Pub Date : 2024-11-01DOI: 10.1016/j.jacbts.2024.06.001
Bozhi Ye MD , Yanghao Chen MS , Xudong Chen MS , Diyun Xu BA , Yucheng Jiang BA , Wante Lin BA , Danhong Fang MS , Jiachen Xu BA , Jibo Han MS , Xue Han MS , Xiaohong Long MS , Wei Wang BA , Hao Zhou MD , Gaojun Wu MD , Guang Liang PhD
Deubiquitinating enzymes play a vital role in cardiovascular diseases. This study found that cardiomyocyte ubiquitin-specific protease 25 (USP25) expression was downregulated both in myocardial tissue of obesity cardiomyopathy and palmitic acid–stimulated cardiomyocytes. USP25 deficiency exacerbated high-fat diet–induced ventricular remodeling in mice, whereas overexpression of USP25 in cardiomyocytes reversed this pathological phenotype. Mechanistically, USP25 directly binds to TAK1 and P62, and the 178-cysteine of USP25 removes the K63 ubiquitin chain from P62, which promotes the degradation of TAK1 through the autophagy-lysosome pathway, thereby ameliorating obesity-induced ventricular remodeling by reducing inflammation through the TAK1-MAPK pathway. This finding identifies USP25 as a potential therapeutic target for obesity cardiomyopathy.
{"title":"Deubiquitinase USP25 Alleviates Obesity-Induced Cardiac Remodeling and Dysfunction by Downregulating TAK1 and Reducing TAK1-Mediated Inflammation","authors":"Bozhi Ye MD , Yanghao Chen MS , Xudong Chen MS , Diyun Xu BA , Yucheng Jiang BA , Wante Lin BA , Danhong Fang MS , Jiachen Xu BA , Jibo Han MS , Xue Han MS , Xiaohong Long MS , Wei Wang BA , Hao Zhou MD , Gaojun Wu MD , Guang Liang PhD","doi":"10.1016/j.jacbts.2024.06.001","DOIUrl":"10.1016/j.jacbts.2024.06.001","url":null,"abstract":"<div><div>Deubiquitinating enzymes play a vital role in cardiovascular diseases. This study found that cardiomyocyte ubiquitin-specific protease 25 (USP25) expression was downregulated both in myocardial tissue of obesity cardiomyopathy and palmitic acid–stimulated cardiomyocytes. USP25 deficiency exacerbated high-fat diet–induced ventricular remodeling in mice, whereas overexpression of USP25 in cardiomyocytes reversed this pathological phenotype. Mechanistically, USP25 directly binds to TAK1 and P62, and the 178-cysteine of USP25 removes the K63 ubiquitin chain from P62, which promotes the degradation of TAK1 through the autophagy-lysosome pathway, thereby ameliorating obesity-induced ventricular remodeling by reducing inflammation through the TAK1-MAPK pathway. This finding identifies USP25 as a potential therapeutic target for obesity cardiomyopathy.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 11","pages":"Pages 1287-1304"},"PeriodicalIF":8.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.jacbts.2024.06.007
Ali Fatehi Hassanabad MD, MSc , Darrell D. Belke PhD , Paul M.K. Gordon PhD , Guoqi Teng MD, PhD , Jameson A. Dundas BSc , Anna N. Zarzycki BSc , Jeannine Turnbull BSc, MSc , Justin F. Deniset PhD , Paul W.M. Fedak MD, PhD
Human pericardial fluid (PF) is a rich reservoir of biologically active markers. The acellular compartment of PF can drive cardiac fibroblast activity in vitro. This process is mediated through the transforming growth factor-β pathway. Of clinical importance, the PF of patients with coronary artery disease has an increased profibrotic capacity compared with the PF of patients without coronary artery disease.
