Pub Date : 2025-10-17DOI: 10.1038/s44161-025-00737-8
Josephine M. E. Tan, Lan Cheng, Ryan P. Calhoun, Angela H. Weller, Karima Drareni, Skylar Fong, Eirlys Barbara, Hee-Woong Lim, Chenyi Xue, Hanna Winter, Gaëlle Auguste, Clint L. Miller, Muredach P. Reilly, Lars Maegdefessel, Esther Lutgens, Patrick Seale
Vascular smooth muscle cells (SMCs) undergo phenotype switching to acquire various fates in response to pathological stimuli. Among these, ‘synthetic’ SMCs—defined by migration, proliferation and extracellular matrix production—accumulate in atherosclerotic lesions and contribute to fibrous cap formation. The mechanisms driving this synthetic transition remain unclear. Here we identify PRDM16, a gene linked to cardiovascular disease, as a critical transcriptional repressor of the synthetic SMC phenotype. PRDM16 expression declined during SMC modulation, and its deletion in mice induced a synthetic program across all SMC subtypes even without pathological stimuli. Under atherogenic conditions, PRDM16 deficiency resulted in the formation of fibroproliferative plaques with more synthetic SMCs and fewer foam cells. Conversely, enforced PRDM16 expression suppressed SMC migration, proliferation and fibrosis. Mechanistically, PRDM16 occupied chromatin and suppressed activating marks at synthetic loci. These findings establish PRDM16 as a gatekeeper of SMC fate and reveal its role in shaping atherosclerotic plaque composition. Tan et al. identify PRDM16 as a key repressor of fibrotic switching in smooth muscle cells and show that its downregulation in atherosclerosis drives smooth muscle cells toward a synthetic fate, promoting fibrous plaques.
{"title":"PRDM16 regulates smooth muscle cell identity and atherosclerotic plaque composition","authors":"Josephine M. E. Tan, Lan Cheng, Ryan P. Calhoun, Angela H. Weller, Karima Drareni, Skylar Fong, Eirlys Barbara, Hee-Woong Lim, Chenyi Xue, Hanna Winter, Gaëlle Auguste, Clint L. Miller, Muredach P. Reilly, Lars Maegdefessel, Esther Lutgens, Patrick Seale","doi":"10.1038/s44161-025-00737-8","DOIUrl":"10.1038/s44161-025-00737-8","url":null,"abstract":"Vascular smooth muscle cells (SMCs) undergo phenotype switching to acquire various fates in response to pathological stimuli. Among these, ‘synthetic’ SMCs—defined by migration, proliferation and extracellular matrix production—accumulate in atherosclerotic lesions and contribute to fibrous cap formation. The mechanisms driving this synthetic transition remain unclear. Here we identify PRDM16, a gene linked to cardiovascular disease, as a critical transcriptional repressor of the synthetic SMC phenotype. PRDM16 expression declined during SMC modulation, and its deletion in mice induced a synthetic program across all SMC subtypes even without pathological stimuli. Under atherogenic conditions, PRDM16 deficiency resulted in the formation of fibroproliferative plaques with more synthetic SMCs and fewer foam cells. Conversely, enforced PRDM16 expression suppressed SMC migration, proliferation and fibrosis. Mechanistically, PRDM16 occupied chromatin and suppressed activating marks at synthetic loci. These findings establish PRDM16 as a gatekeeper of SMC fate and reveal its role in shaping atherosclerotic plaque composition. Tan et al. identify PRDM16 as a key repressor of fibrotic switching in smooth muscle cells and show that its downregulation in atherosclerosis drives smooth muscle cells toward a synthetic fate, promoting fibrous plaques.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 11","pages":"1573-1588"},"PeriodicalIF":10.8,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00737-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145314214","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 : 2025-10-16DOI: 10.1038/s44161-025-00738-7
This study examines electrical conduction through fibrotic regions in a mouse model of arrhythmogenic cardiomyopathy. A correlative imaging approach that integrates macroscopic cardiac electrophysiology with microscale whole-heart morphological reconstructions showed that the effect of fibrosis on conduction depends on the pacing frequency.
