Pub Date : 2024-10-01DOI: 10.1038/s44161-024-00552-7
{"title":"Evolution of cardiac genomic elements in humans and non-human primates.","authors":"","doi":"10.1038/s44161-024-00552-7","DOIUrl":"https://doi.org/10.1038/s44161-024-00552-7","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362510","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 : 2024-09-25DOI: 10.1038/s44161-024-00546-5
Nalan Tetik-Elsherbiny, Adel Elsherbiny, Aadhyaa Setya, Johannes Gahn, Yongqin Tang, Purnima Gupta, Yanliang Dou, Heike Serke, Thomas Wieland, Alexandre Dubrac, Joerg Heineke, Michael Potente, Julio Cordero, Roxana Ola, Gergana Dobreva
Signal-responsive gene expression is essential for vascular development, yet the mechanisms integrating signaling inputs with transcriptional activities are largely unknown. Here we show that RNF20, the primary E3 ubiquitin ligase for histone H2B, plays a multifaceted role in sprouting angiogenesis. RNF20 mediates RNA polymerase (Pol II) promoter-proximal pausing at genes highly paused in endothelial cells, involved in VEGFA signaling, stress response, cell cycle control and mRNA splicing. It also orchestrates large-scale mRNA processing events that alter the bioavailability and function of critical pro-angiogenic factors, such as VEGFA. Mechanistically, RNF20 restricts ERG-dependent Pol II pause release at highly paused genes while binding to Notch1 to promote H2B monoubiquitination at Notch target genes and Notch-dependent gene expression. This balance is crucial, as loss of Rnf20 leads to uncontrolled tip cell specification. Our findings highlight the pivotal role of RNF20 in regulating VEGF-Notch signaling circuits during vessel growth, underscoring its potential for therapeutic modulation of angiogenesis.
{"title":"RNF20-mediated transcriptional pausing and VEGFA splicing orchestrate vessel growth.","authors":"Nalan Tetik-Elsherbiny, Adel Elsherbiny, Aadhyaa Setya, Johannes Gahn, Yongqin Tang, Purnima Gupta, Yanliang Dou, Heike Serke, Thomas Wieland, Alexandre Dubrac, Joerg Heineke, Michael Potente, Julio Cordero, Roxana Ola, Gergana Dobreva","doi":"10.1038/s44161-024-00546-5","DOIUrl":"10.1038/s44161-024-00546-5","url":null,"abstract":"<p><p>Signal-responsive gene expression is essential for vascular development, yet the mechanisms integrating signaling inputs with transcriptional activities are largely unknown. Here we show that RNF20, the primary E3 ubiquitin ligase for histone H2B, plays a multifaceted role in sprouting angiogenesis. RNF20 mediates RNA polymerase (Pol II) promoter-proximal pausing at genes highly paused in endothelial cells, involved in VEGFA signaling, stress response, cell cycle control and mRNA splicing. It also orchestrates large-scale mRNA processing events that alter the bioavailability and function of critical pro-angiogenic factors, such as VEGFA. Mechanistically, RNF20 restricts ERG-dependent Pol II pause release at highly paused genes while binding to Notch1 to promote H2B monoubiquitination at Notch target genes and Notch-dependent gene expression. This balance is crucial, as loss of Rnf20 leads to uncontrolled tip cell specification. Our findings highlight the pivotal role of RNF20 in regulating VEGF-Notch signaling circuits during vessel growth, underscoring its potential for therapeutic modulation of angiogenesis.</p>","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333948","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 : 2024-09-25DOI: 10.1038/s44161-024-00545-6
Lars Lind, Mohsen Mazidi, Robert Clarke, Derrick A Bennett, Rui Zheng
Several large-scale studies have measured plasma levels of the proteome in individuals with cardiovascular diseases (CVDs)1-7. However, since the majority of such proteins are interrelated2, it is difficult for observational studies to distinguish which proteins are likely to be of etiological relevance. Here we evaluate whether plasma levels of 2,919 proteins measured in 52,164 UK Biobank participants are associated with incident myocardial infarction, ischemic stroke or heart failure. Of those proteins, 126 were associated with all three CVD outcomes and 118 were associated with at least one CVD in the China Kadoorie Biobank. Mendelian randomization and colocalization analyses indicated that genetically determined levels of 47 and 18 proteins, respectively, were associated with CVDs, including FGF5, PROCR and FURIN. While the majority of protein-CVD observational associations were noncausal, these three proteins showed evidence to support potential causality and are therefore promising targets for drug treatment for CVD outcomes.