{"title":"Pericardial Fluid of Patients With Coronary Artery Disease Can Drive Fibrosis Via TGF-Beta Pathway","authors":"Ali Fatehi Hassanabad MD, MSc , Darrell D. Belke PhD , Paul M.K. Gordon PhD , Guoqi Teng MD, PhD , Jameson A. Dundas BSc , Anna N. Zarzycki BSc , Jeannine Turnbull BSc, MSc , Justin F. Deniset PhD , Paul W.M. Fedak MD, PhD","doi":"10.1016/j.jacbts.2024.06.007","DOIUrl":"10.1016/j.jacbts.2024.06.007","url":null,"abstract":"<div><div>Human pericardial fluid (PF) is a rich reservoir of biologically active markers. The acellular compartment of PF can drive cardiac fibroblast activity in vitro. This process is mediated through the transforming growth factor-β pathway. Of clinical importance, the PF of patients with coronary artery disease has an increased profibrotic capacity compared with the PF of patients without coronary artery disease.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 11","pages":"Pages 1329-1344"},"PeriodicalIF":8.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.jacbts.2024.09.012
Jonathan A. Kirk PhD
{"title":"When Off-Target Is the Target","authors":"Jonathan A. Kirk PhD","doi":"10.1016/j.jacbts.2024.09.012","DOIUrl":"10.1016/j.jacbts.2024.09.012","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 11","pages":"Pages 1326-1328"},"PeriodicalIF":8.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.jacbts.2024.04.005
Clarissa Becher MSc , Marius Wits MSc , Frances S. de Man Prof , Gonzalo Sanchez-Duffhues PhD , Marie-Jose Goumans Prof
Pulmonary arterial hypertension (PAH) is a rare progressive disease characterized by pulmonary artery vascular remodeling, increased vascular resistance, and subsequent right ventricular hypertrophy and right heart failure. It is triggered by disrupted transforming growth factor (TGF)-β signaling, including loss-of-function mutations in the bone morphogenetic protein (BMP) receptor 2. Emerging treatments aim to inhibit elevated TGF-β levels or enhance diminished endothelial BMP signaling. This review aims to summarize the role of the TGF-β superfamily in the pathobiology of PAH and recent discoveries highlighting altered expression of TGF-β–related soluble factors in PAH patients that can serve as potential biomarkers and drug targets. The discussion focuses on how these altered factors can guide treatment decisions and monitor therapeutic responses, facilitating personalized patient care through the integration of diagnostics and therapy, that is, precision medicine. This approach tailors treatment strategies to individual patients based on their unique disease characteristics.
{"title":"Targeting Soluble TGF-β Factors","authors":"Clarissa Becher MSc , Marius Wits MSc , Frances S. de Man Prof , Gonzalo Sanchez-Duffhues PhD , Marie-Jose Goumans Prof","doi":"10.1016/j.jacbts.2024.04.005","DOIUrl":"10.1016/j.jacbts.2024.04.005","url":null,"abstract":"<div><div>Pulmonary arterial hypertension (PAH) is a rare progressive disease characterized by pulmonary artery vascular remodeling, increased vascular resistance, and subsequent right ventricular hypertrophy and right heart failure. It is triggered by disrupted transforming growth factor (TGF)-β signaling, including loss-of-function mutations in the bone morphogenetic protein (BMP) receptor 2. Emerging treatments aim to inhibit elevated TGF-β levels or enhance diminished endothelial BMP signaling. This review aims to summarize the role of the TGF-β superfamily in the pathobiology of PAH and recent discoveries highlighting altered expression of TGF-β–related soluble factors in PAH patients that can serve as potential biomarkers and drug targets. The discussion focuses on how these altered factors can guide treatment decisions and monitor therapeutic responses, facilitating personalized patient care through the integration of diagnostics and therapy, that is, precision medicine. This approach tailors treatment strategies to individual patients based on their unique disease characteristics.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 11","pages":"Pages 1360-1374"},"PeriodicalIF":8.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.jacbts.2024.06.004
Yueshen Sun MB , Congting Guo BS , Zhan Chen BS , Junsen Lin BS , Luzi Yang MM , Yueyang Zhang BS , Chenyang Wu BS , Dongyu Zhao PhD , Blake Jardin MS , William T. Pu MD , Mingming Zhao PhD , Erdan Dong MD , Xiaomin Hu PhD , Shuyang Zhang MD , Yuxuan Guo PhD
The truncating mutations of LMNA are the major causes of cardiomyopathy. Here we studied 3 mouse models that carry germline, cardiomyocyte-specific, or genetic mosaic Lmna truncating mutations. Whereas the germline mutant manifested cardiac maturation defects, cardiomyocyte-specific mutation triggered pathological hypertrophy. In genetic mosaic analysis, no morphological defects were observed. Three adeno-associated virus (AAV) vectors were applied to addback lamin-A in a ubiquitous, cardiomyocyte-specific, or cardiomyocyte-excluded manner. Strikingly, only ubiquitous and cardiomyocyte-excluded AAV vectors mitigated the cardiac defects. Therefore, Lmna regulates cardiac morphology and function via a non-cell-autonomous mechanism. Noncardiomyocytes are key targets in AAV lamin-A therapy for Lmna-associated cardiac defects.
