Pub Date : 2025-01-10DOI: 10.1038/s44161-024-00597-8
Martin A. Schwartz
Atherosclerosis and other vascular inflammatory diseases are determined by the balance between pro- and anti-inflammatory pathways. A report now identifies IGFBP6 as a component of an anti-inflammatory, protective program in vascular endothelial cells and demonstrates that major vault protein is the key downstream effector.
{"title":"IGFBP6 contributes to vascular resilience","authors":"Martin A. Schwartz","doi":"10.1038/s44161-024-00597-8","DOIUrl":"10.1038/s44161-024-00597-8","url":null,"abstract":"Atherosclerosis and other vascular inflammatory diseases are determined by the balance between pro- and anti-inflammatory pathways. A report now identifies IGFBP6 as a component of an anti-inflammatory, protective program in vascular endothelial cells and demonstrates that major vault protein is the key downstream effector.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 2","pages":"122-123"},"PeriodicalIF":9.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-10DOI: 10.1038/s44161-024-00591-0
Meiming Su, Wenqi Zhao, Hui Jiang, Yaping Zhao, Zhaopeng Liao, Zhenghong Liu, Mengyun Xu, Shanshan Jiang, Lili Wu, Yi Yang, Zhihua Wang, Zhutian Zeng, Yun Fang, Chaojun Tang, Clint L. Miller, Paul C. Evans, Li Wang, Maciej Banach, Hanjoong Jo, Bradford C. Berk, Stefan Offermanns, Yu Huang, Junbo Ge, Suowen Xu, Jianping Weng
Beyond dyslipidemia, inflammation contributes to the development of atherosclerosis. However, intrinsic factors that counteract vascular inflammation and atherosclerosis remain scarce. Here we identify insulin-like growth factor binding protein 6 (IGFBP6) as a homeostasis-associated molecule that restrains endothelial inflammation and atherosclerosis. IGFBP6 levels are significantly reduced in human atherosclerotic arteries and patient serum. Reduction of IGFBP6 in human endothelial cells by siRNA increases inflammatory molecule expression and monocyte adhesion. Conversely, pro-inflammatory effects mediated by disturbed flow (DF) and tumor necrosis factor (TNF) are reversed by IGFBP6 overexpression. Mechanistic investigations further reveal that IGFBP6 executes anti-inflammatory effects directly through the major vault protein (MVP)–c-Jun N-terminal kinase (JNK)/nuclear factor kappa B (NF-κB) signaling axis. Finally, IGFBP6-deficient mice show aggravated diet- and DF-induced atherosclerosis, whereas endothelial-cell-specific IGFBP6-overexpressing mice protect against atherosclerosis. Based on these findings, we propose that reduction of endothelial IGFBP6 is a predisposing factor in vascular inflammation and atherosclerosis, which can be therapeutically targeted. Su, Zhao, Jiang and colleagues identify IGFBP6 as an intrinsic downregulator of the inflammatory response lost in disturbed flow-induced atherosclerotic plaque development, suggesting that its restoration may represent a viable therapeutic strategy.
