Pub Date : 2025-09-26DOI: 10.1038/s44161-025-00721-2
Jonathan S. Achter, Thomas H. L. Jensen, Paola Pisano, Johan S. Bundgaard, Daniel Raaschou-Oddershede, Kasper Rossing, Michael Wierer, Alicia Lundby
Proteomic technologies have advanced our understanding of disease mechanisms, patient stratification and targeted therapies. However, applying cardiac proteomics in translational research requires overcoming the barrier of tissue accessibility. Formalin-fixed, paraffin-embedded (FFPE) heart tissue, widely preserved in pathology collections, remains a largely untapped resource. Here we demonstrate that proteomic profiles are well preserved in FFPE human heart specimens and compatible with high-resolution, quantitative analysis. Quantifying approximately 4,000 proteins per sample, we show this approach effectively distinguishes disease states and subanatomical regions, revealing distinct underlying protein signatures. Specifically, the human sinoatrial node exhibited enrichment of collagen VI and G protein-coupled receptor signaling. Myocardial biopsies from patients with arrhythmogenic cardiomyopathy were characterized by fibrosis and metabolic/cytoskeletal derangements, clearly separating them from donor heart biopsies. This study establishes FFPE heart tissue as a robust resource for cardiac proteomics, enabling retrospective molecular profiling at scale and unlocking archived specimens for disease discovery and precision cardiology. Achter et al. established a protocol for quantitative proteomic profiling of formalin-fixed, paraffin-embedded human cardiac tissues, benchmarked against fresh-frozen samples. They applied it to stratify patients with arrhythmogenic cardiomyopathy and performed deep proteomic analysis of the human sinoatrial node.
{"title":"Quantitative proteomics of formalin-fixed, paraffin-embedded cardiac specimens uncovers protein signatures of specialized regions and patient groups","authors":"Jonathan S. Achter, Thomas H. L. Jensen, Paola Pisano, Johan S. Bundgaard, Daniel Raaschou-Oddershede, Kasper Rossing, Michael Wierer, Alicia Lundby","doi":"10.1038/s44161-025-00721-2","DOIUrl":"10.1038/s44161-025-00721-2","url":null,"abstract":"Proteomic technologies have advanced our understanding of disease mechanisms, patient stratification and targeted therapies. However, applying cardiac proteomics in translational research requires overcoming the barrier of tissue accessibility. Formalin-fixed, paraffin-embedded (FFPE) heart tissue, widely preserved in pathology collections, remains a largely untapped resource. Here we demonstrate that proteomic profiles are well preserved in FFPE human heart specimens and compatible with high-resolution, quantitative analysis. Quantifying approximately 4,000 proteins per sample, we show this approach effectively distinguishes disease states and subanatomical regions, revealing distinct underlying protein signatures. Specifically, the human sinoatrial node exhibited enrichment of collagen VI and G protein-coupled receptor signaling. Myocardial biopsies from patients with arrhythmogenic cardiomyopathy were characterized by fibrosis and metabolic/cytoskeletal derangements, clearly separating them from donor heart biopsies. This study establishes FFPE heart tissue as a robust resource for cardiac proteomics, enabling retrospective molecular profiling at scale and unlocking archived specimens for disease discovery and precision cardiology. Achter et al. established a protocol for quantitative proteomic profiling of formalin-fixed, paraffin-embedded human cardiac tissues, benchmarked against fresh-frozen samples. They applied it to stratify patients with arrhythmogenic cardiomyopathy and performed deep proteomic analysis of the human sinoatrial node.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1409-1423"},"PeriodicalIF":10.8,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00721-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145180745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-25DOI: 10.1038/s44161-025-00722-1
Fanhua Guo, Chenyang Zhao, Qinyang Shou, Ning Jin, Kay Jann, Xingfeng Shao, Danny JJ Wang
Arterial pulsation is crucial for promoting neurofluid circulation. Most previous studies quantified pulsatility via blood velocity-based indices in large arteries. Here we propose an innovative method to quantify the microvascular volumetric pulsatility index (mvPI) across cortical layers and white matter (WM) using high-resolution four-dimensional (4D) vascular space occupancy (VASO) and arterial spin labeling (ASL) magnetic resonance imaging (MRI) at 7 T with simultaneous pulse recording. We assessed aging-related changes in mvPI in 11 young (28.4 ± 5.8 years) and 12 older (60.2 ± 6.8 years) participants and compared mvPI with large artery pulsatility assessed by 4D-flow MRI. mvPI peaked in the pial surface (0.18 ± 0.04). Deep WM mvPI was significantly higher in older participants (P = 0.006) than young ones. Deep WM mvPI correlated with large artery velocity PI (r = 0.56, P = 0.0099). We performed test–retest scans, non-parametric reliability test and simulations to demonstrate the reproducibility and accuracy of the method. In conclusion, our non-invasive method enables in vivo fine-grained measurement of mvPI, with implications for glymphatic function, aging and neurodegenerative diseases. Guo, Zhao and colleagues use high-resolution 7 T MRI to measure the pulsatility of cerebral small vessels and uncover age-related differences in vascular dynamics, which offer new insights into mechanisms of brain aging and vascular risks.