{"title":"Non-Cell-Autonomous Cardiomyocyte Regulation Complicates Gene Supplementation Therapy for Lmna-Associated Cardiac Defects in Mice","authors":"Yueshen Sun MB , Congting Guo BS , Zhan Chen BS , Junsen Lin BS , Luzi Yang MM , Yueyang Zhang BS , Chenyang Wu BS , Dongyu Zhao PhD , Blake Jardin MS , William T. Pu MD , Mingming Zhao PhD , Erdan Dong MD , Xiaomin Hu PhD , Shuyang Zhang MD , Yuxuan Guo PhD","doi":"10.1016/j.jacbts.2024.06.004","DOIUrl":"10.1016/j.jacbts.2024.06.004","url":null,"abstract":"<div><div>The truncating mutations of <em>LMNA</em> are the major causes of cardiomyopathy. Here we studied 3 mouse models that carry germline, cardiomyocyte-specific, or genetic mosaic <em>Lmna</em> truncating mutations. Whereas the germline mutant manifested cardiac maturation defects, cardiomyocyte-specific mutation triggered pathological hypertrophy. In genetic mosaic analysis, no morphological defects were observed. Three adeno-associated virus (AAV) vectors were applied to addback lamin-A in a ubiquitous, cardiomyocyte-specific, or cardiomyocyte-excluded manner. Strikingly, only ubiquitous and cardiomyocyte-excluded AAV vectors mitigated the cardiac defects. Therefore, <em>Lmna</em> regulates cardiac morphology and function via a non-cell-autonomous mechanism. Noncardiomyocytes are key targets in AAV lamin-A therapy for <em>Lmna</em>-associated cardiac defects.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 11","pages":"Pages 1308-1325"},"PeriodicalIF":8.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.jacbts.2024.08.001
Hanming Zhang PhD
{"title":"Targeting USP25 in the Heart","authors":"Hanming Zhang PhD","doi":"10.1016/j.jacbts.2024.08.001","DOIUrl":"10.1016/j.jacbts.2024.08.001","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 11","pages":"Pages 1305-1307"},"PeriodicalIF":8.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.jacbts.2024.07.008
Mona E. Ahmed MD, PhD , David M. Leistner MD , Diaa Hakim MD, PhD , Youssef Abdelwahed MD , Ahmet U. Coskun PhD , Charles Maynard PhD , Claudio Seppelt MD , Gregor Nelles MD , Denitsa Meteva MD , Nicholas V. Cefalo BS , Peter Libby MD , Ulf Landmesser MD , Peter H. Stone MD
Low endothelial shear stress (ESS) and associated adverse biomechanical features stimulate inflammation, contribute to atherogenesis, and predispose to coronary plaque disruption. The mechanistic links between adverse flow-related hemodynamics and inflammatory mediators implicated in plaque erosion, however, remain little explored. We investigated the relationship of high-risk ESS metrics to culprit lesion proinflammatory/proatherogenic cells and cytokines/chemokines implicated in coronary plaque erosion in patients with acute coronary syndromes. In eroded plaques, low ESS, high ESS gradient, and steepness of plaque topographical slope associated with increased numbers of local T cells and subsets (CD4+, CD8+, natural killer T cells) as well as inflammatory mediators (interleukin [IL]-6, macrophage inflammatory protein-1β, IL-1β, IL-2).