{"title":"Measured and genetically predicted protein levels and cardiovascular diseases in UK Biobank and China Kadoorie Biobank.","authors":"Lars Lind, Mohsen Mazidi, Robert Clarke, Derrick A Bennett, Rui Zheng","doi":"10.1038/s44161-024-00545-6","DOIUrl":"https://doi.org/10.1038/s44161-024-00545-6","url":null,"abstract":"<p><p>Several large-scale studies have measured plasma levels of the proteome in individuals with cardiovascular diseases (CVDs)<sup>1-7</sup>. However, since the majority of such proteins are interrelated<sup>2</sup>, it is difficult for observational studies to distinguish which proteins are likely to be of etiological relevance. Here we evaluate whether plasma levels of 2,919 proteins measured in 52,164 UK Biobank participants are associated with incident myocardial infarction, ischemic stroke or heart failure. Of those proteins, 126 were associated with all three CVD outcomes and 118 were associated with at least one CVD in the China Kadoorie Biobank. Mendelian randomization and colocalization analyses indicated that genetically determined levels of 47 and 18 proteins, respectively, were associated with CVDs, including FGF5, PROCR and FURIN. While the majority of protein-CVD observational associations were noncausal, these three proteins showed evidence to support potential causality and are therefore promising targets for drug treatment for CVD outcomes.</p>","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333947","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 : 2024-09-24DOI: 10.1038/s44161-024-00544-7
Jorge Ruiz-Orera, Duncan C Miller, Johannes Greiner, Carolin Genehr, Aliki Grammatikaki, Susanne Blachut, Jeanne Mbebi, Giannino Patone, Anna Myronova, Eleonora Adami, Nikita Dewani, Ning Liang, Oliver Hummel, Michael B Muecke, Thomas B Hildebrandt, Guido Fritsch, Lisa Schrade, Wolfram H Zimmermann, Ivanela Kondova, Sebastian Diecke, Sebastiaan van Heesch, Norbert Hübner
Evolutionary innovations can be driven by changes in the rates of RNA translation and the emergence of new genes and small open reading frames (sORFs). In this study, we characterized the transcriptional and translational landscape of the hearts of four primate and two rodent species through integrative ribosome and transcriptomic profiling, including adult left ventricle tissues and induced pluripotent stem cell-derived cardiomyocyte cell cultures. We show here that the translational efficiencies of subunits of the mitochondrial oxidative phosphorylation chain complexes IV and V evolved rapidly across mammalian evolution. Moreover, we discovered hundreds of species-specific and lineage-specific genomic innovations that emerged during primate evolution in the heart, including 551 genes, 504 sORFs and 76 evolutionarily conserved genes displaying human-specific cardiac-enriched expression. Overall, our work describes the evolutionary processes and mechanisms that have shaped cardiac transcription and translation in recent primate evolution and sheds light on how these can contribute to cardiac development and disease.