{"title":"Assessing cerebral microvascular volumetric with high-resolution 4D cerebral blood volume MRI at 7 T","authors":"Fanhua Guo, Chenyang Zhao, Qinyang Shou, Ning Jin, Kay Jann, Xingfeng Shao, Danny JJ Wang","doi":"10.1038/s44161-025-00722-1","DOIUrl":"10.1038/s44161-025-00722-1","url":null,"abstract":"Arterial pulsation is crucial for promoting neurofluid circulation. Most previous studies quantified pulsatility via blood velocity-based indices in large arteries. Here we propose an innovative method to quantify the microvascular volumetric pulsatility index (mvPI) across cortical layers and white matter (WM) using high-resolution four-dimensional (4D) vascular space occupancy (VASO) and arterial spin labeling (ASL) magnetic resonance imaging (MRI) at 7 T with simultaneous pulse recording. We assessed aging-related changes in mvPI in 11 young (28.4 ± 5.8 years) and 12 older (60.2 ± 6.8 years) participants and compared mvPI with large artery pulsatility assessed by 4D-flow MRI. mvPI peaked in the pial surface (0.18 ± 0.04). Deep WM mvPI was significantly higher in older participants (P = 0.006) than young ones. Deep WM mvPI correlated with large artery velocity PI (r = 0.56, P = 0.0099). We performed test–retest scans, non-parametric reliability test and simulations to demonstrate the reproducibility and accuracy of the method. In conclusion, our non-invasive method enables in vivo fine-grained measurement of mvPI, with implications for glymphatic function, aging and neurodegenerative diseases. Guo, Zhao and colleagues use high-resolution 7 T MRI to measure the pulsatility of cerebral small vessels and uncover age-related differences in vascular dynamics, which offer new insights into mechanisms of brain aging and vascular risks.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1424-1438"},"PeriodicalIF":10.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00722-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145152332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-24DOI: 10.1038/s44161-025-00712-3
Sumeet A. Khetarpal, Haobo Li, Tevis Vitale, James Rhee, Saketh Challa, Claire Castro, Steffen Pabel, Yizhi Sun, Jing Liu, Dina Bogoslavski, Ariana Vargas-Castillo, Amanda L. Smythers, Katherine A. Blackmore, Louisa Grauvogel, Melanie J. Mittenbühler, Melin J. Khandekar, Casie Curtin, Jose Max Narvaez-Paliza, Chunyan Wang, Nicholas E. Houstis, Hans-Georg Sprenger, Sean J. Jurgens, Kiran J. Biddinger, Alexandra Kuznetsov, Rebecca Freeman, Patrick T. Ellinor, Matthias Nahrendorf, Joao A. Paulo, Steven P. Gygi, Phillip A. Dumesic, Aarti Asnani, Krishna G. Aragam, Pere Puigserver, Jason D. Roh, Bruce M. Spiegelman, Anthony Rosenzweig
Endurance exercise promotes adaptive growth and improved function of myocytes, which is supported by increased mitochondrial activity. In skeletal muscle, these benefits are in part transcriptionally coordinated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The importance of PGC-1α to exercise-induced adaptations in the heart has been unclear. Here we show that deleting PGC-1α specifically in cardiomyocytes prevents the expected benefits from exercise training and instead leads to heart failure after just 6 weeks of training. Consistent with this, in humans, rare genetic variants in PPARGC1A, which encodes PGC-1α, are associated with increased risk of heart failure. In this model, we identify growth differentiation factor 15 (GDF15) as a key heart-secreted mediator that contributes to this dysfunction. Blocking cardiac Gdf15 expression improves cardiac performance and exercise capacity in these mice. Finally, in human heart tissue, lower cardiomyocyte PPARGC1A expression is associated with higher GDF15 expression and reduced cardiomyocyte density. These findings uncover a crucial role for cardiomyocyte PGC-1α in enabling healthy cardiac adaptation to exercise in part through suppression of GDF15. Khetarpal et al. show that the metabolic regulator PGC-1α is essential in heart muscle cells for exercise-driven cardiac growth, and that suppression of the stress-induced myokine GDF15 is required to enable cardiomyocyte adaptations to training.