{"title":"Myocardial fibrosis promotes arrhythmias at fast pacing rates","authors":"","doi":"10.1038/s44161-025-00738-7","DOIUrl":"10.1038/s44161-025-00738-7","url":null,"abstract":"This study examines electrical conduction through fibrotic regions in a mouse model of arrhythmogenic cardiomyopathy. A correlative imaging approach that integrates macroscopic cardiac electrophysiology with microscale whole-heart morphological reconstructions showed that the effect of fibrosis on conduction depends on the pacing frequency.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 11","pages":"1462-1463"},"PeriodicalIF":10.8,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145310310","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 : 2025-10-14DOI: 10.1038/s44161-025-00716-z
Yang Lin, Fuqiang Geng, Jae-Hung Shieh, Lisa K. Torres, Musia Sominskaia, Meng Gao, Matthew Wingo, Kevin Chen, Samir Rustam, Raul Chavez, Renat Shaykhiev, Aleksandra Kopacz, Bradley Pearson, David Redmond, Ryan Schreiner, Shahin Rafii
Tissue-specific endothelial cells (ECs) regulate metabolism, inflammation, coagulation, organ development and regeneration. However, therapeutic application of EC transplantation requires scalable expansion of engraftable ECs that sustain their angiogenic and angiocrine functions. Here we identify a non-canonical aryl hydrocarbon receptor (AHR) pathway switched on by canonical AHR inhibitors that reactivates quiescent EC proliferation. Incubation of tissue-specific human ECs with AHR inhibitors, such as StemRegenin1 (SR1), increased EC proliferation by three-fold within an 8-day period. AHR inhibitors induced 100-fold greater expansion of 200,000 primary human adipose ECs to 2.4 × 1012 ECs, retaining in vivo vessel-forming and homeostatic functions in the recipient mice. AHR inhibitors induce a non-canonical AHR pathway by ornithine decarboxylase 1 (ODC1)-dependent synthesis of polyamines that drives EC cell cycle progression, detoxification of reactive oxygen species and oxidative phosphorylation metabolism, thereby recruiting hibernating ECs to accompany expanding EC populations without imposing replicative senescence. Therefore, AHR inhibitors, through transcriptional-independent protein–protein interactions, shepherd unrestricted human-scalable functional EC expansion, enabling cell therapies. Lin, Geng and colleagues identify a non-canonical AHR pathway that is activated by canonical AHR inhibitors, promoting the proliferation of quiescent endothelial cells with potential applications in cell therapy.
{"title":"A non-canonical aryl hydrocarbon receptor pathway authorizes and safeguards clinical-scale expansion of functional human endothelial cells","authors":"Yang Lin, Fuqiang Geng, Jae-Hung Shieh, Lisa K. Torres, Musia Sominskaia, Meng Gao, Matthew Wingo, Kevin Chen, Samir Rustam, Raul Chavez, Renat Shaykhiev, Aleksandra Kopacz, Bradley Pearson, David Redmond, Ryan Schreiner, Shahin Rafii","doi":"10.1038/s44161-025-00716-z","DOIUrl":"10.1038/s44161-025-00716-z","url":null,"abstract":"Tissue-specific endothelial cells (ECs) regulate metabolism, inflammation, coagulation, organ development and regeneration. However, therapeutic application of EC transplantation requires scalable expansion of engraftable ECs that sustain their angiogenic and angiocrine functions. Here we identify a non-canonical aryl hydrocarbon receptor (AHR) pathway switched on by canonical AHR inhibitors that reactivates quiescent EC proliferation. Incubation of tissue-specific human ECs with AHR inhibitors, such as StemRegenin1 (SR1), increased EC proliferation by three-fold within an 8-day period. AHR inhibitors induced 100-fold greater expansion of 200,000 primary human adipose ECs to 2.4 × 1012 ECs, retaining in vivo vessel-forming and homeostatic functions in the recipient mice. AHR inhibitors induce a non-canonical AHR pathway by ornithine decarboxylase 1 (ODC1)-dependent synthesis of polyamines that drives EC cell cycle progression, detoxification of reactive oxygen species and oxidative phosphorylation metabolism, thereby recruiting hibernating ECs to accompany expanding EC populations without imposing replicative senescence. Therefore, AHR inhibitors, through transcriptional-independent protein–protein interactions, shepherd unrestricted human-scalable functional EC expansion, enabling cell therapies. Lin, Geng and colleagues identify a non-canonical AHR pathway that is activated by canonical AHR inhibitors, promoting the proliferation of quiescent endothelial cells with potential applications in cell therapy.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1329-1344"},"PeriodicalIF":10.8,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145290307","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 : 2025-10-10DOI: 10.1038/s44161-025-00727-w