{"title":"Endothelial Shear Stress Metrics Associate With Proinflammatory Pathways at the Culprit Site of Coronary Erosion","authors":"Mona E. Ahmed MD, PhD , David M. Leistner MD , Diaa Hakim MD, PhD , Youssef Abdelwahed MD , Ahmet U. Coskun PhD , Charles Maynard PhD , Claudio Seppelt MD , Gregor Nelles MD , Denitsa Meteva MD , Nicholas V. Cefalo BS , Peter Libby MD , Ulf Landmesser MD , Peter H. Stone MD","doi":"10.1016/j.jacbts.2024.07.008","DOIUrl":"10.1016/j.jacbts.2024.07.008","url":null,"abstract":"<div><div>Low endothelial shear stress (ESS) and associated adverse biomechanical features stimulate inflammation, contribute to atherogenesis, and predispose to coronary plaque disruption. The mechanistic links between adverse flow-related hemodynamics and inflammatory mediators implicated in plaque erosion, however, remain little explored. We investigated the relationship of high-risk ESS metrics to culprit lesion proinflammatory/proatherogenic cells and cytokines/chemokines implicated in coronary plaque erosion in patients with acute coronary syndromes. In eroded plaques, low ESS, high ESS gradient, and steepness of plaque topographical slope associated with increased numbers of local T cells and subsets (CD4<sup>+</sup>, CD8<sup>+</sup>, natural killer T cells) as well as inflammatory mediators (interleukin [IL]-6, macrophage inflammatory protein-1β, IL-1β, IL-2).</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 11","pages":"Pages 1269-1283"},"PeriodicalIF":8.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142698425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.jacbts.2024.07.003
Marijn C. Peters PhD , Arnaud Zaldumbide PhD , Esmee J. Groeneveld BSc , Martijn J.W.E. Rabelink BSc , Janneke H. Peerlings MSc , Antoon van den Bogaerdt MSc , Carlijn V.C. Bouten PhD , Rob C. Hoeben PhD , Marie-Jose Goumans PhD , Abraham van Wijk MD, PhD
Children born with defective heart valves require multiple donor valve replacements throughout life, because these cannot grow and can cause early failure through immune degeneration. This study tests the lentiviral delivery of viral immune evasion genes US2 and human serpin 9 to shield human heart valves from immune rejection. The results show we can efficiently down-regulate human leukocyte antigen expression in heart valve cells and in intact heart valve tissue resulting in decreased activity of a human leukocyte antigen–reactive CD8+ T-cell clone without inducing cytotoxicity. This study demonstrates immune shielding of human heart valves and brings us closer to a durable valve graft in pediatric patients.
先天性心脏瓣膜有缺陷的儿童一生中需要多次供体瓣膜置换，因为这些瓣膜无法生长，并可能因免疫变性而导致早期衰竭。这项研究测试了慢病毒递送病毒免疫逃避基因 US2 和人类血清素 9 以保护人类心脏瓣膜免受免疫排斥。结果表明，我们可以有效下调心脏瓣膜细胞和完整心脏瓣膜组织中人类白细胞抗原的表达，从而降低人类白细胞抗原反应性 CD8+ T 细胞克隆的活性，而不会诱导细胞毒性。这项研究证明了人类心脏瓣膜的免疫屏蔽作用，使我们更接近于为儿科患者提供持久的瓣膜移植。
{"title":"Immune Shielding of Human Heart Valves","authors":"Marijn C. Peters PhD , Arnaud Zaldumbide PhD , Esmee J. Groeneveld BSc , Martijn J.W.E. Rabelink BSc , Janneke H. Peerlings MSc , Antoon van den Bogaerdt MSc , Carlijn V.C. Bouten PhD , Rob C. Hoeben PhD , Marie-Jose Goumans PhD , Abraham van Wijk MD, PhD","doi":"10.1016/j.jacbts.2024.07.003","DOIUrl":"10.1016/j.jacbts.2024.07.003","url":null,"abstract":"<div><div>Children born with defective heart valves require multiple donor valve replacements throughout life, because these cannot grow and can cause early failure through immune degeneration. This study tests the lentiviral delivery of viral immune evasion genes US2 and human serpin 9 to shield human heart valves from immune rejection. The results show we can efficiently down-regulate human leukocyte antigen expression in heart valve cells and in intact heart valve tissue resulting in decreased activity of a human leukocyte antigen–reactive CD8+ T-cell clone without inducing cytotoxicity. This study demonstrates immune shielding of human heart valves and brings us closer to a durable valve graft in pediatric patients.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 11","pages":"Pages 1345-1359"},"PeriodicalIF":8.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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