{"title":"Cardiac adaptation to endurance exercise training requires suppression of GDF15 via PGC-1α","authors":"Sumeet A. Khetarpal, Haobo Li, Tevis Vitale, James Rhee, Saketh Challa, Claire Castro, Steffen Pabel, Yizhi Sun, Jing Liu, Dina Bogoslavski, Ariana Vargas-Castillo, Amanda L. Smythers, Katherine A. Blackmore, Louisa Grauvogel, Melanie J. Mittenbühler, Melin J. Khandekar, Casie Curtin, Jose Max Narvaez-Paliza, Chunyan Wang, Nicholas E. Houstis, Hans-Georg Sprenger, Sean J. Jurgens, Kiran J. Biddinger, Alexandra Kuznetsov, Rebecca Freeman, Patrick T. Ellinor, Matthias Nahrendorf, Joao A. Paulo, Steven P. Gygi, Phillip A. Dumesic, Aarti Asnani, Krishna G. Aragam, Pere Puigserver, Jason D. Roh, Bruce M. Spiegelman, Anthony Rosenzweig","doi":"10.1038/s44161-025-00712-3","DOIUrl":"10.1038/s44161-025-00712-3","url":null,"abstract":"Endurance exercise promotes adaptive growth and improved function of myocytes, which is supported by increased mitochondrial activity. In skeletal muscle, these benefits are in part transcriptionally coordinated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The importance of PGC-1α to exercise-induced adaptations in the heart has been unclear. Here we show that deleting PGC-1α specifically in cardiomyocytes prevents the expected benefits from exercise training and instead leads to heart failure after just 6 weeks of training. Consistent with this, in humans, rare genetic variants in PPARGC1A, which encodes PGC-1α, are associated with increased risk of heart failure. In this model, we identify growth differentiation factor 15 (GDF15) as a key heart-secreted mediator that contributes to this dysfunction. Blocking cardiac Gdf15 expression improves cardiac performance and exercise capacity in these mice. Finally, in human heart tissue, lower cardiomyocyte PPARGC1A expression is associated with higher GDF15 expression and reduced cardiomyocyte density. These findings uncover a crucial role for cardiomyocyte PGC-1α in enabling healthy cardiac adaptation to exercise in part through suppression of GDF15. Khetarpal et al. show that the metabolic regulator PGC-1α is essential in heart muscle cells for exercise-driven cardiac growth, and that suppression of the stress-induced myokine GDF15 is required to enable cardiomyocyte adaptations to training.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1277-1294"},"PeriodicalIF":10.8,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139652","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 : 2025-09-17DOI: 10.1038/s44161-025-00711-4
Benjamin G. Chapman, Konstantinos Klaourakis, Carla de Villiers, Mala Gunadasa-Rohling, Maria-Alexa Cosma, Susanna T. E. Cooper, Kshitij Mohan, Michael Weinberger, Carolyn A. Carr, David R. Greaves, David G. Jackson, Daniela Pezzolla, Robin P. Choudhury, Joaquim M. Vieira, Paul R. Riley
