Nature cardiovascular research最新文献_第9页

Network-based prioritization and validation of regulators of vascular smooth muscle cell proliferation in disease 基于网络的疾病中血管平滑肌细胞增殖调节因子的优先排序和验证

Nature cardiovascular research Pub Date : 2024-06-06 DOI: 10.1038/s44161-024-00474-4

Jordi Lambert, Sebnem Oc, Matthew D. Worssam, Daniel Häußler, Charles U. Solomon, Nichola L. Figg, Ruby Baxter, Maria Imaz, James C. K. Taylor, Kirsty Foote, Alison Finigan, Krishnaa T. Mahbubani, Tom R. Webb, Shu Ye, Martin R. Bennett, Achim Krüger, Mikhail Spivakov, Helle F. Jørgensen

{"title":"Network-based prioritization and validation of regulators of vascular smooth muscle cell proliferation in disease","authors":"Jordi Lambert, Sebnem Oc, Matthew D. Worssam, Daniel Häußler, Charles U. Solomon, Nichola L. Figg, Ruby Baxter, Maria Imaz, James C. K. Taylor, Kirsty Foote, Alison Finigan, Krishnaa T. Mahbubani, Tom R. Webb, Shu Ye, Martin R. Bennett, Achim Krüger, Mikhail Spivakov, Helle F. Jørgensen","doi":"10.1038/s44161-024-00474-4","DOIUrl":"10.1038/s44161-024-00474-4","url":null,"abstract":"Aberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation characterize vascular diseases causing heart attack and stroke. Here we elucidate molecular determinants governing VSMC proliferation by reconstructing gene regulatory networks from single-cell transcriptomics and epigenetic profiling. We detect widespread activation of enhancers at disease-relevant loci in proliferation-predisposed VSMCs. We compared gene regulatory network rewiring between injury-responsive and nonresponsive VSMCs, which suggested shared transcription factors but differing target loci between VSMC states. Through in silico perturbation analysis, we identified and prioritized previously unrecognized regulators of proliferation, including RUNX1 and TIMP1. Moreover, we showed that the pioneer transcription factor RUNX1 increased VSMC responsiveness and that TIMP1 feeds back to promote VSMC proliferation through CD74-mediated STAT3 signaling. Both RUNX1 and the TIMP1–CD74 axis were expressed in human VSMCs, showing low levels in normal arteries and increased expression in disease, suggesting clinical relevance and potential as vascular disease targets. Lambert, Oc et al. reconstruct gene regulatory networks from single-cell transcriptomics and epigenetic profiling, compare mouse and human data, and report previously unrecognized regulators of vascular smooth muscle cell proliferation in disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 6","pages":"714-733"},"PeriodicalIF":0.0,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00474-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141377420","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}

引用次数: 0

Age-dependent shortcut of the platelet differentiation cascade drives thrombocytosis and thrombotic diseases 血小板分化级联随年龄增长而缩短，导致血小板增多和血栓性疾病

Nature cardiovascular research Pub Date : 2024-06-06 DOI: 10.1038/s44161-024-00501-4

Gerburg Schwaerzer

引用次数: 0

Trimming down with semaglutide improves cardiac health in non-diabetic patients 使用塞马鲁肽减肥可改善非糖尿病患者的心脏健康

Nature cardiovascular research Pub Date : 2024-06-06 DOI: 10.1038/s44161-024-00498-w

Andrea Tavosanis

引用次数: 0

Macrophages upregulate mural cell-like markers and support healing of ischemic injury by adopting functions important for vascular support 巨噬细胞上调壁细胞样标志物，并通过承担对血管支持很重要的功能来支持缺血性损伤的愈合

Nature cardiovascular research Pub Date : 2024-06-06 DOI: 10.1038/s44161-024-00478-0

Catarina Amoedo-Leite, Kristel Parv, Chiara Testini, Carmen Herrera-Hidalgo, Feifei Xu, Antoine Giraud, Marta Malaquias, Erik Fasterius, Daniel Holl, Cedric Seignez, Christian Göritz, Gustaf Christoffersson, Mia Phillipson

