Pub Date : 2026-01-02DOI: 10.1161/CIRCRESAHA.125.327876
Marie-Louise Bang
{"title":"Molecular Duet at the Z-Disc: How α-Actinin-4 Fine Tunes Cardiac Contraction.","authors":"Marie-Louise Bang","doi":"10.1161/CIRCRESAHA.125.327876","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.125.327876","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"138 1","pages":"e327876"},"PeriodicalIF":16.2,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1161/RES.0000000000000740
Stefanos Zafeiropoulos, Umair Ahmed, Alexandra Bekiaridou, Naveen Jayaprakash, Ibrahim T Mughrabi, Nafiseh Saleknezhad, Chrystal Chadwick, Anna Daytz, Izumi Kurata-Sato, Yemil Atish-Fregoso, Kaitlin Carroll, Yousef Al-Abed, Marat Fudim, Christopher Puleo, George Giannakoulas, Mark R Nicolls, Betty Diamond, Stavros Zanos
{"title":"Correction to: Ultrasound Neuromodulation of an Anti-Inflammatory Pathway at the Spleen Improves Experimental Pulmonary Hypertension.","authors":"Stefanos Zafeiropoulos, Umair Ahmed, Alexandra Bekiaridou, Naveen Jayaprakash, Ibrahim T Mughrabi, Nafiseh Saleknezhad, Chrystal Chadwick, Anna Daytz, Izumi Kurata-Sato, Yemil Atish-Fregoso, Kaitlin Carroll, Yousef Al-Abed, Marat Fudim, Christopher Puleo, George Giannakoulas, Mark R Nicolls, Betty Diamond, Stavros Zanos","doi":"10.1161/RES.0000000000000740","DOIUrl":"https://doi.org/10.1161/RES.0000000000000740","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"138 1","pages":"e000740"},"PeriodicalIF":16.2,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1161/CIRCRESAHA.125.326002
Robert S Gardner, Nathan R Tucker, Kaushik Amancherla
Advances in single-cell genomics and transcriptomics have transformed our understanding of human disease by uncovering previously masked cellular heterogeneity and therapeutic targets. Yet, adoption of these technologies in cardiovascular disease has lagged behind in large part due to technical and logistical challenges, but advances in tissue procurement and molecular approaches have brought the human heart firmly into the single-cell era. With an increasing number of studies addressing human myocardium, substantial insights have been elucidated into myocardial cellular composition and molecular heterogeneity in health and disease, and cell-specific contributions to cardiovascular disease. In this review, we provide an overview of the rapidly expanding body of single-cell and single-nuclear studies that interrogate the human myocardium, highlighting how these platforms are redefining our understanding of cardiovascular disease. Specifically, we provide a snapshot of major experimental and computational approaches within the single-cell space, prioritize the impact of these technologies in human cardiovascular disease, and describe a roadmap to how insights gained from these approaches may accelerate their translation from bench to bedside application.