RNA翻译速率的变化以及新基因和小开放阅读框（sORF）的出现可以推动进化创新。在这项研究中，我们通过核糖体和转录组综合分析，包括成人左心室组织和诱导多能干细胞衍生的心肌细胞培养物，描述了四种灵长类动物和两种啮齿类动物心脏的转录和翻译情况。我们在这里发现，线粒体氧化磷酸化链复合物 IV 和 V 亚基的翻译效率在哺乳动物进化过程中迅速进化。此外，我们还发现了灵长类动物心脏进化过程中出现的数百个物种特异性和品系特异性基因组创新，其中包括 551 个基因、504 个 sORF 和 76 个进化保守基因，这些基因显示出人类特异性的心脏丰富表达。总之，我们的工作描述了近代灵长类动物进化过程中形成心脏转录和翻译的进化过程和机制，并揭示了这些过程和机制如何促进心脏发育和疾病的发生。
{"title":"Evolution of translational control and the emergence of genes and open reading frames in human and non-human primate hearts.","authors":"Jorge Ruiz-Orera, Duncan C Miller, Johannes Greiner, Carolin Genehr, Aliki Grammatikaki, Susanne Blachut, Jeanne Mbebi, Giannino Patone, Anna Myronova, Eleonora Adami, Nikita Dewani, Ning Liang, Oliver Hummel, Michael B Muecke, Thomas B Hildebrandt, Guido Fritsch, Lisa Schrade, Wolfram H Zimmermann, Ivanela Kondova, Sebastian Diecke, Sebastiaan van Heesch, Norbert Hübner","doi":"10.1038/s44161-024-00544-7","DOIUrl":"https://doi.org/10.1038/s44161-024-00544-7","url":null,"abstract":"<p><p>Evolutionary innovations can be driven by changes in the rates of RNA translation and the emergence of new genes and small open reading frames (sORFs). In this study, we characterized the transcriptional and translational landscape of the hearts of four primate and two rodent species through integrative ribosome and transcriptomic profiling, including adult left ventricle tissues and induced pluripotent stem cell-derived cardiomyocyte cell cultures. We show here that the translational efficiencies of subunits of the mitochondrial oxidative phosphorylation chain complexes IV and V evolved rapidly across mammalian evolution. Moreover, we discovered hundreds of species-specific and lineage-specific genomic innovations that emerged during primate evolution in the heart, including 551 genes, 504 sORFs and 76 evolutionarily conserved genes displaying human-specific cardiac-enriched expression. Overall, our work describes the evolutionary processes and mechanisms that have shaped cardiac transcription and translation in recent primate evolution and sheds light on how these can contribute to cardiac development and disease.</p>","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333946","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 : 2024-09-18DOI: 10.1038/s44161-024-00542-9
Khanh V Doan,Timothy S Luongo,Thato T Ts'olo,Won Dong Lee,David W Frederick,Sarmistha Mukherjee,Gabriel K Adzika,Caroline E Perry,Ryan B Gaspar,Nicole Walker,Megan C Blair,Nicole Bye,James G Davis,Corey D Holman,Qingwei Chu,Lin Wang,Joshua D Rabinowitz,Daniel P Kelly,Thomas P Cappola,Kenneth B Margulies,Joseph A Baur
Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD+ levels, and supplementation with NAD+ precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD+ along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD+ loss as all were ameliorated by restoring cardiac NAD+ levels with the NAD+ precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD+ concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics.
{"title":"Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.","authors":"Khanh V Doan,Timothy S Luongo,Thato T Ts'olo,Won Dong Lee,David W Frederick,Sarmistha Mukherjee,Gabriel K Adzika,Caroline E Perry,Ryan B Gaspar,Nicole Walker,Megan C Blair,Nicole Bye,James G Davis,Corey D Holman,Qingwei Chu,Lin Wang,Joshua D Rabinowitz,Daniel P Kelly,Thomas P Cappola,Kenneth B Margulies,Joseph A Baur","doi":"10.1038/s44161-024-00542-9","DOIUrl":"https://doi.org/10.1038/s44161-024-00542-9","url":null,"abstract":"Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD+ levels, and supplementation with NAD+ precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD+ along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD+ loss as all were ameliorated by restoring cardiac NAD+ levels with the NAD+ precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD+ concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247373","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 : 2024-09-13DOI: 10.1038/s44161-024-00539-4
Kazu Kikuchi
The endocardium is activated immediately after injury and promotes cardiac muscle regeneration by producing growth factors. Research now shows that innate immune signaling is crucial for the regenerative function of the endocardium.
{"title":"Success in heart regeneration depends on endocardial innate immune signaling","authors":"Kazu Kikuchi","doi":"10.1038/s44161-024-00539-4","DOIUrl":"10.1038/s44161-024-00539-4","url":null,"abstract":"The endocardium is activated immediately after injury and promotes cardiac muscle regeneration by producing growth factors. Research now shows that innate immune signaling is crucial for the regenerative function of the endocardium.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231135","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 : 2024-09-13DOI: 10.1038/s44161-024-00534-9
Fibromuscular dysplasia (FMD) is a poorly understood blood vessel disorder that affects up to 5% of adults. Using a systems genetics approach, we identified an FMD-associated gene co-expression network that governs vascular cell function and developed a mouse model of FMD that recapitulates certain aspects of the human disease.