In adult mice, myocardial infarction (MI) activates the cardiac lymphatics, which undergo sprouting angiogenesis (lymphangiogenesis), drain interstitial fluid and traffic macrophages to mediastinal lymph nodes (MLNs). This prevents edema and reduces inflammatory/fibrotic immune cell content to improve cardiac function. Here we investigated the role of cardiac lymphatics and macrophage clearance across the neonatal mouse regenerative window. The response to injury revealed limited lymphangiogenesis and clearance of macrophages from postnatal day 1 compared to postnatal day 7 infarcted hearts. This coincides with the maturation of lymphatic endothelial cell junctions from impermeable to permeable and with altered signaling between lymphatic endothelial cells and macrophages. Mice lacking the lymphatic endothelial receptor-1 (LYVE-1), where macrophage lymphatic trafficking is impaired in adults, experienced worse long-term outcomes after MI induced at postnatal day 1, suggesting an alternative role for LYVE-1 in macrophages. Macrophage-specific deletion of Lyve1 during neonatal heart injury impaired heart regeneration. This study demonstrates that immature cardiac lymphatics are impermeable to clearance in early neonates, ensuring retention of pro-regenerative LYVE-1-dependent macrophages. Chapman, Klaourakis and colleagues reveal that a lymphatic vasculature with poor clearance capacity in perinatal, regeneration-competent mouse hearts is required to retain pro-reparative macrophages and allow cardiac regeneration.
{"title":"Cardiac lymphatics retain LYVE-1-dependent macrophages during neonatal mouse heart regeneration","authors":"Benjamin G. Chapman, Konstantinos Klaourakis, Carla de Villiers, Mala Gunadasa-Rohling, Maria-Alexa Cosma, Susanna T. E. Cooper, Kshitij Mohan, Michael Weinberger, Carolyn A. Carr, David R. Greaves, David G. Jackson, Daniela Pezzolla, Robin P. Choudhury, Joaquim M. Vieira, Paul R. Riley","doi":"10.1038/s44161-025-00711-4","DOIUrl":"10.1038/s44161-025-00711-4","url":null,"abstract":"In adult mice, myocardial infarction (MI) activates the cardiac lymphatics, which undergo sprouting angiogenesis (lymphangiogenesis), drain interstitial fluid and traffic macrophages to mediastinal lymph nodes (MLNs). This prevents edema and reduces inflammatory/fibrotic immune cell content to improve cardiac function. Here we investigated the role of cardiac lymphatics and macrophage clearance across the neonatal mouse regenerative window. The response to injury revealed limited lymphangiogenesis and clearance of macrophages from postnatal day 1 compared to postnatal day 7 infarcted hearts. This coincides with the maturation of lymphatic endothelial cell junctions from impermeable to permeable and with altered signaling between lymphatic endothelial cells and macrophages. Mice lacking the lymphatic endothelial receptor-1 (LYVE-1), where macrophage lymphatic trafficking is impaired in adults, experienced worse long-term outcomes after MI induced at postnatal day 1, suggesting an alternative role for LYVE-1 in macrophages. Macrophage-specific deletion of Lyve1 during neonatal heart injury impaired heart regeneration. This study demonstrates that immature cardiac lymphatics are impermeable to clearance in early neonates, ensuring retention of pro-regenerative LYVE-1-dependent macrophages. Chapman, Klaourakis and colleagues reveal that a lymphatic vasculature with poor clearance capacity in perinatal, regeneration-competent mouse hearts is required to retain pro-reparative macrophages and allow cardiac regeneration.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1258-1276"},"PeriodicalIF":10.8,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00711-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-17DOI: 10.1038/s44161-025-00707-0
Tim Koopmans, Eva van Rooij
The lymphatic vasculature has emerged as a key component of the heart’s response to injury, influencing both regeneration and maladaptive remodeling. Research now highlights the role of lymphatic clearance in shaping the composition of tissue-resident macrophages within the neonatal heart.