Daria Amiad Pavlov, Julie Heffler, Carmen Suay-Corredera, Mohammad Dehghany, Kaitlyn M. Shen, Noam Zuela-Sopilniak, Rani Randell, Keita Uchida, Rajan Jain, Vivek Shenoy, Jan Lammerding, Benjamin Prosser
Nuclear homeostasis requires balanced forces between the cytoskeleton and the nucleus. Mutations in LMNA, which encodes lamin A/C, weaken the nuclear lamina, leading to nuclear damage and muscle disease. Disrupting the linker of nucleoskeleton and cytoskeleton (LINC) complex, which connects the cytoskeleton to the nucleus, may ameliorate LMNA-associated cardiomyopathy, yet the cardioprotective mechanism remains unclear. Here we developed an assay to quantify the coupling between cardiomyocyte contraction and nuclear deformation and interrogate its dependence on the nuclear lamina and LINC complex. The LINC complex was mostly dispensable for transferring contractile strain to the nucleus, and its disruption did not rescue elevated nuclear strain in lamin A/C-deficient cardiomyocytes. Instead, LINC complex disruption eliminated the microtubule cage encircling the nucleus. Microtubule disruption prevented nuclear damage and preserved cardiac function in lamin A/C deficiency. Computational modeling revealed that microtubule forces create local stress concentrations that damage lamin A/C-deficient nuclei. These findings identify microtubule-dependent force transmission as a pathological driver and therapeutic target for LMNA cardiomyopathy. Amiad Pavlov, Heffler, et al. demonstrate that stress transmitted to the cardiomyocyte nucleus by the microtubule cage drives LMNA-associated cardiomyopathy and may represent a promising therapeutic target.
{"title":"Microtubule forces drive nuclear damage in LMNA cardiomyopathy","authors":"Daria Amiad Pavlov, Julie Heffler, Carmen Suay-Corredera, Mohammad Dehghany, Kaitlyn M. Shen, Noam Zuela-Sopilniak, Rani Randell, Keita Uchida, Rajan Jain, Vivek Shenoy, Jan Lammerding, Benjamin Prosser","doi":"10.1038/s44161-025-00727-w","DOIUrl":"10.1038/s44161-025-00727-w","url":null,"abstract":"Nuclear homeostasis requires balanced forces between the cytoskeleton and the nucleus. Mutations in LMNA, which encodes lamin A/C, weaken the nuclear lamina, leading to nuclear damage and muscle disease. Disrupting the linker of nucleoskeleton and cytoskeleton (LINC) complex, which connects the cytoskeleton to the nucleus, may ameliorate LMNA-associated cardiomyopathy, yet the cardioprotective mechanism remains unclear. Here we developed an assay to quantify the coupling between cardiomyocyte contraction and nuclear deformation and interrogate its dependence on the nuclear lamina and LINC complex. The LINC complex was mostly dispensable for transferring contractile strain to the nucleus, and its disruption did not rescue elevated nuclear strain in lamin A/C-deficient cardiomyocytes. Instead, LINC complex disruption eliminated the microtubule cage encircling the nucleus. Microtubule disruption prevented nuclear damage and preserved cardiac function in lamin A/C deficiency. Computational modeling revealed that microtubule forces create local stress concentrations that damage lamin A/C-deficient nuclei. These findings identify microtubule-dependent force transmission as a pathological driver and therapeutic target for LMNA cardiomyopathy. Amiad Pavlov, Heffler, et al. demonstrate that stress transmitted to the cardiomyocyte nucleus by the microtubule cage drives LMNA-associated cardiomyopathy and may represent a promising therapeutic target.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 11","pages":"1501-1520"},"PeriodicalIF":10.8,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00727-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276848","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 : 2025-10-09DOI: 10.1038/s44161-025-00733-y
Nieves García-Quintáns, Juan A. Bernal
Cardiac dysfunction in diabetes is linked to metabolic stress, lipid overload and fibrosis. A study now demonstrates impaired glycogen clearance as a central disease mechanism, in which failed glycophagy drives glycogen accumulation and creates a metabolic ‘sugar trap’ that can be targeted therapeutically.