{"title":"Macrophages upregulate mural cell-like markers and support healing of ischemic injury by adopting functions important for vascular support","authors":"Catarina Amoedo-Leite, Kristel Parv, Chiara Testini, Carmen Herrera-Hidalgo, Feifei Xu, Antoine Giraud, Marta Malaquias, Erik Fasterius, Daniel Holl, Cedric Seignez, Christian Göritz, Gustaf Christoffersson, Mia Phillipson","doi":"10.1038/s44161-024-00478-0","DOIUrl":"10.1038/s44161-024-00478-0","url":null,"abstract":"Sterile inflammation after injury is important for tissue restoration. In injured human and mouse tissues, macrophages were recently found to accumulate perivascularly. This study investigates if macrophages adopt a mural cell phenotype important for restoration after ischemic injury. Single-cell RNA sequencing of fate-mapped macrophages from ischemic mouse muscles demonstrates a macrophage-toward-mural cell switch of a subpopulation of macrophages with downregulated myeloid cell genes and upregulated mural cell genes, including PDGFRβ. This observation was further strengthened when including unspliced transcripts in the analysis. The macrophage switch was proven functionally relevant, as induction of macrophage-specific PDGFRβ deficiency prevented their perivascular macrophage phenotype, impaired vessel maturation and increased vessel leakiness, which ultimately reduced limb function. In conclusion, macrophages in adult ischemic tissue were demonstrated to undergo a cellular program to morphologically, transcriptomically and functionally resemble mural cells while weakening their macrophage identity. The macrophage-to-mural cell-like phenotypic switch is crucial for restoring tissue function and warrants further exploration as a potential target for immunotherapies to enhance healing. Amoedo-Leite et al. report that, in ischemic tissue, a subset of macrophages adopts mural cell-like morphology, gene expression and function, which is crucial for injury healing.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 6","pages":"685-700"},"PeriodicalIF":0.0,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00478-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141378906","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}

引用次数: 0

A self-reinforcing cycle hypothesis in heart failure pathogenesis 心力衰竭发病机制中的自我强化循环假说

Nature cardiovascular research Pub Date : 2024-06-03 DOI: 10.1038/s44161-024-00480-6

Carlos Fernandez-Patron, Gary D. Lopaschuk, Eugenio Hardy

{"title":"A self-reinforcing cycle hypothesis in heart failure pathogenesis","authors":"Carlos Fernandez-Patron, Gary D. Lopaschuk, Eugenio Hardy","doi":"10.1038/s44161-024-00480-6","DOIUrl":"10.1038/s44161-024-00480-6","url":null,"abstract":"Heart failure is a progressive syndrome with high morbidity and mortality rates. Here, we suggest that chronic exposure of the heart to risk factors for heart failure damages heart mitochondria, thereby impairing energy production to levels that can suppress the heart’s ability to pump blood and repair mitochondria (both energy-consuming processes). As damaged mitochondria accumulate, the heart becomes deprived of energy in a ‘self-reinforcing cycle’, which can persist after the heart is no longer chronically exposed to (or after antagonism of) the risk factors that initiated the cycle. Together with other previously described pathological mechanisms, this proposed cycle can help explain (1) why heart failure progresses, (2) why it can recur after cessation of treatment, and (3) why heart failure is often accompanied by dysfunction of multiple organs. Ideally, therapy of heart failure syndrome would be best attempted before the self-reinforcing cycle is triggered or designed to break the self-reinforcing cycle. Fernandez-Patron et al. propose a unifying framework explaining how diverse risk factors such as hypertension, obesity and diabetes lead pathogenesis and progression of heart failure.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 6","pages":"627-636"},"PeriodicalIF":0.0,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141272025","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}

引用次数: 0

A transcriptional enhancer regulates cardiac maturation 转录增强子调控心脏成熟

Nature cardiovascular research Pub Date : 2024-05-30 DOI: 10.1038/s44161-024-00484-2

Myo Htet, Shunyao Lei, Sheetal Bajpayi, Harshi Gangrade, Marios Arvanitis, Asimina Zoitou, Sean Murphy, Elaine Zhelan Chen, Navid Koleini, Brian Leei Lin, Chulan Kwon, Emmanouil Tampakakis