{"title":"Maintaining the LYVE1 line through macrophage and lymphatic interplay in the regenerating neonatal heart","authors":"Tim Koopmans, Eva van Rooij","doi":"10.1038/s44161-025-00707-0","DOIUrl":"10.1038/s44161-025-00707-0","url":null,"abstract":"The lymphatic vasculature has emerged as a key component of the heart’s response to injury, influencing both regeneration and maladaptive remodeling. Research now highlights the role of lymphatic clearance in shaping the composition of tissue-resident macrophages within the neonatal heart.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1211-1213"},"PeriodicalIF":10.8,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082088","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 : 2025-09-16DOI: 10.1038/s44161-025-00710-5
Chad S. Weldy, Qin Li, João P. Monteiro, Tim S. Peters, Hongchao Guo, Drew Galls, Wenduo Gu, Paul P. Cheng, Markus Ramste, Daniel Li, Brian T. Palmisano, Disha Sharma, Matthew D. Worssam, Quanyi Zhao, Amruta Bhate, Ramendra K. Kundu, Trieu Nguyen, Michal Mokry, Clint L. Miller, Sander W. van der Laan, Jin Billy Li, Thomas Quertermous
Although genetic risk in coronary artery disease (CAD) is linked to changes in gene expression, recent discoveries have revealed a major role for A-to-I RNA editing in CAD. ADAR1 edits immunogenic double-stranded RNA (dsRNA), preventing activation of the dsRNA sensor MDA5 (IFIH1) and downstream interferon-stimulated gene signaling. Using human plaque analysis and human coronary artery smooth muscle cells (SMCs), here, we show that SMCs uniquely require RNA editing and that MDA5 activation regulates SMC phenotype. In a conditional SMC-specific Adar deletion mouse model on an atherosclerosis-prone background, combined with Ifih1 deletion and single-cell RNA sequencing, we demonstrate that ADAR1 preserves vascular integrity and limits atherosclerosis and calcification by suppressing MDA5 activation. Analysis of the Athero-Express carotid endarterectomy cohort further shows that interferon-stimulated gene expression correlates with SMC modulation, plaque instability and calcification. These findings reveal a fundamental mechanism of CAD, where cell type and context-specific RNA editing modulates genetic risk and vascular disease progression. Weldy et al. show that smooth muscle expression of the RNA editing enzyme ADAR1 regulates activation of the double-stranded RNA sensor MDA5 in a novel mechanism of atherosclerosis.
尽管冠状动脉疾病（CAD）的遗传风险与基因表达的变化有关，但最近的发现揭示了a -to- i RNA编辑在CAD中的主要作用。ADAR1编辑免疫原性双链RNA (dsRNA)，阻止dsRNA传感器MDA5 （IFIH1）的激活和下游干扰素刺激的基因信号传导。通过人类斑块分析和人类冠状动脉平滑肌细胞（SMCs），我们发现SMCs独特地需要RNA编辑，MDA5激活调节SMC表型。在动脉粥样硬化易发背景下的条件smc特异性Adar缺失小鼠模型中，结合Ifih1缺失和单细胞RNA测序，我们证明ADAR1通过抑制MDA5的激活来保持血管完整性并限制动脉粥样硬化和钙化。对Athero-Express颈动脉内膜切除术队列的分析进一步表明，干扰素刺激的基因表达与SMC调节、斑块不稳定和钙化相关。这些发现揭示了CAD的基本机制，其中细胞类型和上下文特异性RNA编辑调节遗传风险和血管疾病进展。
{"title":"Smooth muscle expression of RNA editing enzyme ADAR1 controls activation of the RNA sensor MDA5 in atherosclerosis","authors":"Chad S. Weldy, Qin Li, João P. Monteiro, Tim S. Peters, Hongchao Guo, Drew Galls, Wenduo Gu, Paul P. Cheng, Markus Ramste, Daniel Li, Brian T. Palmisano, Disha Sharma, Matthew D. Worssam, Quanyi Zhao, Amruta Bhate, Ramendra K. Kundu, Trieu Nguyen, Michal Mokry, Clint L. Miller, Sander W. van der Laan, Jin Billy Li, Thomas