdown or overexpress SENP1 in vivo. Here, we observed that SENP1 expression was significantly augmented in murine hearts following transverse aortic constriction as well as neonatal rat cardiomyocytes treated with phenylephrine or angiotensin II. Cardiac‐specific SENP1 knockdown markedly exacerbated transverse aortic constriction‐induced cardiac hypertrophy, systolic dysfunction, fibrotic response, and cellular apoptosis. In contrast, adenovirus‐mediated SENP1 overexpression in murine myocardium significantly attenuated cardiac remodeling and dysfunction following chronic pressure overload. Mechanistically, JAK2 (Janus kinase 2) and STAT3 (signal transducer and activator of transcription 3) acted as new interacting partners of SENP1 in this process. SENP1‐JAK2/STAT3 interaction suppressed STAT3 nuclear translocation and activation, ultimately inhibiting the transcription of prohypertrophic genes and the initiation of hypertrophic response. Furthermore, cardiomyocyte‐specific STAT3 knockout mice were generated to validate the underlying mechanisms, and the results showed that STAT3 ablation blunted the cardiac hypertrophy‐promoting effects of SENP1 deficiency. Additionally, pharmacological inhibition of SENP1 by Momordin Ic amplified cardiac remodeling post‐transverse aortic constriction.</jats:p>\n          </jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions</jats:title>\n            <jats:p xml:lang=\"en\">Our study provided evidence that SENP1 protected against pressure overload‐induced cardiac remodeling and dysfunction via inhibiting STAT3 signaling. SENP1 supplementation might constitute a new promising treatment against cardiac hypertrophy. Notably, cardiovascular side effects should be seriously considered while applying systemic SENP1 blockers to suppress tumors.</jats:p>\n          </jats:sec>","journal":"Journal of the American Heart Association","year":2022,"id":654682,"datarank":0.49983067652628066,"base_score":3.332204510175204,"endowment":3.332204510175204,"self_citation_contribution":0.49983067652628066,"citation_network_contribution":0.0,"self_endowment_contribution":0.49983067652628066,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":435824,"name":"Di Fan","orcid":"0000-0002-7223-0345","position":1,"is_corresponding":false},{"id":1468018,"name":"Zhen Guo","orcid":"0000-0003-4022-7755","position":2,"is_corresponding":false},{"id":1708660,"name":"Fang‐Yuan Liu","orcid":null,"position":3,"is_corresponding":false},{"id":1562913,"name":"Ming‐Yu Wang","orcid":null,"position":4,"is_corresponding":false},{"id":977510,"name":"Peng An","orcid":"0000-0002-2313-5181","position":5,"is_corresponding":false},{"id":1250936,"name":"Zheng Yang","orcid":"0000-0002-7081-6588","position":6,"is_corresponding":false},{"id":435827,"name":"Qizhu Tang","orcid":"0000-0003-2210-3169","position":7,"is_corresponding":false},{"id":531567,"name":"Dan Yang","orcid":"0000-0001-5959-1202","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"SENP1 Protects Against Pressure Overload‐Induced Cardiac Remodeling and Dysfunction Via Inhibiting STAT3 Signaling","abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background</jats:title>\n            <jats:p xml:lang=\"en\">SENP1 (sentrin/small ubiquitin‐like modifier‐specific protease 1) has emerged as a significant modulator involved in the pathogenesis of a variety of human diseases, especially cancer. However, the regulatory roles of SENP1 in cardiovascular biology and diseases remain controversial. Our current study aims to clarify the function and regulation of SENP1 in pressure overload‐induced cardiac remodeling and dysfunction.