{"title":"Targeting glycogen clearance to treat diabetic cardiomyopathy","authors":"Nieves García-Quintáns, Juan A. Bernal","doi":"10.1038/s44161-025-00733-y","DOIUrl":"10.1038/s44161-025-00733-y","url":null,"abstract":"Cardiac dysfunction in diabetes is linked to metabolic stress, lipid overload and fibrosis. A study now demonstrates impaired glycogen clearance as a central disease mechanism, in which failed glycophagy drives glycogen accumulation and creates a metabolic ‘sugar trap’ that can be targeted therapeutically.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 11","pages":"1454-1456"},"PeriodicalIF":10.8,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260257","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 : 2025-10-08DOI: 10.1038/s44161-025-00724-z
Masahiro Yamazoe, Kenneth K. Y. Ting, I-Hsiu Lee, Aneesh Bapat, Andrew Lewis, Ling Xiao, Fadi E. Pulous, Kyle Mentkowski, Alexandre Paccalet, Noor Momin, Hana Seung, Theresa Dolejsi, Nina Kumowski, Maximilian J. Schloss, Yoshiko Iwamoto, Gustavo Ramos, Kenneth Chan, Charalambos Antoniades, Barbara Casadei, Filip K. Swirski, Patrick T. Ellinor, Kamila Naxerova, Steffen Pabel, Maarten Hulsmans, Matthias Nahrendorf
Atrial fibrillation, the most frequent cardiac arrhythmia, causes heart failure and stroke. Here we describe that combining the typical risk factors of atrial fibrillation (hypertension, obesity and mitral valve regurgitation (HOMER)) activates adaptive immunity in wild-type mice, ultimately causing electrical remodeling of cardiomyocytes. In HOMER mice, dendritic cells expanded in the left atria and heart-draining lymph nodes, where we detected cardiomyocyte-derived proteins. Systemically expanding B cells, while exposed to interferon-α, produced autoantibodies that disrupted calcium handling in cardiomyocytes. Depleting B cells by using μMT HOMER mice or plasma cells by using Mb1cre/+ Prdm1fl/fl HOMER mice reduced atrial fibrillation while mitigating the prolonged action potential duration we observed in the left atria of HOMER mice. CD20 antibody B cell depletion, a clinical tool in treating lymphoma and autoimmune disease, reduced atrial fibrillation fivefold in HOMER mice. Targeting humoral immunity may provide therapeutic avenues for patients with autoantibody-induced atrial fibrillation. Yamazoe et al. show that B cell-derived autoantibodies contribute to the development of atrial fibrillation, suggesting that targeting the humoral immune response may represent a viable therapeutic approach.
{"title":"B cells promote atrial fibrillation via autoantibodies","authors":"Masahiro Yamazoe, Kenneth K. Y. Ting, I-Hsiu Lee, Aneesh Bapat, Andrew Lewis, Ling Xiao, Fadi E. Pulous, Kyle Mentkowski, Alexandre Paccalet, Noor Momin, Hana Seung, Theresa Dolejsi, Nina Kumowski, Maximilian J. Schloss, Yoshiko Iwamoto, Gustavo Ramos, Kenneth Chan, Charalambos Antoniades, Barbara Casadei, Filip K. Swirski, Patrick T. Ellinor, Kamila Naxerova, Steffen Pabel, Maarten Hulsmans, Matthias Nahrendorf","doi":"10.1038/s44161-025-00724-z","DOIUrl":"10.1038/s44161-025-00724-z","url":null,"abstract":"Atrial fibrillation, the most frequent cardiac arrhythmia, causes heart failure and stroke. Here we describe that combining the typical risk factors of atrial fibrillation (hypertension, obesity and mitral valve regurgitation (HOMER)) activates adaptive immunity in wild-type mice, ultimately causing electrical remodeling of cardiomyocytes. In HOMER mice, dendritic cells expanded in the left atria and heart-draining lymph nodes, where we detected cardiomyocyte-derived proteins. Systemically expanding B cells, while exposed to interferon-α, produced autoantibodies that disrupted calcium handling in cardiomyocytes. Depleting B cells by using μMT HOMER mice or plasma cells by using Mb1cre/+ Prdm1fl/fl HOMER mice reduced atrial fibrillation while mitigating the prolonged action potential duration we observed in the left atria of HOMER mice. CD20 antibody B cell depletion, a clinical tool in treating lymphoma and autoimmune disease, reduced atrial fibrillation fivefold in HOMER mice. Targeting humoral immunity may provide therapeutic avenues for patients with autoantibody-induced atrial fibrillation. Yamazoe et al. show that B cell-derived autoantibodies contribute to the development of atrial fibrillation, suggesting that targeting the humoral immune response may represent a viable therapeutic approach.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1381-1396"},"PeriodicalIF":10.8,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00724-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253960","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 : 2025-10-07DOI: 10.1038/s44161-025-00714-1