除了血脂异常，炎症还会导致动脉粥样硬化。然而，对抗血管炎症和动脉粥样硬化的内在因素仍然很少。在这里，我们发现胰岛素样生长因子结合蛋白6 （IGFBP6）是一种抑制内皮炎症和动脉粥样硬化的体内平衡相关分子。IGFBP6水平在人动脉粥样硬化动脉和患者血清中显著降低。通过siRNA减少人内皮细胞中的IGFBP6增加炎症分子表达和单核细胞粘附。相反，由血流紊乱（DF）和肿瘤坏死因子（TNF）介导的促炎作用被IGFBP6过表达逆转。机制研究进一步揭示IGFBP6直接通过主要拱顶蛋白(MVP)-c-Jun n -末端激酶(JNK)/核因子κB （NF-κB）信号轴发挥抗炎作用。最后，igfbp6缺陷小鼠表现出饮食和df诱导的动脉粥样硬化加重，而内皮细胞特异性igfbp6过表达小鼠则对动脉粥样硬化有保护作用。基于这些发现，我们提出内皮细胞IGFBP6的减少是血管炎症和动脉粥样硬化的一个易感因素，可以作为治疗目标。
{"title":"Endothelial IGFBP6 suppresses vascular inflammation and atherosclerosis","authors":"Meiming Su, Wenqi Zhao, Hui Jiang, Yaping Zhao, Zhaopeng Liao, Zhenghong Liu, Mengyun Xu, Shanshan Jiang, Lili Wu, Yi Yang, Zhihua Wang, Zhutian Zeng, Yun Fang, Chaojun Tang, Clint L. Miller, Paul C. Evans, Li Wang, Maciej Banach, Hanjoong Jo, Bradford C. Berk, Stefan Offermanns, Yu Huang, Junbo Ge, Suowen Xu, Jianping Weng","doi":"10.1038/s44161-024-00591-0","DOIUrl":"10.1038/s44161-024-00591-0","url":null,"abstract":"Beyond dyslipidemia, inflammation contributes to the development of atherosclerosis. However, intrinsic factors that counteract vascular inflammation and atherosclerosis remain scarce. Here we identify insulin-like growth factor binding protein 6 (IGFBP6) as a homeostasis-associated molecule that restrains endothelial inflammation and atherosclerosis. IGFBP6 levels are significantly reduced in human atherosclerotic arteries and patient serum. Reduction of IGFBP6 in human endothelial cells by siRNA increases inflammatory molecule expression and monocyte adhesion. Conversely, pro-inflammatory effects mediated by disturbed flow (DF) and tumor necrosis factor (TNF) are reversed by IGFBP6 overexpression. Mechanistic investigations further reveal that IGFBP6 executes anti-inflammatory effects directly through the major vault protein (MVP)–c-Jun N-terminal kinase (JNK)/nuclear factor kappa B (NF-κB) signaling axis. Finally, IGFBP6-deficient mice show aggravated diet- and DF-induced atherosclerosis, whereas endothelial-cell-specific IGFBP6-overexpressing mice protect against atherosclerosis. Based on these findings, we propose that reduction of endothelial IGFBP6 is a predisposing factor in vascular inflammation and atherosclerosis, which can be therapeutically targeted. Su, Zhao, Jiang and colleagues identify IGFBP6 as an intrinsic downregulator of the inflammatory response lost in disturbed flow-induced atherosclerotic plaque development, suggesting that its restoration may represent a viable therapeutic strategy.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 2","pages":"145-162"},"PeriodicalIF":9.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-08DOI: 10.1038/s44161-024-00593-y
Young-June Jin, Guozheng Liang, Rui Li, ShengPeng Wang, Mohamad Wessam Alnouri, Mette Bentsen, Carsten Kuenne, Stefan Günther, Yang Yan, Yongxin Li, Nina Wettschureck, Stefan Offermanns
Atherosclerotic lesions develop preferentially in arterial regions exposed to disturbed blood flow, where endothelial cells acquire an inflammatory phenotype. How disturbed flow induces endothelial cell inflammation is incompletely understood. Here we show that histone H3.3 phosphorylation at serine 31 (H3.3S31) regulates disturbed-flow-induced endothelial inflammation by allowing rapid induction of FOS and FOSB, required for inflammatory gene expression. We identified protein kinase N1 (PKN1) as the kinase responsible for disturbed-flow-induced H3.3S31 phosphorylation. Disturbed flow activates PKN1 in an integrin α5β1-dependent manner and induces its translocation into the nucleus, and PKN1 is also involved in the phosphorylation of the AP-1 transcription factor JUN. Mice with endothelium-specific PKN1 loss or endothelial expression of S31 phosphorylation-deficient H.3.3 mutants show reduced endothelial inflammation and disturbed-flow-induced vascular remodeling in vitro and in vivo. Together, we identified a pathway whereby disturbed flow through PKN1-mediated histone phosphorylation and FOS/FOSB induction promotes inflammatory gene expression and vascular inflammation. Jin et al. identified PKN1 as the kinase responsible for histone phosphorylation-mediated FOS/FOSB induction and vessel inflammation in regions of disturbed blood flow, highlighting an additional regulation layer for atherosclerotic plaque development.