{"title":"Leveraging Single-Cell Technologies to Advance Understanding of Myocardial Disease.","authors":"Robert S Gardner, Nathan R Tucker, Kaushik Amancherla","doi":"10.1161/CIRCRESAHA.125.326002","DOIUrl":"10.1161/CIRCRESAHA.125.326002","url":null,"abstract":"<p><p>Advances in single-cell genomics and transcriptomics have transformed our understanding of human disease by uncovering previously masked cellular heterogeneity and therapeutic targets. Yet, adoption of these technologies in cardiovascular disease has lagged behind in large part due to technical and logistical challenges, but advances in tissue procurement and molecular approaches have brought the human heart firmly into the single-cell era. With an increasing number of studies addressing human myocardium, substantial insights have been elucidated into myocardial cellular composition and molecular heterogeneity in health and disease, and cell-specific contributions to cardiovascular disease. In this review, we provide an overview of the rapidly expanding body of single-cell and single-nuclear studies that interrogate the human myocardium, highlighting how these platforms are redefining our understanding of cardiovascular disease. Specifically, we provide a snapshot of major experimental and computational approaches within the single-cell space, prioritize the impact of these technologies in human cardiovascular disease, and describe a roadmap to how insights gained from these approaches may accelerate their translation from bench to bedside application.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"138 1","pages":"e326002"},"PeriodicalIF":16.2,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12768456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145891841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1161/CIRCRESAHA.125.325797
Nazia Hilal, Maniteja Arava, Sangita Choudhury
Single-cell genomics has emerged as a transformative approach to unravel the complexity of somatic variation in specific cells within the human body. This field has profound implications for understanding the role of somatic mutations in aging, cardiovascular disease, and tissue-specific pathologies. By focusing on circulating cells and cardiac resident cells, including cardiomyocytes, within the heart, this review explores how single-cell genomics provides insights into cellular heterogeneity and clonal evolution. We discuss the implications of somatic variation for cardiovascular health, highlight technological innovation, and future directions in this rapidly evolving field. This review sheds light on national initiatives, such as the National Institutes of Health Somatic Mosaicism Across Human Tissues Network (SMaHT) and the European Somatic Mutations in Vascular-Wall Function and Age-Associated Disease (EU SOMATICART) project, which aim to generate reference atlases of somatic mutations across human tissues. It also explores challenges and future directions in leveraging single-cell approaches to improve diagnostics and therapeutics in cardiovascular disease.
{"title":"Single-Cell Genomics and Somatic Variation in Circulating and Cardiac Resident Cells.","authors":"Nazia Hilal, Maniteja Arava, Sangita Choudhury","doi":"10.1161/CIRCRESAHA.125.325797","DOIUrl":"10.1161/CIRCRESAHA.125.325797","url":null,"abstract":"<p><p>Single-cell genomics has emerged as a transformative approach to unravel the complexity of somatic variation in specific cells within the human body. This field has profound implications for understanding the role of somatic mutations in aging, cardiovascular disease, and tissue-specific pathologies. By focusing on circulating cells and cardiac resident cells, including cardiomyocytes, within the heart, this review explores how single-cell genomics provides insights into cellular heterogeneity and clonal evolution. We discuss the implications of somatic variation for cardiovascular health, highlight technological innovation, and future directions in this rapidly evolving field. This review sheds light on national initiatives, such as the National Institutes of Health Somatic Mosaicism Across Human Tissues Network (SMaHT) and the European Somatic Mutations in Vascular-Wall Function and Age-Associated Disease (EU SOMATICART) project, which aim to generate reference atlases of somatic mutations across human tissues. It also explores challenges and future directions in leveraging single-cell approaches to improve diagnostics and therapeutics in cardiovascular disease.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"138 1","pages":"e325797"},"PeriodicalIF":16.2,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12768450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02Epub Date: 2025-11-14DOI: 10.1161/CIRCRESAHA.125.326357
Colin E Evans, Sushreesangita P Behera, Xianming Zhang, Narsa Machireddy, Kefyalew D Addisu, Mollie Phillips, Rana Dhar, Mrinmay Chakrabarti, Bowen Wang, Odile David, You-Yang Zhao