Quertermous","doi":"10.1038/s44161-025-00710-5","DOIUrl":"10.1038/s44161-025-00710-5","url":null,"abstract":"Although genetic risk in coronary artery disease (CAD) is linked to changes in gene expression, recent discoveries have revealed a major role for A-to-I RNA editing in CAD. ADAR1 edits immunogenic double-stranded RNA (dsRNA), preventing activation of the dsRNA sensor MDA5 (IFIH1) and downstream interferon-stimulated gene signaling. Using human plaque analysis and human coronary artery smooth muscle cells (SMCs), here, we show that SMCs uniquely require RNA editing and that MDA5 activation regulates SMC phenotype. In a conditional SMC-specific Adar deletion mouse model on an atherosclerosis-prone background, combined with Ifih1 deletion and single-cell RNA sequencing, we demonstrate that ADAR1 preserves vascular integrity and limits atherosclerosis and calcification by suppressing MDA5 activation. Analysis of the Athero-Express carotid endarterectomy cohort further shows that interferon-stimulated gene expression correlates with SMC modulation, plaque instability and calcification. These findings reveal a fundamental mechanism of CAD, where cell type and context-specific RNA editing modulates genetic risk and vascular disease progression. Weldy et al. show that smooth muscle expression of the RNA editing enzyme ADAR1 regulates activation of the double-stranded RNA sensor MDA5 in a novel mechanism of atherosclerosis.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1241-1257"},"PeriodicalIF":10.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00710-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-15DOI: 10.1038/s44161-025-00709-y
Guillermo Turiel, Thibaut Desgeorges, Evi Masschelein, Zheng Fan, David Lussi, Christophe M. Capelle, Giulia Bernardini, Raphaela Ardicoglu, Katharina Schönberger, Manuela Birrer, Sandro F. Fucentese, Jing Zhang, Daniela Latorre, Stephan Engelberger, Katrien De Bock
Peripheral artery disease (PAD) results from atherosclerosis and chronic narrowing of lower limb arteries, leading to decreased muscle perfusion. Current treatments are suboptimal, partly due to limited understanding of PAD muscle pathology. Here we used single-cell RNA sequencing and spatial transcriptomics to analyze the composition of the muscle microenvironment in non-ischemic patients and patients with PAD. We identified ATF3/ATF4+ endothelial cells (ECs) that exhibit altered angiogenic and immune regulatory profiles during PAD and confirmed that ATF4 signaling in ECs is required for effective ischemia recovery. In addition, capillary ECs display features of endothelial-to-mesenchymal transition. Furthermore, LYVE1hiMHCIIlow macrophages are the dominant macrophage population in human muscle, adopting a more pro-inflammatory profile during PAD. Finally, we analyzed alterations in intercellular communication within the muscle microenvironment during PAD and confirmed that EC-derived factors can influence macrophage polarization. This dataset deeply characterizes the PAD muscle microenvironment and provides a resource for exploration of targeted therapies. Using single-cell and spatial transcriptomics on muscle samples from non-ischemic patients and patients with peripheral artery disease (PAD), Turiel et al. identify cellular and molecular changes in the muscle microenvironment during PAD, focusing on endothelial cell–macrophage interactions.