{"title":"A transcriptional enhancer regulates cardiac maturation","authors":"Myo Htet, Shunyao Lei, Sheetal Bajpayi, Harshi Gangrade, Marios Arvanitis, Asimina Zoitou, Sean Murphy, Elaine Zhelan Chen, Navid Koleini, Brian Leei Lin, Chulan Kwon, Emmanouil Tampakakis","doi":"10.1038/s44161-024-00484-2","DOIUrl":"10.1038/s44161-024-00484-2","url":null,"abstract":"Cardiomyocyte maturation is crucial for generating adult cardiomyocytes and the application of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). However, regulation at the cis-regulatory element level and its role in heart disease remain unclear. Alpha-actinin 2 (ACTN2) levels increase during CM maturation. In this study, we investigated a clinically relevant, conserved ACTN2 enhancer’s effects on CM maturation using hPSC and mouse models. Heterozygous ACTN2 enhancer deletion led to abnormal CM morphology, reduced function and mitochondrial respiration. Transcriptomic analyses in vitro and in vivo showed disrupted CM maturation and upregulated anabolic mammalian target for rapamycin (mTOR) signaling, promoting senescence and hindering maturation. As confirmation, ACTN2 enhancer deletion induced heat shock protein 90A expression, a chaperone mediating mTOR activation. Conversely, targeting the ACTN2 enhancer via enhancer CRISPR activation (enCRISPRa) promoted hPSC-CM maturation. Our studies reveal the transcriptional enhancer’s role in cardiac maturation and disease, offering insights into potentially fine-tuning gene expression to modulate cardiomyocyte physiology. Htet et al. identify and characterize a transcriptional enhancer that regulates cardiomyocyte maturation and function in human pluripotent stem cell and mouse models.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 6","pages":"666-684"},"PeriodicalIF":0.0,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141425155","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}

引用次数: 0

Cardiac ACTN2 enhancer regulates cardiometabolism and maturation 心脏 ACTN2 增强子调节心脏代谢和成熟

Nature cardiovascular research Pub Date : 2024-05-30 DOI: 10.1038/s44161-024-00483-3

Francisco X. Galdos, Carissa Lee, Sean M. Wu

引用次数: 0

Immunometabolism in atherosclerotic disorders 动脉粥样硬化疾病中的免疫代谢

Nature cardiovascular research Pub Date : 2024-05-23 DOI: 10.1038/s44161-024-00473-5

Andrew J. Fleetwood, Jonathan Noonan, Nicole La Gruta, Axel Kallies, Andrew J. Murphy

{"title":"Immunometabolism in atherosclerotic disorders","authors":"Andrew J. Fleetwood, Jonathan Noonan, Nicole La Gruta, Axel Kallies, Andrew J. Murphy","doi":"10.1038/s44161-024-00473-5","DOIUrl":"10.1038/s44161-024-00473-5","url":null,"abstract":"Cardiovascular diseases (CVDs), including atherosclerosis, myocardial infarction and heart failure, are the leading causes of morbidity and mortality worldwide. Emerging evidence suggests a crucial role for immune cell dysfunction and inflammation in the progression of this complex set of diseases. Recent advances demonstrate that immune cells, tightly linked to CVD pathogenesis, are sensitive to environmental signals and respond by engaging immunometabolic networks that shape their behavior. Inflammatory cues and altered nutrient availability within atherosclerotic plaques or following ischemia synergize to elicit metabolic shifts in immune cells that influence the course of disease pathology. Understanding these metabolic adaptations and how they contribute to cellular dysfunction may reveal novel therapeutic approaches for the treatment of CVD. Here we provide a comprehensive summary of the metabolic reprogramming that occurs in immune cells and their progenitors during CVD, offering insights into the potential therapeutic interventions to mitigate disease progression. Fleetwood et al. review the role of immune cell dysfunction and inflammation in cardiovascular diseases. Their Review explores immune cell metabolic reprogramming in response to environmental cues, offering insights into potential therapeutic strategies for cardiovascular diseases.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 6","pages":"637-650"},"PeriodicalIF":0.0,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141106488","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}

引用次数: 0

Genetically proxied HTRA1 protease activity and circulating levels independently predict risk of ischemic stroke and coronary artery disease 基因替代的 HTRA1 蛋白酶活性和循环水平可独立预测缺血性中风和冠心病的风险

Nature cardiovascular research Pub Date : 2024-05-20 DOI: 10.1038/s44161-024-00475-3

Rainer Malik, Nathalie Beaufort, Jiang Li, Koki Tanaka, Marios K. Georgakis, Yunye He, Masaru Koido, Chikashi Terao, BioBank Japan, Christopher D. Anderson, Yoichiro Kamatani, Ramin Zand, Martin Dichgans

