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}
Pub Date : 2025-01-02DOI: 10.1038/s44161-024-00581-2
Soyeon Kim, Hyunwoong Ko, Woojae Myung, Joohyun Yoon, Kiwon Kim, Sang-Hyuk Jung, Injeong Shim, Soojin Cha, Beomsu Kim, Jae Myeong Kang, Woong-Yang Park, Pradeep Natarajan, Ron Do, Hong-Hee Won
Participation in leisure and social activities (LSA) is associated with better health outcomes and lower mortality1–3. Previous observational studies demonstrated a relationship between engagement in LSA and both mental and physical health4,5. Although several studies6 examined the association between LSA and health outcomes, including cardiovascular disease, their possible causal relationship has not been studied. In this study, we investigated the causal relationship between LSA and various health outcomes, including cardiovascular disease, using data from genome-wide association study summary statistics (sample size = 63,926–1,557,411) and a Mendelian randomization approach. Genetically predicted LSA were associated with a reduced risk of several health outcomes, including coronary artery disease and coronary atherosclerosis. Mediation analysis indicated that these effects were partly mediated by modifiable risk factors, such as body mass index, smoking and lipid levels. These findings highlight the importance of LSA in disease prevention and health promotion. In a genetic study, Kim, Ko et al. demonstrate that participating in leisure and social activities reduces the risk of various diseases, including cardiovascular disease.
{"title":"Association between genetically predicted leisure and social activities and cardiovascular disease and other health outcomes","authors":"Soyeon Kim, Hyunwoong Ko, Woojae Myung, Joohyun Yoon, Kiwon Kim, Sang-Hyuk Jung, Injeong Shim, Soojin Cha, Beomsu Kim, Jae Myeong Kang, Woong-Yang Park, Pradeep Natarajan, Ron Do, Hong-Hee Won","doi":"10.1038/s44161-024-00581-2","DOIUrl":"10.1038/s44161-024-00581-2","url":null,"abstract":"Participation in leisure and social activities (LSA) is associated with better health outcomes and lower mortality1–3. Previous observational studies demonstrated a relationship between engagement in LSA and both mental and physical health4,5. Although several studies6 examined the association between LSA and health outcomes, including cardiovascular disease, their possible causal relationship has not been studied. In this study, we investigated the causal relationship between LSA and various health outcomes, including cardiovascular disease, using data from genome-wide association study summary statistics (sample size = 63,926–1,557,411) and a Mendelian randomization approach. Genetically predicted LSA were associated with a reduced risk of several health outcomes, including coronary artery disease and coronary atherosclerosis. Mediation analysis indicated that these effects were partly mediated by modifiable risk factors, such as body mass index, smoking and lipid levels. These findings highlight the importance of LSA in disease prevention and health promotion. In a genetic study, Kim, Ko et al. demonstrate that participating in leisure and social activities reduces the risk of various diseases, including cardiovascular disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 1","pages":"15-25"},"PeriodicalIF":9.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924162","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/s44161-024-00568-z
Paul Cheng, Thomas Quertermous
Single-cell transcriptomic studies have primarily focused on cell-autonomous mechanisms in coronary atherosclerosis. A study mapping the spatial transcriptome of cells in the diseased coronary artery elucidates the co-localization of vascular cell lineages, suggesting cell–cell communications in the neointima and in vascular adventitia.
{"title":"Spatial transcriptomic mapping of coronary atherosclerosis in the luminal plaque and beyond","authors":"Paul Cheng, Thomas Quertermous","doi":"10.1038/s44161-024-00568-z","DOIUrl":"10.1038/s44161-024-00568-z","url":null,"abstract":"Single-cell transcriptomic studies have primarily focused on cell-autonomous mechanisms in coronary atherosclerosis. A study mapping the spatial transcriptome of cells in the diseased coronary artery elucidates the co-localization of vascular cell lineages, suggesting cell–cell communications in the neointima and in vascular adventitia.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 1","pages":"8-10"},"PeriodicalIF":9.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924226","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 : 2024-12-23DOI: 10.1038/s44161-024-00582-1
Tore Bleckwehl, Anne Babler, Merel Tebens, Sidrah Maryam, Michael Nyberg, Markus Bosteen, Maurice Halder, Isaac Shaw, Susanne Fleig, Charles Pyke, Henning Hvid, Louise Marie Voetmann, Jaap D. van Buul, Judith C. Sluimer, Vivek Das, Simon Baumgart, Rafael Kramann, Sikander Hayat
Atherosclerosis is a pervasive contributor to ischemic heart disease and stroke. Despite the advance of lipid-lowering therapies and anti-hypertensive agents, the residual risk of an atherosclerotic event remains high, and developing therapeutic strategies has proven challenging. This is due to the complexity of atherosclerosis with a spatial interplay of multiple cell types within the vascular wall. In this study, we generated an integrative high-resolution map of human atherosclerotic plaques combining single-cell RNA sequencing from multiple studies and spatial transcriptomics data from 12 human specimens with different stages of atherosclerosis. Here we show cell-type-specific and atherosclerosis-specific expression changes and spatially constrained alterations in cell–cell communication. We highlight the possible recruitment of lymphocytes via ACKR1 endothelial cells of the vasa vasorum, the migration of vascular smooth muscle cells toward the lumen by transforming into fibromyocytes and cell–cell communication in the plaque region, indicating an intricate cellular interplay within the adventitia and the subendothelial space in human atherosclerosis. Bleckwehl et al. present a spatial transcriptomic map of atherosclerotic plaques across disease stages, revealing cellular recruitment and migration patterns and intercellular communication dynamics as a valuable resource for future research.
