Pub Date : 2025-10-01DOI: 10.1016/j.jacbts.2025.04.007
Varsha Tandra PhD , Lingxian Zhang PhD , Chang Min Lee , Yongbing Wu MD, PhD , Guihua Yue MD, PhD , Honglin Li PhD , Huabo Su PhD , Jie Li MD, PhD
Ufmylation is a novel ubiquitin-like protein modification that plays a critical role in maintaining the homeostasis of different tissues, but its role in the heart remains poorly understood. Here, we showed that mice lacking UFM1 ligase 1 (UFL1), an enzyme essential for ufmylation, in the heart developed peripartum cardiomyopathy. Loss of UFL1 reversed pregnancy-induced adaptive cardiac transcriptome alterations. Moreover, loss of UFL1 triggered excessive endoplasmic reticulum stress, inhibited mitochondrial oxidative metabolism, and caused augmented mTOR signaling, leading to pronounced pathological remodeling and heart failure. These results demonstrate that ufmylation is essential for physiological cardiac remodeling and that disruption of ufmylation predisposes the heart to peripartum cardiomyopathy.
{"title":"Ufmylation Suppresses Unfolded Protein Response to Prevent Peripartum Cardiomyopathy","authors":"Varsha Tandra PhD , Lingxian Zhang PhD , Chang Min Lee , Yongbing Wu MD, PhD , Guihua Yue MD, PhD , Honglin Li PhD , Huabo Su PhD , Jie Li MD, PhD","doi":"10.1016/j.jacbts.2025.04.007","DOIUrl":"10.1016/j.jacbts.2025.04.007","url":null,"abstract":"<div><div>Ufmylation is a novel ubiquitin-like protein modification that plays a critical role in maintaining the homeostasis of different tissues, but its role in the heart remains poorly understood. Here, we showed that mice lacking UFM1 ligase 1 (UFL1), an enzyme essential for ufmylation, in the heart developed peripartum cardiomyopathy. Loss of UFL1 reversed pregnancy-induced adaptive cardiac transcriptome alterations. Moreover, loss of UFL1 triggered excessive endoplasmic reticulum stress, inhibited mitochondrial oxidative metabolism, and caused augmented mTOR signaling, leading to pronounced pathological remodeling and heart failure. These results demonstrate that ufmylation is essential for physiological cardiac remodeling and that disruption of ufmylation predisposes the heart to peripartum cardiomyopathy.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 10","pages":"Article 101293"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01DOI: 10.1016/j.jacbts.2025.04.011
Jake E. Doiron PhD , Mahmoud H. Elbatreek PhD , Huijing Xia PhD , Xiaoman Yu MS , Natalie D. Gehred BA , Tatiana Gromova BS , Jingshu Chen PhD , Ian H. Driver PhD , Naoto Muraoka PhD , Martin Jensen PhD , Smitha Shambhu MS , W.H. Wilson Tang MD , Kyle B. LaPenna PhD , Thomas E. Sharp III PhD , Traci T. Goodchild PhD , Ming Xian PhD , Shi Xu PhD , Heather Quiriarte MS , Timothy D. Allerton PhD , Alexia Zagouras MD, MS , David J. Lefer PhD
Heart failure with preserved ejection fraction (HFpEF) presents significant treatment challenges. We assessed hydrogen sulfide (H2S) bioavailability in HFpEF patients and 2 animal models: the "2-hit" L-NAME + high-fat diet mouse model and ZSF1 obese rats. H2S levels were significantly reduced in patients and both models, linked to decreased cystathionine-γ-lyase expression and increased sulfide quinone oxidoreductase. Cystathionine-γ-lyase knockout worsened HFpEF, whereas pharmacological supplementation with an H2S donor improved diastolic function and reduced cardiac fibrosis. H2S supplement synergized with GLP-1/glucagon agonist and ameliorated HFpEF. These findings suggest that enhancing H2S bioavailability may provide a novel therapeutic strategy for HFpEF.
{"title":"Hydrogen Sulfide Deficiency and Therapeutic Targeting in Cardiometabolic HFpEF","authors":"Jake E. Doiron PhD , Mahmoud H. Elbatreek PhD , Huijing Xia PhD , Xiaoman Yu MS , Natalie D. Gehred BA , Tatiana Gromova BS , Jingshu Chen PhD , Ian H. Driver PhD , Naoto Muraoka PhD , Martin Jensen PhD , Smitha Shambhu MS , W.H. Wilson Tang MD , Kyle B. LaPenna PhD , Thomas E. Sharp III PhD , Traci T. Goodchild PhD , Ming Xian PhD , Shi Xu PhD , Heather Quiriarte MS , Timothy D. Allerton PhD , Alexia Zagouras MD, MS , David J. Lefer PhD","doi":"10.1016/j.jacbts.2025.04.011","DOIUrl":"10.1016/j.jacbts.2025.04.011","url":null,"abstract":"<div><div>Heart failure with preserved ejection fraction (HFpEF) presents significant treatment challenges. We assessed hydrogen sulfide (H<sub>2</sub>S) bioavailability in HFpEF patients and 2 animal models: the \"2-hit\" L-NAME + high-fat diet mouse model and ZSF1 obese rats. H<sub>2</sub>S levels were significantly reduced in patients and both models, linked to decreased cystathionine-γ-lyase expression and increased sulfide quinone oxidoreductase. Cystathionine-γ-lyase knockout worsened HFpEF, whereas pharmacological supplementation with an H<sub>2</sub>S donor improved diastolic function and reduced cardiac fibrosis. H<sub>2</sub>S supplement synergized with GLP-1/glucagon agonist and ameliorated HFpEF. These findings suggest that enhancing H<sub>2</sub>S bioavailability may provide a novel therapeutic strategy for HFpEF.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 10","pages":"Article 101297"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Inappropriate endothelial cell (EC) interactions contribute to heart failure; however, their precise mechanisms remain poorly understood. This study investigated EC-fibroblast interactions mediated by Scarb1 using single-cell RNA-sequencing analysis in a mouse heart failure model. ECs exhibited inflammatory and fibrotic gene expression, with Scarb1-mediated fibroblast-EC interactions driving disease progression. EC-specific Scarb1 knockout and systemic SCARB1 inhibition attenuated heart failure progression. In vitro and spatial omics analyses confirmed the role of SCARB1 in ECs and cell-cell interaction during heart failure progression. These findings highlight SCARB1 as a promising therapeutic target for EC-focused interventions.