Nicolas Barbera, Lily Lei, Alexia Wallace, Faruk Erin, R. Noah Perry, Hester M. den Ruijter, Mete Civelek
Genome-wide association studies have identified over 300 genomic loci associated with coronary artery disease (CAD) risk, but identifying functional variants remains challenging due to linkage disequilibrium. Here we show a comprehensive functional characterization of CAD-associated variants in primary vascular smooth muscle cells (SMCs). We performed lentivirus-based massively parallel reporter assays (lentiMPRAs) on 25,892 CAD-associated variants, testing their allele-specific enhancer activity in quiescent and proliferative SMCs. We identified 122 candidate variants with enhancer activity and allelic imbalance, including 23 variants showing condition-biased and 41 showing sex-biased effects. Integrating lentiMPRA with CUT&RUN epigenome profiling and expression quantitative trait loci data, we prioritized 49 functionally relevant variants. CRISPRi experiments on eight variants confirmed their regulatory effects on nine variant–gene pairs: rs35976034 (MAP1S), rs4888409 (CFDP1), rs73193808 (MAP3K7CL), rs67631072 (INPP5B/FHL3), rs1651285 (SNHG18), rs17293632 (SMAD3), rs2238792 (ARVCF) and rs4627080 (NRIP3). Our results fine-map the causal variants that confer CAD risk through their effects on vascular SMCs. Barbera et al. identify and map genetic variants that alter the characteristics of vascular smooth muscle cells and contribute to the risk of coronary artery disease.
{"title":"Coronary artery disease-associated variants regulate vascular smooth muscle cell gene expression","authors":"Nicolas Barbera, Lily Lei, Alexia Wallace, Faruk Erin, R. Noah Perry, Hester M. den Ruijter, Mete Civelek","doi":"10.1038/s44161-025-00714-1","DOIUrl":"10.1038/s44161-025-00714-1","url":null,"abstract":"Genome-wide association studies have identified over 300 genomic loci associated with coronary artery disease (CAD) risk, but identifying functional variants remains challenging due to linkage disequilibrium. Here we show a comprehensive functional characterization of CAD-associated variants in primary vascular smooth muscle cells (SMCs). We performed lentivirus-based massively parallel reporter assays (lentiMPRAs) on 25,892 CAD-associated variants, testing their allele-specific enhancer activity in quiescent and proliferative SMCs. We identified 122 candidate variants with enhancer activity and allelic imbalance, including 23 variants showing condition-biased and 41 showing sex-biased effects. Integrating lentiMPRA with CUT&RUN epigenome profiling and expression quantitative trait loci data, we prioritized 49 functionally relevant variants. CRISPRi experiments on eight variants confirmed their regulatory effects on nine variant–gene pairs: rs35976034 (MAP1S), rs4888409 (CFDP1), rs73193808 (MAP3K7CL), rs67631072 (INPP5B/FHL3), rs1651285 (SNHG18), rs17293632 (SMAD3), rs2238792 (ARVCF) and rs4627080 (NRIP3). Our results fine-map the causal variants that confer CAD risk through their effects on vascular SMCs. Barbera et al. identify and map genetic variants that alter the characteristics of vascular smooth muscle cells and contribute to the risk of coronary artery disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1295-1310"},"PeriodicalIF":10.8,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245566","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 : 2025-10-07DOI: 10.1038/s44161-025-00715-0
Stephen B. Montgomery
Massively parallel reporter assays (MRPAs) are used in vascular smooth muscle cells to measure the functional effects of over 25,000 variants associated with coronary artery disease. This approach identifies regulatory variants in moderate linkage to disease-associated loci, implicating a broader spectrum of causal variants.