{"title":"Encompassing view of spatial and single-cell RNA sequencing renews the role of the microvasculature in human atherosclerosis","authors":"Tore Bleckwehl, Anne Babler, Merel Tebens, Sidrah Maryam, Michael Nyberg, Markus Bosteen, Maurice Halder, Isaac Shaw, Susanne Fleig, Charles Pyke, Henning Hvid, Louise Marie Voetmann, Jaap D. van Buul, Judith C. Sluimer, Vivek Das, Simon Baumgart, Rafael Kramann, Sikander Hayat","doi":"10.1038/s44161-024-00582-1","DOIUrl":"10.1038/s44161-024-00582-1","url":null,"abstract":"Atherosclerosis is a pervasive contributor to ischemic heart disease and stroke. Despite the advance of lipid-lowering therapies and anti-hypertensive agents, the residual risk of an atherosclerotic event remains high, and developing therapeutic strategies has proven challenging. This is due to the complexity of atherosclerosis with a spatial interplay of multiple cell types within the vascular wall. In this study, we generated an integrative high-resolution map of human atherosclerotic plaques combining single-cell RNA sequencing from multiple studies and spatial transcriptomics data from 12 human specimens with different stages of atherosclerosis. Here we show cell-type-specific and atherosclerosis-specific expression changes and spatially constrained alterations in cell–cell communication. We highlight the possible recruitment of lymphocytes via ACKR1 endothelial cells of the vasa vasorum, the migration of vascular smooth muscle cells toward the lumen by transforming into fibromyocytes and cell–cell communication in the plaque region, indicating an intricate cellular interplay within the adventitia and the subendothelial space in human atherosclerosis. Bleckwehl et al. present a spatial transcriptomic map of atherosclerotic plaques across disease stages, revealing cellular recruitment and migration patterns and intercellular communication dynamics as a valuable resource for future research.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 1","pages":"26-44"},"PeriodicalIF":9.4,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883830","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 : 2024-12-11DOI: 10.1038/s44161-024-00578-x
Clonal hematopoiesis of cells carrying an ASXL1 mutation promotes atherosclerosis. An unexpected function of ASXL1 — direct inhibition of IL-1 receptor and Toll-like receptor signaling — was lost by ASXL1 mutation, leading to prolonged inflammation. IRAK inhibitors reduced the atherosclerotic plaque size, implicating IRAK inhibitors in the therapies of cardiovascular diseases driven by ASXL1-associated clonal hematopoiesis.
{"title":"ASXL1 mutation accelerates atherosclerosis by promoting activation of myeloid cells","authors":"","doi":"10.1038/s44161-024-00578-x","DOIUrl":"10.1038/s44161-024-00578-x","url":null,"abstract":"Clonal hematopoiesis of cells carrying an ASXL1 mutation promotes atherosclerosis. An unexpected function of ASXL1 — direct inhibition of IL-1 receptor and Toll-like receptor signaling — was lost by ASXL1 mutation, leading to prolonged inflammation. IRAK inhibitors reduced the atherosclerotic plaque size, implicating IRAK inhibitors in the therapies of cardiovascular diseases driven by ASXL1-associated clonal hematopoiesis.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 12","pages":"1387-1388"},"PeriodicalIF":9.4,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811346","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 : 2024-12-10DOI: 10.1038/s44161-024-00589-8
The bHLH transcription factor Hand2 positively regulates pdgfra expression to promote early cardiogenesis in zebrafish. Hand2 can function in this process independently of direct DNA binding by interacting with Tcf3a, another bHLH transcription factor.