{"title":"Phosphorylation of endothelial histone H3.3 serine 31 by PKN1 links flow-induced signaling to proatherogenic gene expression","authors":"Young-June Jin, Guozheng Liang, Rui Li, ShengPeng Wang, Mohamad Wessam Alnouri, Mette Bentsen, Carsten Kuenne, Stefan Günther, Yang Yan, Yongxin Li, Nina Wettschureck, Stefan Offermanns","doi":"10.1038/s44161-024-00593-y","DOIUrl":"10.1038/s44161-024-00593-y","url":null,"abstract":"Atherosclerotic lesions develop preferentially in arterial regions exposed to disturbed blood flow, where endothelial cells acquire an inflammatory phenotype. How disturbed flow induces endothelial cell inflammation is incompletely understood. Here we show that histone H3.3 phosphorylation at serine 31 (H3.3S31) regulates disturbed-flow-induced endothelial inflammation by allowing rapid induction of FOS and FOSB, required for inflammatory gene expression. We identified protein kinase N1 (PKN1) as the kinase responsible for disturbed-flow-induced H3.3S31 phosphorylation. Disturbed flow activates PKN1 in an integrin α5β1-dependent manner and induces its translocation into the nucleus, and PKN1 is also involved in the phosphorylation of the AP-1 transcription factor JUN. Mice with endothelium-specific PKN1 loss or endothelial expression of S31 phosphorylation-deficient H.3.3 mutants show reduced endothelial inflammation and disturbed-flow-induced vascular remodeling in vitro and in vivo. Together, we identified a pathway whereby disturbed flow through PKN1-mediated histone phosphorylation and FOS/FOSB induction promotes inflammatory gene expression and vascular inflammation. Jin et al. identified PKN1 as the kinase responsible for histone phosphorylation-mediated FOS/FOSB induction and vessel inflammation in regions of disturbed blood flow, highlighting an additional regulation layer for atherosclerotic plaque development.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 2","pages":"180-196"},"PeriodicalIF":9.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00593-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142959940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-03DOI: 10.1038/s44161-024-00594-x
Miao Cui
Myocardial infarction can lead to arrythmias, which increase mortality, but the mechanisms behind this are unclear. A study shows that the capacity to regenerate the cardiac conduction system is reduced with age, resulting in pathological remodeling and an increased risk of arrythmia after myocardial infarction.
{"title":"Conduction system regeneration and remodeling after myocardial infarction","authors":"Miao Cui","doi":"10.1038/s44161-024-00594-x","DOIUrl":"10.1038/s44161-024-00594-x","url":null,"abstract":"Myocardial infarction can lead to arrythmias, which increase mortality, but the mechanisms behind this are unclear. A study shows that the capacity to regenerate the cardiac conduction system is reduced with age, resulting in pathological remodeling and an increased risk of arrythmia after myocardial infarction.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 2","pages":"124-125"},"PeriodicalIF":9.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-03DOI: 10.1038/s44161-024-00601-1
Andrea Tavosanis
{"title":"Tirzepatide improves cardiorenal health in obese individuals with HFpEF","authors":"Andrea Tavosanis","doi":"10.1038/s44161-024-00601-1","DOIUrl":"10.1038/s44161-024-00601-1","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 1","pages":"5-5"},"PeriodicalIF":9.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-03DOI: 10.1038/s44161-024-00586-x
Judy R. Sayers, Hector Martinez-Navarro, Xin Sun, Carla de Villiers, Sarah Sigal, Michael Weinberger, Claudio Cortes Rodriguez, Leto Luana Riebel, Lucas Arantes Berg, Julia Camps, Neil Herring, Blanca Rodriguez, Tatjana Sauka-Spengler, Paul R. Riley
Arrhythmias are a hallmark of myocardial infarction (MI) and increase patient mortality. How insult to the cardiac conduction system causes arrhythmias following MI is poorly understood. Here, we demonstrate conduction system restoration during neonatal mouse heart regeneration versus pathological remodeling at non-regenerative stages. Tissue-cleared whole-organ imaging identified disorganized bundling of conduction fibers after MI and global His–Purkinje disruption. Single-cell RNA sequencing (scRNA-seq) revealed specific molecular changes to regenerate the conduction network versus aberrant electrical alterations during fibrotic repair. This manifested functionally as a transition from normal rhythm to pathological conduction delay beyond the regenerative window. Modeling in the infarcted human heart implicated the non-regenerative phenotype as causative for heart block, as observed in patients. These findings elucidate the mechanisms underpinning conduction system regeneration and reveal how MI-induced damage elicits clinical arrhythmogenesis. Sayers et al. reveal that heart regeneration during the neonatal period in mice extends to conduction system restoration after insult, highlighting the difference between this process and pathological remodeling in the adult heart.