</jats:p>\n          </jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results</jats:title>\n            <jats:p xml:lang=\"en\">We used a preclinical mouse model of transverse aortic constriction coupled with in vitro studies in neonatal rat cardiomyocytes to study the role of SENP1 in cardiac hypertrophy. Gene delivery system was used to knockdown or overexpress SENP1 in vivo. Here, we observed that SENP1 expression was significantly augmented in murine hearts following transverse aortic constriction as well as neonatal rat cardiomyocytes treated with phenylephrine or angiotensin II. Cardiac‐specific SENP1 knockdown markedly exacerbated transverse aortic constriction‐induced cardiac hypertrophy, systolic dysfunction, fibrotic response, and cellular apoptosis. In contrast, adenovirus‐mediated SENP1 overexpression in murine myocardium significantly attenuated cardiac remodeling and dysfunction following chronic pressure overload. Mechanistically, JAK2 (Janus kinase 2) and STAT3 (signal transducer and activator of transcription 3) acted as new interacting partners of SENP1 in this process. SENP1‐JAK2/STAT3 interaction suppressed STAT3 nuclear translocation and activation, ultimately inhibiting the transcription of prohypertrophic genes and the initiation of hypertrophic response. Furthermore, cardiomyocyte‐specific STAT3 knockout mice were generated to validate the underlying mechanisms, and the results showed that STAT3 ablation blunted the cardiac hypertrophy‐promoting effects of SENP1 deficiency. Additionally, pharmacological inhibition of SENP1 by Momordin Ic amplified cardiac remodeling post‐transverse aortic constriction.</jats:p>\n          </jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions</jats:title>\n            <jats:p xml:lang=\"en\">Our study provided evidence that SENP1 protected against pressure overload‐induced cardiac remodeling and dysfunction via inhibiting STAT3 signaling. SENP1 supplementation might constitute a new promising treatment against cardiac hypertrophy. Notably, cardiovascular side effects should be seriously considered while applying systemic SENP1 blockers to suppress tumors.</jats:p>\n          </jats:sec>","is_dataset_classified":null,"base_score":3.332204510175204,"endowment":3.332204510175204,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"36370010","pmcid":"PMC9750077","openalex_id":"https://openalex.org/W4308814054","authors":[],"funders":[],"total_grants":0,"fwci":1.4911,"citation_percentile":0.82402874,"influential_citations":0,"citation_trend":[{"year":2023,"count":4},{"year":2024,"count":9},{"year":2025,"count":6},{"year":2026,"count":8}],"oa_status":"gold","license":"cc-by-nc","oa_locations":[{"url":"https://www.ahajournals.org/doi/pdf/10.1161/JAHA.122.027004","host_type":"journal"},{"url":"https://www.ahajournals.org/doi/pdf/10.1161/JAHA.122.027004","host_type":"publisher"},{"url":"https://www.ahajournals.org/doi/full/10.1161/JAHA.122.027004","host_type":"publisher"},{"url":"https://doi.org/10.1161/jaha.122.027004","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/36370010","host_type":"repository"},{"url":"https://doaj.org/article/ea5060ace79a4478b136f89d5225228d","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9750077","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC9750077","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC9750077?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Coenzyme Q10 studies and effects","Advanced Glycation End Products research","GDF15 and Related Biomarkers","Animals","Humans","Mice","Rats","Cardiomegaly","Cysteine Endopeptidases","Disease Models, Animal","Mice, Inbred C57BL","Mice, Knockout","Myocytes, Cardiac","Signal Transduction","STAT3 Transcription Factor","Ventricular Remodeling"],"mesh_terms":["Animals","Cysteine Endopeptidases","Disease Models, Animal","Cardiomegaly","Humans","Mice, Inbred C57BL","Signal Transduction","Mice, Knockout","Ventricular Remodeling","Myocytes, Cardiac","STAT3 Transcription Factor","Mice","Rats"],"keywords":["Pressure overload","STAT3","Ventricular remodeling","Signal transduction","Internal medicine","Chemistry","Medicine","Cardiology","Cell biology","Biology","Heart failure","Cardiac hypertrophy","JAK2","Cardiac remodeling","Senp1"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-11T07:49:20.462750Z","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":[]}