{"title":"Mapping causal non-coding variants in coronary artery disease","authors":"Stephen B. Montgomery","doi":"10.1038/s44161-025-00715-0","DOIUrl":"10.1038/s44161-025-00715-0","url":null,"abstract":"Massively parallel reporter assays (MRPAs) are used in vascular smooth muscle cells to measure the functional effects of over 25,000 variants associated with coronary artery disease. This approach identifies regulatory variants in moderate linkage to disease-associated loci, implicating a broader spectrum of causal variants.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1214-1215"},"PeriodicalIF":10.8,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245859","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 : 2025-10-07DOI: 10.1038/s44161-025-00713-2
Megan Mulholland, Anthi Chalou, Samuel H. A. Andersson, Marie A. C. Depuydt, Yinda Yu, Shiying Lin, Klara Tallbäck, Astrid Ericsson, Gabriel Jakobsson, Jill de Mol, Dmytro Kryvokhyzha, Andrew H. Lichtman, Amanda C. Foks, Alexandru Schiopu, Harry Björkbacka, Bram Slütter, Anton Gisterå, Daniel Engelbertsen
Immune checkpoint inhibitors (ICIs), targeting checkpoint receptors such as programmed cell death protein 1 (PD-1), are associated with increased risk of cardiovascular events, but the underlying mechanisms remain poorly understood. Here we show that PD-1+ T cells from murine atherosclerotic aortas mainly display a progenitor exhausted phenotype (PD-1intSlamf6+Tim3−), produce IFNγ in vivo, exhibit signs of recent proliferation and maintain polyfunctionality. PD-1 blockade induced marked changes in plaque immune phenotype, with increased PD-1high T cell accumulation, IFNγ production, formation of lymphocyte foci and neutrophil recruitment. Depletion of PD-1high T cells prior to PD-1 blockade did not impede T cell recruitment, suggesting a role for progenitor exhausted PD-1int T cells in ICI-driven T cell plaque accumulation. Human circulating PD-1+ T cells produced IFNγ and were associated with subclinical coronary atherosclerosis. Our studies highlight IFNγ-producing PD-1+ T cells as a potential key immune cell population mediating increased cardiovascular risk in patients with cancer receiving ICI. Mulholland et al. identify progenitor exhausted T cells, expressing intermediate levels of PD-1 (PD-1int), as a prominent source of pro-inflammatory cytokines in the murine atherosclerotic aorta and potential cellular targets driving checkpoint inhibition-elicited pro-atherosclerotic immune responses. They further demonstrate elevated levels of circulating PD-1-expressing T cells in individuals with subclinical cardiovascular disease.
{"title":"Progenitor exhausted PD-1+ T cells are cellular targets of immune checkpoint inhibition in atherosclerosis","authors":"Megan Mulholland, Anthi Chalou, Samuel H. A. Andersson, Marie A. C. Depuydt, Yinda Yu, Shiying Lin, Klara Tallbäck, Astrid Ericsson, Gabriel Jakobsson, Jill de Mol, Dmytro Kryvokhyzha, Andrew H. Lichtman, Amanda C. Foks, Alexandru Schiopu, Harry Björkbacka, Bram Slütter, Anton Gisterå, Daniel Engelbertsen","doi":"10.1038/s44161-025-00713-2","DOIUrl":"10.1038/s44161-025-00713-2","url":null,"abstract":"Immune checkpoint inhibitors (ICIs), targeting checkpoint receptors such as programmed cell death protein 1 (PD-1), are associated with increased risk of cardiovascular events, but the underlying mechanisms remain poorly understood. Here we show that PD-1+ T cells from murine atherosclerotic aortas mainly display a progenitor exhausted phenotype (PD-1intSlamf6+Tim3−), produce IFNγ in vivo, exhibit signs of recent proliferation and maintain polyfunctionality. PD-1 blockade induced marked changes in plaque immune phenotype, with increased PD-1high T cell accumulation, IFNγ production, formation of lymphocyte foci and neutrophil recruitment. Depletion of PD-1high T cells prior to PD-1 blockade did not impede T cell recruitment, suggesting a role for progenitor exhausted PD-1int T cells in ICI-driven T cell plaque accumulation. Human circulating PD-1+ T cells produced IFNγ and were associated with subclinical coronary atherosclerosis. Our studies highlight IFNγ-producing PD-1+ T cells as a potential key immune cell population mediating increased cardiovascular risk in patients with cancer receiving ICI. Mulholland et al. identify progenitor exhausted T cells, expressing intermediate levels of PD-1 (PD-1int), as a prominent source of pro-inflammatory cytokines in the murine atherosclerotic aorta and potential cellular targets driving checkpoint inhibition-elicited pro-atherosclerotic immune responses. They further demonstrate elevated levels of circulating PD-1-expressing T cells in individuals with subclinical cardiovascular disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1311-1328"},"PeriodicalIF":10.8,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00713-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245944","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：