<p><strong>Background: </strong>Patients with sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) commonly suffer from severe pulmonary thrombosis, but clinical trials of anticoagulant therapies in patients with sepsis and ARDS have failed. Patients with ARDS plus thrombocytopenia also exhibit increased mortality, and widespread pulmonary thrombosis is often seen in patients with COVID-19 ARDS.</p><p><strong>Methods: </strong>Different amounts of microbeads were administered intravenously to adult mice to induce various levels of pulmonary thrombosis. ALI was induced by either intraperitoneal lipopolysaccharide or cecal ligation and puncture. Endothelial cell (EC)-targeted nanoparticles were used to deliver plasmid DNA expressing the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) system for EC-specific gene knockout of Alox15 (arachidonate 15-lipoxygenase) or plasmid DNA expressing Alox15 for EC-specific overexpression. Lipidomic profiling and in vivo rescue studies with the identified Alox15-regulated lipids were performed. In addition, thrombocytopenia was induced by genetic depletion of platelets using <i>DTR</i><sup><i>Pf4Cre</i></sup> mice, and the effects of restoration of pulmonary thrombosis were assessed.</p><p><strong>Results: </strong>We show that although severe pulmonary thrombosis or thrombocytopenia augments sepsis-induced ALI, the induction of mild pulmonary thrombosis conversely reduces EC apoptosis, ALI, and mortality via sustained expression of endothelial Alox15. Endothelial <i>Alox15</i> knockout in adult mice abolished the protective impact of mild lung thrombosis. Conversely, overexpression of endothelial <i>Alox15</i> inhibited the increases in ALI caused by severe pulmonary thrombosis. Treatment of the endothelial <i>Alox15</i> knockout mice with 1-palmitoyl-2-oleoyl-3-arachidonoyl-rac-glycerol (C<sub>57</sub>H<sub>100</sub>O<sub>6</sub>), a top candidate of the 32 Alox15-regulated lipids identified by lipidomic profiling, markedly reversed the defective phenotype, suggesting that Alox15 protects from lung injury via protective lipids. The clinical relevance of the findings was supported by the observation of reduced ALOX15-expressing ECs in lung autopsy samples of patients with ARDS. In addition, restoration of pulmonary thrombosis in thrombocytopenic mice normalized endotoxemia-induced ALI.</p><p><strong>Conclusions: </strong>We have demonstrated that moderate levels of lung thrombosis protect against sepsis-induced inflammatory lung injury via endothelial Alox15. Overexpression of endothelial Alox15 inhibits severe pulmonary thrombosis-induced increases in ALI. Thus, upregulation of ALOX15 expression or treatment with ALOX15-dependent protective lipid(s) represents a promising therapeutic strategy for treatment of ARDS, especially in subpopulations of patients with thrombocytopenia or widespread
{"title":"The Unexpected Protective Role of Thrombosis in Lung Injury via Endothelial Alox15.","authors":"Colin E Evans, Sushreesangita P Behera, Xianming Zhang, Narsa Machireddy, Kefyalew D Addisu, Mollie Phillips, Rana Dhar, Mrinmay Chakrabarti, Bowen Wang, Odile David, You-Yang Zhao","doi":"10.1161/CIRCRESAHA.125.326357","DOIUrl":"10.1161/CIRCRESAHA.125.326357","url":null,"abstract":"<p><strong>Background: </strong>Patients with sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) commonly suffer from severe pulmonary thrombosis, but clinical trials of anticoagulant therapies in patients with sepsis and ARDS have failed. Patients with ARDS plus thrombocytopenia also exhibit increased mortality, and widespread pulmonary thrombosis is often seen in patients with COVID-19 ARDS.</p><p><strong>Methods: </strong>Different amounts of microbeads were administered intravenously to adult mice to induce various levels of pulmonary thrombosis. ALI was induced by either intraperitoneal lipopolysaccharide or cecal ligation and puncture. Endothelial cell (EC)-targeted nanoparticles were used to deliver plasmid DNA expressing the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) system for EC-specific gene knockout of Alox15 (arachidonate 15-lipoxygenase) or plasmid DNA expressing Alox15 for EC-specific overexpression. Lipidomic profiling and in vivo rescue studies with the identified Alox15-regulated lipids were performed. In addition, thrombocytopenia was induced by genetic depletion of platelets using <i>DTR</i><sup><i>Pf4Cre</i></sup> mice, and the effects of restoration of pulmonary thrombosis were assessed.</p><p><strong>Results: </strong>We show that although severe pulmonary thrombosis or thrombocytopenia augments sepsis-induced ALI, the induction of mild pulmonary thrombosis conversely reduces EC apoptosis, ALI, and mortality via sustained expression of endothelial Alox15. Endothelial <i>Alox15</i> knockout in adult mice abolished the protective impact of mild lung thrombosis. Conversely, overexpression of endothelial <i>Alox15</i> inhibited the increases in ALI caused by severe pulmonary thrombosis. Treatment of the endothelial <i>Alox15</i> knockout mice with 1-palmitoyl-2-oleoyl-3-arachidonoyl-rac-glycerol (C<sub>57</sub>H<sub>100</sub>O<sub>6</sub>), a top candidate of the 32 Alox15-regulated lipids identified by lipidomic profiling, markedly reversed the defective phenotype, suggesting that Alox15 protects from lung injury via protective lipids. The clinical relevance of the findings was supported by the observation of reduced ALOX15-expressing ECs in lung autopsy samples of patients with ARDS. In addition, restoration of pulmonary thrombosis in thrombocytopenic mice normalized endotoxemia-induced ALI.