{"title":"Identifying a gene-regulatory network that drives fibromuscular dysplasia","authors":"","doi":"10.1038/s44161-024-00534-9","DOIUrl":"10.1038/s44161-024-00534-9","url":null,"abstract":"Fibromuscular dysplasia (FMD) is a poorly understood blood vessel disorder that affects up to 5% of adults. Using a systems genetics approach, we identified an FMD-associated gene co-expression network that governs vascular cell function and developed a mouse model of FMD that recapitulates certain aspects of the human disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231159","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 : 2024-09-13DOI: 10.1038/s44161-024-00533-w
Valentina d’Escamard, Daniella Kadian-Dodov, Lijiang Ma, Sizhao Lu, Annette King, Yang Xu, Shouneng Peng, Bhargravi V′Gangula, Yu Zhou, Allison Thomas, Katherine C. Michelis, Emir Bander, Rihab Bouchareb, Adrien Georges, Aya Nomura-Kitabayashi, Robert J. Wiener, Kevin D. Costa, Elena Chepurko, Vadim Chepurko, Marika Fava, Temo Barwari, Anelechi Anyanwu, Farzan Filsoufi, Sander Florman, Nabila Bouatia-Naji, Lukas E. Schmidt, Manuel Mayr, Michael G. Katz, Ke Hao, Mary C. M. Weiser-Evans, Johan L. M. Björkegren, Jeffrey W. Olin, Jason C. Kovacic
Fibromuscular dysplasia (FMD) is a poorly understood disease affecting 3–5% of adult females. The pathobiology of FMD involves arterial lesions of stenosis, dissection, tortuosity, dilation and aneurysm, which can lead to hypertension, stroke, myocardial infarction and even death. Currently, there are no animal models for FMD and few insights as to its pathobiology. In this study, by integrating DNA genotype and RNA sequence data from primary fibroblasts of 83 patients with FMD and 71 matched healthy controls, we inferred 18 gene regulatory co-expression networks, four of which were found to act together as an FMD-associated supernetwork in the arterial wall. After in vivo perturbation of this co-expression supernetwork by selective knockout of a top network key driver, mice developed arterial dilation, a hallmark of FMD. Molecular studies indicated that this supernetwork governs multiple aspects of vascular cell physiology and functionality, including collagen/matrix production. These studies illuminate the complex causal mechanisms of FMD and suggest a potential therapeutic avenue for this challenging disease. By integrating DNA genotype and RNA sequencing data from human samples, d’Escamard et al. identify a gene regulatory co-expression supernetwork that plays an important role in fibromuscular dysplasia, a poorly understood disease affecting 3–5% of adult females.