{"title":"Single-cell compendium of muscle microenvironment in peripheral artery disease reveals altered endothelial diversity and LYVE1+ macrophage activation","authors":"Guillermo Turiel, Thibaut Desgeorges, Evi Masschelein, Zheng Fan, David Lussi, Christophe M. Capelle, Giulia Bernardini, Raphaela Ardicoglu, Katharina Schönberger, Manuela Birrer, Sandro F. Fucentese, Jing Zhang, Daniela Latorre, Stephan Engelberger, Katrien De Bock","doi":"10.1038/s44161-025-00709-y","DOIUrl":"10.1038/s44161-025-00709-y","url":null,"abstract":"Peripheral artery disease (PAD) results from atherosclerosis and chronic narrowing of lower limb arteries, leading to decreased muscle perfusion. Current treatments are suboptimal, partly due to limited understanding of PAD muscle pathology. Here we used single-cell RNA sequencing and spatial transcriptomics to analyze the composition of the muscle microenvironment in non-ischemic patients and patients with PAD. We identified ATF3/ATF4+ endothelial cells (ECs) that exhibit altered angiogenic and immune regulatory profiles during PAD and confirmed that ATF4 signaling in ECs is required for effective ischemia recovery. In addition, capillary ECs display features of endothelial-to-mesenchymal transition. Furthermore, LYVE1hiMHCIIlow macrophages are the dominant macrophage population in human muscle, adopting a more pro-inflammatory profile during PAD. Finally, we analyzed alterations in intercellular communication within the muscle microenvironment during PAD and confirmed that EC-derived factors can influence macrophage polarization. This dataset deeply characterizes the PAD muscle microenvironment and provides a resource for exploration of targeted therapies. Using single-cell and spatial transcriptomics on muscle samples from non-ischemic patients and patients with peripheral artery disease (PAD), Turiel et al. identify cellular and molecular changes in the muscle microenvironment during PAD, focusing on endothelial cell–macrophage interactions.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1221-1240"},"PeriodicalIF":10.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00709-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071307","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}
Heart failure (HF) is a growing global health issue. While most studies focus on cardiomyocytes, here we highlight the role of cardiac fibroblasts (CFs) in HF. Single-cell RNA sequencing of mouse hearts under pressure overload identified six CF subclusters, with one specific to the HF stage. This HF-specific CF population highly expresses the transcription factor Myc. Deleting Myc in CFs improves cardiac function without reducing fibrosis. MYC directly regulates the expression of the chemokine CXCL1, which is elevated in HF-specific CFs and downregulated in Myc-deficient CFs. The CXCL1 receptor, CXCR2, is expressed in cardiomyocytes, and blocking the CXCL1–CXCR2 axis mitigates HF. CXCL1 impairs contractility in neonatal rat and human iPSC-derived cardiomyocytes. Human CFs from failing hearts also express MYC and CXCL1, unlike those from controls. These findings reveal that HF-specific CFs contribute to HF via the MYC–CXCL1–CXCR2 pathway, offering a promising therapeutic target beyond cardiomyocytes. Komuro et al. identify a heart failure-specific subpopulation of cardiac fibroblasts that promotes cardiac dysfunction via the MYC–CXCL1–CXCR2 axis, highlighting a potential therapeutic target beyond cardiomyocytes.