</p><p><strong>Conclusions: </strong>We have demonstrated that moderate levels of lung thrombosis protect against sepsis-induced inflammatory lung injury via endothelial Alox15. Overexpression of endothelial Alox15 inhibits severe pulmonary thrombosis-induced increases in ALI. Thus, upregulation of ALOX15 expression or treatment with ALOX15-dependent protective lipid(s) represents a promising therapeutic strategy for treatment of ARDS, especially in subpopulations of patients with thrombocytopenia or widespread ","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e326357"},"PeriodicalIF":16.2,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12724588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145512099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1161/CIRCRESAHA.125.325793
Rebecca L Harper, Patrick M Lelliott, Shawn B Bender, Alexander R Pinto
The cardiovascular system, composed of the heart and vasculature, is essential for blood circulation, nutrient exchange, and waste removal. In the past, our understanding of cardiovascular development and function has largely been shaped by bulk tissue analyses, which obscures cellular heterogeneity. The emergence of single-cell omics has transformed the field by enabling unbiased transcriptional profiling of individual cells, revealing the diversity of stem cells and progenitor cells driving embryogenesis, resulting in the various mature cardiovascular cell types in the adult heart and vasculature. This technology has provided unprecedented insights into the molecular mechanisms governing cardiovascular development and function by identifying novel cell subpopulations, characterizing their unique properties, and tracing their temporal evolution through advanced analytical approaches. In this review, we discuss how single-cell omics has reshaped our understanding of cardiovascular developmental biology, highlight key analytical tools and emerging approaches, examine preclinical models that have facilitated these discoveries, and explore how these technologies have defined the cellular landscape of the heart and vasculature. We conclude by looking ahead to emerging technologies such as spatial transcriptomics and clonal barcoding for lineage tracing, as well as new strategies in addressing the gender gap in cardiovascular research.
{"title":"Unraveling Cardiovascular Development and Function: Insights From Single-Cell Omics.","authors":"Rebecca L Harper, Patrick M Lelliott, Shawn B Bender, Alexander R Pinto","doi":"10.1161/CIRCRESAHA.125.325793","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.125.325793","url":null,"abstract":"<p><p>The cardiovascular system, composed of the heart and vasculature, is essential for blood circulation, nutrient exchange, and waste removal. In the past, our understanding of cardiovascular development and function has largely been shaped by bulk tissue analyses, which obscures cellular heterogeneity. The emergence of single-cell omics has transformed the field by enabling unbiased transcriptional profiling of individual cells, revealing the diversity of stem cells and progenitor cells driving embryogenesis, resulting in the various mature cardiovascular cell types in the adult heart and vasculature. This technology has provided unprecedented insights into the molecular mechanisms governing cardiovascular development and function by identifying novel cell subpopulations, characterizing their unique properties, and tracing their temporal evolution through advanced analytical approaches. In this review, we discuss how single-cell omics has reshaped our understanding of cardiovascular developmental biology, highlight key analytical tools and emerging approaches, examine preclinical models that have facilitated these discoveries, and explore how these technologies have defined the cellular landscape of the heart and vasculature. We conclude by looking ahead to emerging technologies such as spatial transcriptomics and clonal barcoding for lineage tracing, as well as new strategies in addressing the gender gap in cardiovascular research.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"138 1","pages":"e325793"},"PeriodicalIF":16.2,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1161/RES.0000000000000743
{"title":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000743","DOIUrl":"https://doi.org/10.1161/RES.0000000000000743","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"138 1","pages":"e000743"},"PeriodicalIF":16.2,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145891864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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