{"title":"Cardiac conduction system regeneration prevents arrhythmias after myocardial infarction","authors":"Judy R. Sayers, Hector Martinez-Navarro, Xin Sun, Carla de Villiers, Sarah Sigal, Michael Weinberger, Claudio Cortes Rodriguez, Leto Luana Riebel, Lucas Arantes Berg, Julia Camps, Neil Herring, Blanca Rodriguez, Tatjana Sauka-Spengler, Paul R. Riley","doi":"10.1038/s44161-024-00586-x","DOIUrl":"10.1038/s44161-024-00586-x","url":null,"abstract":"Arrhythmias are a hallmark of myocardial infarction (MI) and increase patient mortality. How insult to the cardiac conduction system causes arrhythmias following MI is poorly understood. Here, we demonstrate conduction system restoration during neonatal mouse heart regeneration versus pathological remodeling at non-regenerative stages. Tissue-cleared whole-organ imaging identified disorganized bundling of conduction fibers after MI and global His–Purkinje disruption. Single-cell RNA sequencing (scRNA-seq) revealed specific molecular changes to regenerate the conduction network versus aberrant electrical alterations during fibrotic repair. This manifested functionally as a transition from normal rhythm to pathological conduction delay beyond the regenerative window. Modeling in the infarcted human heart implicated the non-regenerative phenotype as causative for heart block, as observed in patients. These findings elucidate the mechanisms underpinning conduction system regeneration and reveal how MI-induced damage elicits clinical arrhythmogenesis. Sayers et al. reveal that heart regeneration during the neonatal period in mice extends to conduction system restoration after insult, highlighting the difference between this process and pathological remodeling in the adult heart.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 2","pages":"163-179"},"PeriodicalIF":9.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00586-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-02DOI: 10.1038/s44161-024-00570-5
Irina-Elena Lupu, David E. Grainger, Nils Kirschnick, Sarah Weischer, Erica Zhao, Ines Martinez-Corral, Hans Schoofs, Marie Vanhollebeke, Grace Jones, Jonathan Godwin, Aden Forrow, Ines Lahmann, Paul R. Riley, Thomas Zobel, Kari Alitalo, Taija Mäkinen, Friedemann Kiefer, Oliver A. Stone
During embryogenesis, endothelial cells (ECs) are generally described to arise from a common pool of progenitors termed angioblasts, which diversify through iterative steps of differentiation to form functionally distinct subtypes of ECs. A key example is the formation of lymphatic ECs (LECs), which are thought to arise largely through transdifferentiation from venous endothelium. Opposing this model, here we show that the initial expansion of mammalian LECs is primarily driven by the in situ differentiation of mesenchymal progenitors and does not require transition through an intermediate venous state. Single-cell genomics and lineage-tracing experiments revealed a population of paraxial mesoderm-derived Etv2+Prox1+ progenitors that directly give rise to LECs. Morphometric analyses of early LEC proliferation and migration, and mutants that disrupt lymphatic development supported these findings. Collectively, this work establishes a cellular blueprint for LEC specification and indicates that discrete pools of mesenchymal progenitors can give rise to specialized subtypes of ECs. Lupu, Grainger, Kirschnick et al. show that, contrary to prevailing belief, the initial specification of mammalian lymphatic endothelial cells primarily occurs from previously unidentified mesenchymal angioblasts rather than from venous endothelium.