{"title":"DNA-binding-deficient Hand2 dimerizes with Tcf3a to control zebrafish cardiogenesis","authors":"","doi":"10.1038/s44161-024-00589-8","DOIUrl":"10.1038/s44161-024-00589-8","url":null,"abstract":"The bHLH transcription factor Hand2 positively regulates pdgfra expression to promote early cardiogenesis in zebrafish. Hand2 can function in this process independently of direct DNA binding by interacting with Tcf3a, another bHLH transcription factor.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 12","pages":"1383-1384"},"PeriodicalIF":9.4,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142808876","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 : 2024-12-10DOI: 10.1038/s44161-024-00574-1
Yanli Xu, Rupal Gehlot, Samuel J. Capon, Marga Albu, Jonas Gretz, Joshua Bloomekatz, Kenny Mattonet, Dubravka Vucicevic, Sweta Talyan, Khrievono Kikhi, Stefan Günther, Mario Looso, Beth A. Firulli, Miloslav Sanda, Anthony B. Firulli, Scott Allen Lacadie, Deborah Yelon, Didier Y. R. Stainier
The basic helix–loop–helix transcription factor HAND2 has multiple roles during vertebrate organogenesis, including cardiogenesis. However, much remains to be uncovered about its mechanism of action. Here, we show the generation of several hand2 mutant alleles in zebrafish and demonstrate that dimerization-deficient mutants display the null phenotype but DNA-binding-deficient mutants do not. Rescue experiments with Hand2 variants using a newly identified hand2 enhancer confirmed these observations. To identify Hand2 effectors critical for cardiogenesis, we analyzed the transcriptomes of hand2 loss- and gain-of-function embryonic cardiomyocytes and tested the function of eight candidate genes in vivo; pdgfra was most effective in rescuing myocardial migration in hand2 mutants. Accordingly, we identified a putative Hand2-binding region in the zebrafish pdgfra locus that is important for its expression. In addition, Hand2 loss- and gain-of-function experiments in mouse embryonic stem cell-derived cardiac cells decreased and increased Pdgfra expression, respectively. Altogether, these results further our mechanistic understanding of HAND2 function during early cardiogenesis. Xu and colleagues show that the transcription factor Hand2 promotes pdgfra expression during early cardiogenesis and that it can do so independently of direct DNA binding by interacting with Tcf3.
{"title":"PDGFRA is a conserved HAND2 effector during early cardiac development","authors":"Yanli Xu, Rupal Gehlot, Samuel J. Capon, Marga Albu, Jonas Gretz, Joshua Bloomekatz, Kenny Mattonet, Dubravka Vucicevic, Sweta Talyan, Khrievono Kikhi, Stefan Günther, Mario Looso, Beth A. Firulli, Miloslav Sanda, Anthony B. Firulli, Scott Allen Lacadie, Deborah Yelon, Didier Y. R. Stainier","doi":"10.1038/s44161-024-00574-1","DOIUrl":"10.1038/s44161-024-00574-1","url":null,"abstract":"The basic helix–loop–helix transcription factor HAND2 has multiple roles during vertebrate organogenesis, including cardiogenesis. However, much remains to be uncovered about its mechanism of action. Here, we show the generation of several hand2 mutant alleles in zebrafish and demonstrate that dimerization-deficient mutants display the null phenotype but DNA-binding-deficient mutants do not. Rescue experiments with Hand2 variants using a newly identified hand2 enhancer confirmed these observations. To identify Hand2 effectors critical for cardiogenesis, we analyzed the transcriptomes of hand2 loss- and gain-of-function embryonic cardiomyocytes and tested the function of eight candidate genes in vivo; pdgfra was most effective in rescuing myocardial migration in hand2 mutants. Accordingly, we identified a putative Hand2-binding region in the zebrafish pdgfra locus that is important for its expression. In addition, Hand2 loss- and gain-of-function experiments in mouse embryonic stem cell-derived cardiac cells decreased and increased Pdgfra expression, respectively. Altogether, these results further our mechanistic understanding of HAND2 function during early cardiogenesis. Xu and colleagues show that the transcription factor Hand2 promotes pdgfra expression during early cardiogenesis and that it can do so independently of direct DNA binding by interacting with Tcf3.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 12","pages":"1531-1548"},"PeriodicalIF":9.4,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00574-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807170","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 : 2024-12-09DOI: 10.1038/s44161-024-00584-z
Cerebral cavernous malformations (CCMs) can cause strokes and hemorrhages. A study reveals that blocking the formation of neutrophil extracellular traps (NETs) reduces CCM lesions and the associated clots and neuroinflammation, which suggests that targeting NETs might pave the way for new therapies to manage CCMs.