Pub Date : 2025-10-01DOI: 10.1016/j.jacbts.2025.101392
Anaisa V. Ferreira PhD , Matthias Nahrendorf MD, PhD (Editor-in-Chief, JACC: Basic to Translational Science)
{"title":"Metabolic Memory Resides in the Hematopoietic Marrow and in Arterial Resident Leukocytes","authors":"Anaisa V. Ferreira PhD , Matthias Nahrendorf MD, PhD (Editor-in-Chief, JACC: Basic to Translational Science)","doi":"10.1016/j.jacbts.2025.101392","DOIUrl":"10.1016/j.jacbts.2025.101392","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 10","pages":"Article 101392"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145400871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01DOI: 10.1016/j.jacbts.2025.101332
Debabrata Chowdhury PhD, Guo-Chang Fan PhD
{"title":"Ufmylation-Mediated Unfolded Protein Response as An Innovative Therapeutic Target in Peripartum Cardiomyopathy","authors":"Debabrata Chowdhury PhD, Guo-Chang Fan PhD","doi":"10.1016/j.jacbts.2025.101332","DOIUrl":"10.1016/j.jacbts.2025.101332","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 10","pages":"Article 101332"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01DOI: 10.1016/j.jacbts.2025.101396
AlleaBelle Bradshaw MD, Jennifer S. Lawton MD
{"title":"Incremental Progress in the Enduring Conundrum to Provide an Off-the-Shelf Conduit for CABG That Can Compete With Native Grafts","authors":"AlleaBelle Bradshaw MD, Jennifer S. Lawton MD","doi":"10.1016/j.jacbts.2025.101396","DOIUrl":"10.1016/j.jacbts.2025.101396","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 10","pages":"Article 101396"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145400834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01DOI: 10.1016/j.jacbts.2025.101398
Matthias Nahrendorf MD (Editor-in-Chief: JACC: Basic to Translational Science)
{"title":"Recognizing Early Career Translational Investigators","authors":"Matthias Nahrendorf MD (Editor-in-Chief: JACC: Basic to Translational Science)","doi":"10.1016/j.jacbts.2025.101398","DOIUrl":"10.1016/j.jacbts.2025.101398","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 10","pages":"Article 101398"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145400919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01DOI: 10.1016/j.jacbts.2025.03.004
Daniel F. Hutchison MS , Satadru K. Lahiri PhD , Kurt W. Prins MD, PhD , Xander H.T. Wehrens MD, PhD
Junctophilin-2 (JPH2) is an essential structural protein that maintains the integrity of junctional membrane complexes (JMCs) in cardiomyocytes, thereby playing its canonical role in excitation-contraction (E-C) coupling. Recent studies reveal novel, nonstructural functions of JPH2 in cardiomyocytes, including regulation of mitochondrial function, lipid metabolism, nuclear signaling, and innate immune responses. Calpain-mediated cleavage of JPH2 generates nuclear fragments, which differentially modulate stress responses. Moreover, full-length JPH2 also localizes to the nucleus, where it forms phase-separated nuclear droplets during oxidative stress. Collectively, these findings highlight JPH2 as a multifunctional protein with critical roles beyond its canonical structural function in E-C coupling.
{"title":"Nonstructural Roles of Junctophilin-2 in the Heart","authors":"Daniel F. Hutchison MS , Satadru K. Lahiri PhD , Kurt W. Prins MD, PhD , Xander H.T. Wehrens MD, PhD","doi":"10.1016/j.jacbts.2025.03.004","DOIUrl":"10.1016/j.jacbts.2025.03.004","url":null,"abstract":"<div><div>Junctophilin-2 (JPH2) is an essential structural protein that maintains the integrity of junctional membrane complexes (JMCs) in cardiomyocytes, thereby playing its canonical role in excitation-contraction (E-C) coupling. Recent studies reveal novel, nonstructural functions of JPH2 in cardiomyocytes, including regulation of mitochondrial function, lipid metabolism, nuclear signaling, and innate immune responses. Calpain-mediated cleavage of JPH2 generates nuclear fragments, which differentially modulate stress responses. Moreover, full-length JPH2 also localizes to the nucleus, where it forms phase-separated nuclear droplets during oxidative stress. Collectively, these findings highlight JPH2 as a multifunctional protein with critical roles beyond its canonical structural function in E-C coupling.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 10","pages":"Article 101272"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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