{"title":"Direct specification of lymphatic endothelium from mesenchymal progenitors","authors":"Irina-Elena Lupu, David E. Grainger, Nils Kirschnick, Sarah Weischer, Erica Zhao, Ines Martinez-Corral, Hans Schoofs, Marie Vanhollebeke, Grace Jones, Jonathan Godwin, Aden Forrow, Ines Lahmann, Paul R. Riley, Thomas Zobel, Kari Alitalo, Taija Mäkinen, Friedemann Kiefer, Oliver A. Stone","doi":"10.1038/s44161-024-00570-5","DOIUrl":"10.1038/s44161-024-00570-5","url":null,"abstract":"During embryogenesis, endothelial cells (ECs) are generally described to arise from a common pool of progenitors termed angioblasts, which diversify through iterative steps of differentiation to form functionally distinct subtypes of ECs. A key example is the formation of lymphatic ECs (LECs), which are thought to arise largely through transdifferentiation from venous endothelium. Opposing this model, here we show that the initial expansion of mammalian LECs is primarily driven by the in situ differentiation of mesenchymal progenitors and does not require transition through an intermediate venous state. Single-cell genomics and lineage-tracing experiments revealed a population of paraxial mesoderm-derived Etv2+Prox1+ progenitors that directly give rise to LECs. Morphometric analyses of early LEC proliferation and migration, and mutants that disrupt lymphatic development supported these findings. Collectively, this work establishes a cellular blueprint for LEC specification and indicates that discrete pools of mesenchymal progenitors can give rise to specialized subtypes of ECs. Lupu, Grainger, Kirschnick et al. show that, contrary to prevailing belief, the initial specification of mammalian lymphatic endothelial cells primarily occurs from previously unidentified mesenchymal angioblasts rather than from venous endothelium.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 1","pages":"45-63"},"PeriodicalIF":9.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00570-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-02DOI: 10.1038/s44161-024-00588-9
Mara Bouwman, Dennis E. M. de Bakker, Hessel Honkoop, Alexandra E. Giovou, Danielle Versteeg, Arie R. Boender, Phong D. Nguyen, Merel Slotboom, Daniel Colquhoun, Marta Vigil-Garcia, Lieneke Kooijman, Rob Janssen, Ingeborg B. Hooijkaas, Marie Günthel, Kimberly J. Visser, Mischa Klerk, Lorena Zentilin, Mauro Giacca, Jan Kaslin, Gerard J. J. Boink, Eva van Rooij, Vincent M. Christoffels, Jeroen Bakkers
In contrast to adult mammalian hearts, the adult zebrafish heart efficiently replaces cardiomyocytes lost after injury. Here we reveal shared and species-specific injury response pathways and a correlation between Hmga1, an architectural non-histone protein, and regenerative capacity, as Hmga1 is required and sufficient to induce cardiomyocyte proliferation and required for heart regeneration. In addition, Hmga1 was shown to reactivate developmentally silenced genes, likely through modulation of H3K27me3 levels, poising them for a pro-regenerative gene program. Furthermore, AAV-mediated Hmga1 expression in injured adult mouse hearts led to controlled cardiomyocyte proliferation in the border zone and enhanced heart function, without cardiomegaly and adverse remodeling. Histone modification mapping in mouse border zone cardiomyocytes revealed a similar modulation of H3K27me3 marks, consistent with findings in zebrafish. Our study demonstrates that Hmga1 mediates chromatin remodeling and drives a regenerative program, positioning it as a promising therapeutic target to enhance cardiac regeneration after injury. Bouwman et al. identify Hmga1-mediated chromatin remodeling as the fundamental regulator of zebrafish cardiac regeneration and reveal the potential of Hmga1 to restore heart repair in mice by reactivating developmental genes, suggesting potential therapeutic applications.
{"title":"Cross-species comparison reveals that Hmga1 reduces H3K27me3 levels to promote cardiomyocyte proliferation and cardiac regeneration","authors":"Mara Bouwman, Dennis E. M. de Bakker, Hessel Honkoop, Alexandra E. Giovou, Danielle Versteeg, Arie R. Boender, Phong D. Nguyen, Merel Slotboom, Daniel Colquhoun, Marta Vigil-Garcia, Lieneke Kooijman, Rob Janssen, Ingeborg B. Hooijkaas, Marie Günthel, Kimberly J. Visser, Mischa Klerk, Lorena Zentilin, Mauro Giacca, Jan Kaslin, Gerard J. J. Boink, Eva van Rooij, Vincent M. Christoffels, Jeroen Bakkers","doi":"10.1038/s44161-024-00588-9","DOIUrl":"10.1038/s44161-024-00588-9","url":null,"abstract":"In contrast to adult mammalian hearts, the adult zebrafish heart efficiently replaces cardiomyocytes lost after injury. Here we reveal shared and species-specific injury response pathways and a correlation between Hmga1, an architectural non-histone protein, and regenerative capacity, as Hmga1 is required and sufficient to induce cardiomyocyte proliferation and required