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.
{"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":"https://doi.org/10.1038/s44161-024-00593-y","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142959940","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/s44161-024-00594-x
Miao Cui
{"title":"Conduction system regeneration and remodeling after myocardial infarction.","authors":"Miao Cui","doi":"10.1038/s44161-024-00594-x","DOIUrl":"https://doi.org/10.1038/s44161-024-00594-x","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"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.
{"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":"https://doi.org/10.1038/s44161-024-00586-x","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928842","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 : 2025-01-02DOI: 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}
Pub Date : 2025-01-02DOI: 10.1038/s44161-024-00583-0
Tatiana V. Petrova, Valeria V. Orlova
The origins of mammalian lymphatic vessels have been debated since the early twentieth century; recent data are shifting the balance toward a less widely accepted view.
{"title":"Paraxial mesoderm as a direct gateway to lymphatic endothelial cells","authors":"Tatiana V. Petrova, Valeria V. Orlova","doi":"10.1038/s44161-024-00583-0","DOIUrl":"10.1038/s44161-024-00583-0","url":null,"abstract":"The origins of mammalian lymphatic vessels have been debated since the early twentieth century; recent data are shifting the balance toward a less widely accepted view.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 1","pages":"11-12"},"PeriodicalIF":9.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924219","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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