{"title":"Neutrophil extracellular traps worsen clotting and neuroinflammation in cavernomas","authors":"","doi":"10.1038/s44161-024-00584-z","DOIUrl":"10.1038/s44161-024-00584-z","url":null,"abstract":"Cerebral cavernous malformations (CCMs) can cause strokes and hemorrhages. A study reveals that blocking the formation of neutrophil extracellular traps (NETs) reduces CCM lesions and the associated clots and neuroinflammation, which suggests that targeting NETs might pave the way for new therapies to manage CCMs.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 12","pages":"1385-1386"},"PeriodicalIF":9.4,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142802507","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}
Certain somatic mutations provide a fitness advantage to hematopoietic stem cells and lead to clonal expansion of mutant blood cells, known as clonal hematopoiesis (CH). Among the most common CH mutations, ASXL1 mutations pose the highest risk for cardiovascular diseases (CVDs), yet the mechanisms by which they contribute to CVDs are unclear. Here we show that hematopoietic cells harboring C-terminally truncated ASXL1 mutant (ASXL1-MT) accelerate the development of atherosclerosis in Ldlr–/– mice. Transcriptome analyses of plaque cells showed that monocytes and macrophages expressing ASXL1-MT exhibit inflammatory signatures. Mechanistically, we demonstrate that wild-type ASXL1 has an unexpected non-epigenetic role by suppressing innate immune signaling through the inhibition of IRAK1–TAK1 interaction in the cytoplasm. This regulatory function is lost in ASXL1-MT, resulting in NF-κB activation. Inhibition of IRAK1/4 alleviated atherosclerosis driven by ASXL1-MT and decreased inflammatory monocytes. The present work provides a mechanistic and cellular explanation linking ASXL1 mutations, CH and CVDs. Somatic mutations in ASXL1 lead to clonal hematopoiesis, and Sato et al. elucidate the molecular mechanisms by which mutated ASXL1 in hematopoietic cells drives atherosclerosis in mice.
{"title":"Clonal hematopoiesis-related mutant ASXL1 promotes atherosclerosis in mice via dysregulated innate immunity","authors":"Naru Sato, Susumu Goyama, Yu-Hsuan Chang, Masashi Miyawaki, Takeshi Fujino, Shuhei Koide, Tamami Denda, Xiaoxiao Liu, Koji Ueda, Keita Yamamoto, Shuhei Asada, Reina Takeda, Taishi Yonezawa, Yosuke Tanaka, Hiroaki Honda, Yasunori Ota, Takuma Shibata, Motohiro Sekiya, Tomoya Isobe, Chrystelle Lamagna, Esteban Masuda, Atsushi Iwama, Hitoshi Shimano, Jun-ichiro Inoue, Kensuke Miyake, Toshio Kitamura","doi":"10.1038/s44161-024-00579-w","DOIUrl":"10.1038/s44161-024-00579-w","url":null,"abstract":"Certain somatic mutations provide a fitness advantage to hematopoietic stem cells and lead to clonal expansion of mutant blood cells, known as clonal hematopoiesis (CH). Among the most common CH mutations, ASXL1 mutations pose the highest risk for cardiovascular diseases (CVDs), yet the mechanisms by which they contribute to CVDs are unclear. Here we show that hematopoietic cells harboring C-terminally truncated ASXL1 mutant (ASXL1-MT) accelerate the development of atherosclerosis in Ldlr–/– mice. Transcriptome analyses of plaque cells showed that monocytes and macrophages expressing ASXL1-MT exhibit inflammatory signatures. Mechanistically, we demonstrate that wild-type ASXL1 has an unexpected non-epigenetic role by suppressing innate immune signaling through the inhibition of IRAK1–TAK1 interaction in the cytoplasm. This regulatory function is lost in ASXL1-MT, resulting in NF-κB activation. Inhibition of IRAK1/4 alleviated atherosclerosis driven by ASXL1-MT and decreased inflammatory monocytes. The present work provides a mechanistic and cellular explanation linking ASXL1 mutations, CH and CVDs. Somatic mutations in ASXL1 lead to clonal hematopoiesis, and Sato et al. elucidate the molecular mechanisms by which mutated ASXL1 in hematopoietic cells drives atherosclerosis in mice.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 12","pages":"1568-1583"},"PeriodicalIF":9.4,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142802472","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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