for heart regeneration. In addition, Hmga1 was shown to reactivate developmentally silenced genes, likely through modulation of H3K27me3 levels, poising them for a pro-regenerative gene program. Furthermore, AAV-mediated Hmga1 expression in injured adult mouse hearts led to controlled cardiomyocyte proliferation in the border zone and enhanced heart function, without cardiomegaly and adverse remodeling. Histone modification mapping in mouse border zone cardiomyocytes revealed a similar modulation of H3K27me3 marks, consistent with findings in zebrafish. Our study demonstrates that Hmga1 mediates chromatin remodeling and drives a regenerative program, positioning it as a promising therapeutic target to enhance cardiac regeneration after injury. Bouwman et al. identify Hmga1-mediated chromatin remodeling as the fundamental regulator of zebrafish cardiac regeneration and reveal the potential of Hmga1 to restore heart repair in mice by reactivating developmental genes, suggesting potential therapeutic applications.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 1","pages":"64-82"},"PeriodicalIF":9.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00588-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-02DOI: 10.1038/s44161-024-00585-y
Matthew DeBerge, Kristofor Glinton, Connor Lantz, Zhi-Dong Ge, David P. Sullivan, Swapna Patil, Bo Ryung Lee, Minori I. Thorp, Adam Mullick, Steve Yeh, Shuling Han, Anja M. van der Laan, Hans W. M. Niessen, Xunrong Luo, Nicholas E. S. Sibinga, Edward B. Thorp
Myocardial infarction (MI) mobilizes macrophages, the central protagonists of tissue repair in the infarcted heart. Although necessary for repair, macrophages also contribute to adverse remodeling and progression to heart failure. In this context, specific targeting of inflammatory macrophage activation may attenuate maladaptive responses and enhance cardiac repair. Allograft inflammatory factor 1 (AIF1) is a macrophage-specific protein expressed in a variety of inflammatory settings, but its function after MI is unknown. Here we identify a maladaptive role for macrophage AIF1 after MI in mice. Mechanistic studies show that AIF1 increases actin remodeling in macrophages to promote reactive oxygen species–dependent activation of hypoxia-inducible factor (HIF)-1α. This directs a switch to glycolytic metabolism to fuel macrophage-mediated inflammation, adverse ventricular remodeling and progression to heart failure. Targeted knockdown of Aif1 using antisense oligonucleotides improved cardiac repair, supporting further exploration of macrophage AIF1 as a therapeutic target after MI. DeBerge, Glinton et al. demonstrate that allograft inflammatory factor 1 promotes inflammatory glycolytic reprogramming in cardiac macrophages, leading to adverse remodeling and progression to heart failure after myocardial infarction.
{"title":"Mechanical regulation of macrophage metabolism by allograft inflammatory factor 1 leads to adverse remodeling after cardiac injury","authors":"Matthew DeBerge, Kristofor Glinton, Connor Lantz, Zhi-Dong Ge, David P. Sullivan, Swapna Patil, Bo Ryung Lee, Minori I. Thorp, Adam Mullick, Steve Yeh, Shuling Han, Anja M. van der Laan, Hans W. M. Niessen, Xunrong Luo, Nicholas E. S. Sibinga, Edward B. Thorp","doi":"10.1038/s44161-024-00585-y","DOIUrl":"10.1038/s44161-024-00585-y","url":null,"abstract":"Myocardial infarction (MI) mobilizes macrophages, the central protagonists of tissue repair in the infarcted heart. Although necessary for repair, macrophages also contribute to adverse remodeling and progression to heart failure. In this context, specific targeting of inflammatory macrophage activation may attenuate maladaptive responses and enhance cardiac repair. Allograft inflammatory factor 1 (AIF1) is a macrophage-specific protein expressed in a variety of inflammatory settings, but its function after MI is unknown. Here we identify a maladaptive role for macrophage AIF1 after MI in mice. Mechanistic studies show that AIF1 increases actin remodeling in macrophages to promote reactive oxygen species–dependent activation of hypoxia-inducible factor (HIF)-1α. This directs a switch to glycolytic metabolism to fuel macrophage-mediated inflammation, adverse ventricular remodeling and progression to heart failure. Targeted knockdown of Aif1 using antisense oligonucleotides improved cardiac repair, supporting further exploration of macrophage AIF1 as a therapeutic target after MI. DeBerge, Glinton et al. demonstrate that allograft inflammatory factor 1 promotes inflammatory glycolytic reprogramming in cardiac macrophages, leading to adverse remodeling and progression to heart failure after myocardial infarction.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 1","pages":"83-101"},"PeriodicalIF":9.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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