Pub Date : 2024-06-06DOI: 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
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.
{"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}
Pub Date : 2024-06-06DOI: 10.1038/s44161-024-00498-w
Andrea Tavosanis
{"title":"Trimming down with semaglutide improves cardiac health in non-diabetic patients","authors":"Andrea Tavosanis","doi":"10.1038/s44161-024-00498-w","DOIUrl":"10.1038/s44161-024-00498-w","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 6","pages":"614-614"},"PeriodicalIF":0.0,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141376834","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 : 2024-06-06DOI: 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
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.
{"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}
Pub Date : 2024-06-03DOI: 10.1038/s44161-024-00480-6
Carlos Fernandez-Patron, Gary D. Lopaschuk, Eugenio Hardy
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.
{"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}
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.
心肌细胞成熟对于生成成人心肌细胞和应用人多能干细胞衍生的心肌细胞（hPSC-CMs）至关重要。然而，顺式调节元件水平的调节及其在心脏病中的作用仍不清楚。在CM成熟过程中，α-肌动蛋白2（ACTN2）水平会升高。在这项研究中，我们利用 hPSC 和小鼠模型研究了与临床相关的、保守的 ACTN2 增强子对 CM 成熟的影响。杂合子 ACTN2 增强子缺失会导致 CM 形态异常、功能和线粒体呼吸减弱。体外和体内的转录组分析表明，CM 成熟受到破坏，雷帕霉素哺乳动物靶标（mTOR）信号合成代谢上调，促进衰老并阻碍成熟。经证实，ACTN2 增强子缺失会诱导热休克蛋白 90A 的表达，而热休克蛋白 90A 是一种介导 mTOR 激活的伴侣蛋白。相反，通过增强子CRISPR激活（enCRISPRa）靶向ACTN2增强子可促进hPSC-CM的成熟。我们的研究揭示了转录增强子在心脏成熟和疾病中的作用，为微调基因表达以调节心肌细胞生理学提供了启示。Htet等人在人类多能干细胞和小鼠模型中鉴定并描述了一个调控心肌细胞成熟和功能的转录增强子。
{"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}
Pub Date : 2024-05-30DOI: 10.1038/s44161-024-00483-3
Francisco X. Galdos, Carissa Lee, Sean M. Wu
A study describes the role of the ACTN2 enhancer in myocardial maturation, highlighting its relevance in regulating structural, functional and metabolic dynamics in the heart. These findings offer insights that may advance our understanding of cardiovascular disease.
{"title":"Cardiac ACTN2 enhancer regulates cardiometabolism and maturation","authors":"Francisco X. Galdos, Carissa Lee, Sean M. Wu","doi":"10.1038/s44161-024-00483-3","DOIUrl":"10.1038/s44161-024-00483-3","url":null,"abstract":"A study describes the role of the ACTN2 enhancer in myocardial maturation, highlighting its relevance in regulating structural, functional and metabolic dynamics in the heart. These findings offer insights that may advance our understanding of cardiovascular disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 6","pages":"616-618"},"PeriodicalIF":0.0,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141425156","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 : 2024-05-23DOI: 10.1038/s44161-024-00473-5
Andrew J. Fleetwood, Jonathan Noonan, Nicole La Gruta, Axel Kallies, Andrew J. Murphy
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.
{"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}
Pub Date : 2024-05-20DOI: 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
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.
{"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}
Pub Date : 2024-05-17DOI: 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
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.
{"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}
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