{"title":"Genetically proxied HTRA1 protease activity and circulating levels independently predict risk of ischemic stroke and coronary artery disease","authors":"Rainer Malik, Nathalie Beaufort, Jiang Li, Koki Tanaka, Marios K. Georgakis, Yunye He, Masaru Koido, Chikashi Terao, BioBank Japan, Christopher D. Anderson, Yoichiro Kamatani, Ramin Zand, Martin Dichgans","doi":"10.1038/s44161-024-00475-3","DOIUrl":"10.1038/s44161-024-00475-3","url":null,"abstract":"Genetic variants in HTRA1 are associated with stroke risk. However, the mechanisms mediating this remain largely unknown, as does the full spectrum of phenotypes associated with genetic variation in HTRA1. Here we show that rare HTRA1 variants are linked to ischemic stroke in the UK Biobank and BioBank Japan. Integrating data from biochemical experiments, we next show that variants causing loss of protease function associated with ischemic stroke, coronary artery disease and skeletal traits in the UK Biobank and MyCode cohorts. Moreover, a common variant modulating circulating HTRA1 mRNA and protein levels enhances the risk of ischemic stroke and coronary artery disease while lowering the risk of migraine and macular dystrophy in genome-wide association study, UK Biobank, MyCode and BioBank Japan data. We found no interaction between proxied HTRA1 activity and levels. Our findings demonstrate the role of HTRA1 for cardiovascular diseases and identify two mechanisms as potential targets for therapeutic interventions. Malik, Beaufort et al. show that rare and common genetic variations in HTRA1 associate with stroke and coronary artery disease outcomes via independent mechanisms.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 6","pages":"701-713"},"PeriodicalIF":0.0,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141122531","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}

引用次数: 0

Hyperlipidemia-induced hematopoiesis is repressed by MLKL in endothelial cells of the splenic niche 脾龛内皮细胞中的 MLKL 可抑制高脂血症诱导的造血功能

Nature cardiovascular research Pub Date : 2024-05-17 DOI: 10.1038/s44161-024-00470-8

Adil Rasheed, Sabrina Robichaud, Taylor Dennison, My-Anh Nguyen, Michèle Geoffrion, Jordan N. Reed, Hailey J. Wyatt, Yacine Marouf, Adir Baxi, Richard Lee, Hilal Kazan, Mete Civelek, Coen van Solingen, Mireille Ouimet, Katey J. Rayner

{"title":"Hyperlipidemia-induced hematopoiesis is repressed by MLKL in endothelial cells of the splenic niche","authors":"Adil Rasheed, Sabrina Robichaud, Taylor Dennison, My-Anh Nguyen, Michèle Geoffrion, Jordan N. Reed, Hailey J. Wyatt, Yacine Marouf, Adir Baxi, Richard Lee, Hilal Kazan, Mete Civelek, Coen van Solingen, Mireille Ouimet, Katey J. Rayner","doi":"10.1038/s44161-024-00470-8","DOIUrl":"10.1038/s44161-024-00470-8","url":null,"abstract":"Dysregulation of the hematopoietic niche during hyperlipidemia facilitates pathologic leukocyte production, driving atherogenesis. Although definitive hematopoiesis occurs primarily in the bone marrow, during atherosclerosis this also occurs in the spleen. Cells of the bone marrow niche, particularly endothelial cells, have been studied in atherosclerosis, although little is known about how splenic endothelial cells respond to the atherogenic environment. Here we show unique dysregulated pathways in splenic compared to bone marrow endothelial cells during atherosclerosis, including perturbations of lipid metabolism and endocytic trafficking pathways. As part of this response, we identify the mixed lineage kinase domain-like (MLKL) protein as a repressor of splenic, but not bone marrow, myelopoiesis. Silencing MLKL in splenic endothelial cells results in inefficient endosomal trafficking and lipid accumulation, ultimately promoting the production of myeloid cells that participate in plaque development. These studies identify endocytic trafficking by MLKL as a key mechanism of splenic endothelial cell maintenance, splenic hematopoiesis and, subsequently, atherosclerosis. Rasheed et al. show that dysregulation of lipid metabolism uniquely affects splenic endothelial cells of the hematopoietic niche, which promotes extramedullary myelopoiesis and contributes to plaque accumulation during atherosclerosis.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 5","pages":"594-611"},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140963985","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}

引用次数: 0