{"title":"Integrative gene regulatory network analysis discloses key driver genes of fibromuscular dysplasia","authors":"Valentina d’Escamard, Daniella Kadian-Dodov, Lijiang Ma, Sizhao Lu, Annette King, Yang Xu, Shouneng Peng, Bhargravi V′Gangula, Yu Zhou, Allison Thomas, Katherine C. Michelis, Emir Bander, Rihab Bouchareb, Adrien Georges, Aya Nomura-Kitabayashi, Robert J. Wiener, Kevin D. Costa, Elena Chepurko, Vadim Chepurko, Marika Fava, Temo Barwari, Anelechi Anyanwu, Farzan Filsoufi, Sander Florman, Nabila Bouatia-Naji, Lukas E. Schmidt, Manuel Mayr, Michael G. Katz, Ke Hao, Mary C. M. Weiser-Evans, Johan L. M. Björkegren, Jeffrey W. Olin, Jason C. Kovacic","doi":"10.1038/s44161-024-00533-w","DOIUrl":"10.1038/s44161-024-00533-w","url":null,"abstract":"Fibromuscular dysplasia (FMD) is a poorly understood disease affecting 3–5% of adult females. The pathobiology of FMD involves arterial lesions of stenosis, dissection, tortuosity, dilation and aneurysm, which can lead to hypertension, stroke, myocardial infarction and even death. Currently, there are no animal models for FMD and few insights as to its pathobiology. In this study, by integrating DNA genotype and RNA sequence data from primary fibroblasts of 83 patients with FMD and 71 matched healthy controls, we inferred 18 gene regulatory co-expression networks, four of which were found to act together as an FMD-associated supernetwork in the arterial wall. After in vivo perturbation of this co-expression supernetwork by selective knockout of a top network key driver, mice developed arterial dilation, a hallmark of FMD. Molecular studies indicated that this supernetwork governs multiple aspects of vascular cell physiology and functionality, including collagen/matrix production. These studies illuminate the complex causal mechanisms of FMD and suggest a potential therapeutic avenue for this challenging disease. By integrating DNA genotype and RNA sequencing data from human samples, d’Escamard et al. identify a gene regulatory co-expression supernetwork that plays an important role in fibromuscular dysplasia, a poorly understood disease affecting 3–5% of adult females.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231142","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 : 2024-09-13DOI: 10.1038/s44161-024-00538-5
Pinelopi Goumenaki, Stefan Günther, Khrievono Kikhi, Mario Looso, Rubén Marín-Juez, Didier Y. R. Stainier
The innate immune response is triggered rapidly after injury and its spatiotemporal dynamics are critical for regeneration; however, many questions remain about its exact role. Here we show that MyD88, a key component of the innate immune response, controls not only the inflammatory but also the fibrotic response during zebrafish cardiac regeneration. We find in cryoinjured myd88−/− ventricles a significant reduction in neutrophil and macrophage numbers and the expansion of a collagen-rich endocardial population. Further analyses reveal compromised PI3K/AKT pathway activation in the myd88−/− endocardium and increased myofibroblasts and scarring. Notably, endothelial-specific overexpression of myd88 reverses these neutrophil, fibrotic and scarring phenotypes. Mechanistically, we identify the endocardial-derived chemokine gene cxcl18b as a target of the MyD88 signaling pathway, and using loss-of-function and gain-of-function tools, we show that it controls neutrophil recruitment. Altogether, these findings shed light on the pivotal role of MyD88 in modulating inflammation and fibrosis during tissue regeneration. Goumenaki et al. uncover that during zebrafish cardiac regeneration, MyD88 signaling promotes the inflammatory response to injury and attenuates the endocardial-mediated fibrotic response.
{"title":"The innate immune regulator MyD88 dampens fibrosis during zebrafish heart regeneration","authors":"Pinelopi Goumenaki, Stefan Günther, Khrievono Kikhi, Mario Looso, Rubén Marín-Juez, Didier Y. R. Stainier","doi":"10.1038/s44161-024-00538-5","DOIUrl":"10.1038/s44161-024-00538-5","url":null,"abstract":"The innate immune response is triggered rapidly after injury and its spatiotemporal dynamics are critical for regeneration; however, many questions remain about its exact role. Here we show that MyD88, a key component of the innate immune response, controls not only the inflammatory but also the fibrotic response during zebrafish cardiac regeneration. We find in cryoinjured myd88−/− ventricles a significant reduction in neutrophil and macrophage numbers and the expansion of a collagen-rich endocardial population. Further analyses reveal compromised PI3K/AKT pathway activation in the myd88−/− endocardium and increased myofibroblasts and scarring. Notably, endothelial-specific overexpression of myd88 reverses these neutrophil, fibrotic and scarring phenotypes. Mechanistically, we identify the endocardial-derived chemokine gene cxcl18b as a target of the MyD88 signaling pathway, and using loss-of-function and gain-of-function tools, we show that it controls neutrophil recruitment. Altogether, these findings shed light on the pivotal role of MyD88 in modulating inflammation and fibrosis during tissue regeneration. Goumenaki et al. uncover that during zebrafish cardiac regeneration, MyD88 signaling promotes the inflammatory response to injury and attenuates the endocardial-mediated fibrotic response.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00538-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231130","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}
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