{"title":"Heart failure-specific cardiac fibroblasts contribute to cardiac dysfunction via the MYC–CXCL1–CXCR2 axis","authors":"Jin Komuro, Hisayuki Hashimoto, Toshiomi Katsuki, Dai Kusumoto, Manami Katoh, Toshiyuki Ko, Masamichi Ito, Mikako Katagiri, Masayuki Kubota, Shintaro Yamada, Takahiro Nakamura, Yohei Akiba, Thukaa Kouka, Kaoruko Komuro, Mai Kimura, Shogo Ito, Seitaro Nomura, Issei Komuro, Keiichi Fukuda, Shinsuke Yuasa, Masaki Ieda","doi":"10.1038/s44161-025-00698-y","DOIUrl":"10.1038/s44161-025-00698-y","url":null,"abstract":"Heart failure (HF) is a growing global health issue. While most studies focus on cardiomyocytes, here we highlight the role of cardiac fibroblasts (CFs) in HF. Single-cell RNA sequencing of mouse hearts under pressure overload identified six CF subclusters, with one specific to the HF stage. This HF-specific CF population highly expresses the transcription factor Myc. Deleting Myc in CFs improves cardiac function without reducing fibrosis. MYC directly regulates the expression of the chemokine CXCL1, which is elevated in HF-specific CFs and downregulated in Myc-deficient CFs. The CXCL1 receptor, CXCR2, is expressed in cardiomyocytes, and blocking the CXCL1–CXCR2 axis mitigates HF. CXCL1 impairs contractility in neonatal rat and human iPSC-derived cardiomyocytes. Human CFs from failing hearts also express MYC and CXCL1, unlike those from controls. These findings reveal that HF-specific CFs contribute to HF via the MYC–CXCL1–CXCR2 pathway, offering a promising therapeutic target beyond cardiomyocytes. Komuro et al. identify a heart failure-specific subpopulation of cardiac fibroblasts that promotes cardiac dysfunction via the MYC–CXCL1–CXCR2 axis, highlighting a potential therapeutic target beyond cardiomyocytes.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 9","pages":"1135-1151"},"PeriodicalIF":10.8,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-08DOI: 10.1038/s44161-025-00705-2
Donald M. McDonald, Kari Alitalo, Christer Betsholtz, Britta Engelhardt, Steven T. Proulx, Julie Siegenthaler, Gou Young Koh
The meninges, consisting of the dura, arachnoid and pia mater that surround the brain and spinal cord, have been recognized from the earliest anatomical studies. First identified in 1787, lymphatic vessels in the dura are now receiving greater attention as their contribution to cerebrospinal fluid (CSF) clearance in diverse neurological conditions is being investigated. New methods have increased the understanding of dural lymphatics, but much is still being learned about their heterogeneity, intracranial and extracranial connections, and factors that govern their functions and maintenance. Current research is striving to understand the regulation of CSF drainage and influence of brain antigen and immune cell transit through dural lymphatics on aging impairments and the severity of neurodegenerative and neuroimmune diseases, traumatic brain injury, stroke and other neurological disorders. Achieving these goals should lead to safe and effective methods for manipulating CSF clearance through dural lymphatics for therapeutic benefit. McDonald et al. review studies of lymphatic vessels in the dural layer of the meninges and discuss the role of lymphatics in the function and maintenance of the central nervous system, aging, neuroimmunity and the progression of neurological disorders such as Alzheimer’s disease and Parkinson’s disease.
{"title":"Cerebrospinal fluid draining lymphatics in health and disease: advances and controversies","authors":"Donald M. McDonald, Kari Alitalo, Christer Betsholtz, Britta Engelhardt, Steven T. Proulx, Julie Siegenthaler, Gou Young Koh","doi":"10.1038/s44161-025-00705-2","DOIUrl":"10.1038/s44161-025-00705-2","url":null,"abstract":"The meninges, consisting of the dura, arachnoid and pia mater that surround the brain and spinal cord, have been recognized from the earliest anatomical studies. First identified in 1787, lymphatic vessels in the dura are now receiving greater attention as their contribution to cerebrospinal fluid (CSF) clearance in diverse neurological conditions is being investigated. New methods have increased the understanding of dural lymphatics, but much is still being learned about their heterogeneity, intracranial and extracranial connections, and factors that govern their functions and maintenance. Current research is striving to understand the regulation of CSF drainage and influence of brain antigen and immune cell transit through dural lymphatics on aging impairments and the severity of neurodegenerative and neuroimmune diseases, traumatic brain injury, stroke and other neurological disorders. Achieving these goals should lead to safe and effective methods for manipulating CSF clearance through dural lymphatics for therapeutic benefit. McDonald et al. review studies of lymphatic vessels in the dural layer of the meninges and discuss the role of lymphatics in the function and maintenance of the central nervous system, aging, neuroimmunity and the progression of neurological disorders such as Alzheimer’s disease and Parkinson’s disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 9","pages":"1047-1065"},"PeriodicalIF":10.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145024902","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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