Pub Date : 2026-01-29DOI: 10.1161/circresaha.125.327212
Rocco Caliandro,Merel L Ligtermoet,Alexandra E Giovou,Azra Husetić,Arie R Boender,Huiling Zhou,Jermo Hanemaaijer-van der Veer,Liangyu Hu,Deli Zhang,Lorena Zentilin,Roelof-Jan Oostra,Gerard J J Boink,Mauro Giacca,Vincent M Christoffels,Monika M Gladka
BACKGROUNDLong noncoding RNAs have emerged as critical regulators in cardiovascular biology, influencing cardiac development, remodeling, and regeneration. Zeb2os, a natural antisense transcript of the Zeb2 gene, has been linked to these processes in various organs. Although ZEB2 (zinc finger E-box-binding homeobox 2) promotes cardiac repair, the role of Zeb2os in these processes remains unclear. This study investigates the role of Zeb2os in modulating ZEB2 expression and cardiac remodeling after ischemic injury.METHODSWe used adeno-associated virus vectors to overexpress Zeb2os in mouse models of cardiac IR injury. RNA sequencing, immunofluorescence, and high-resolution respirometry were used to evaluate the effects of Zeb2os delivery on gene expression, ZEB2 reactivation, cardiomyocyte phenotype, scar composition, and mitochondrial function. Experiments in cultured cardiomyocytes under hypoxia further explored the regulatory dynamics between Zeb2os and Zeb2.RESULTSWe identified Zeb2os as a hypoxia-responsive long noncoding RNA that displays an inverse and oscillatory expression pattern with Zeb2 in both in vitro and in vivo models of cardiac injury. Functional experiments revealed that Zeb2os negatively regulates ZEB2 expression, impairing the cardiomyocyte dedifferentiation and metabolic remodeling necessary for effective repair. Adeno-associated virus-mediated delivery of Zeb2os resulted in preserved sarcomere structure, altered scar composition, reduced expression of regenerative genes, and diminished cardiac function following injury. In contrast, silencing of Zeb2os increased ZEB2 protein expression, suggesting a potential therapeutic strategy to enhance repair. Mechanistically, modulation of Zeb2os levels inversely regulated ZEB2 protein expression, whereas ZEB2 modulation did not affect Zeb2os levels, indicating a unidirectional regulatory axis between the 2 transcripts.CONCLUSIONSOur findings identify Zeb2os as a stress-responsive inhibitor of ZEB2 reactivation that limits cardiomyocyte plasticity and hinders repair following ischemic injury. Given its specific activity under ischemic conditions, targeting Zeb2os may represent a novel therapeutic strategy to enhance endogenous cardiac regeneration.
{"title":"Zeb2os Hinders Cardiac Healing by Suppressing ZEB2 Reactivation and Cardiomyocyte Dedifferentiation.","authors":"Rocco Caliandro,Merel L Ligtermoet,Alexandra E Giovou,Azra Husetić,Arie R Boender,Huiling Zhou,Jermo Hanemaaijer-van der Veer,Liangyu Hu,Deli Zhang,Lorena Zentilin,Roelof-Jan Oostra,Gerard J J Boink,Mauro Giacca,Vincent M Christoffels,Monika M Gladka","doi":"10.1161/circresaha.125.327212","DOIUrl":"https://doi.org/10.1161/circresaha.125.327212","url":null,"abstract":"BACKGROUNDLong noncoding RNAs have emerged as critical regulators in cardiovascular biology, influencing cardiac development, remodeling, and regeneration. Zeb2os, a natural antisense transcript of the Zeb2 gene, has been linked to these processes in various organs. Although ZEB2 (zinc finger E-box-binding homeobox 2) promotes cardiac repair, the role of Zeb2os in these processes remains unclear. This study investigates the role of Zeb2os in modulating ZEB2 expression and cardiac remodeling after ischemic injury.METHODSWe used adeno-associated virus vectors to overexpress Zeb2os in mouse models of cardiac IR injury. RNA sequencing, immunofluorescence, and high-resolution respirometry were used to evaluate the effects of Zeb2os delivery on gene expression, ZEB2 reactivation, cardiomyocyte phenotype, scar composition, and mitochondrial function. Experiments in cultured cardiomyocytes under hypoxia further explored the regulatory dynamics between Zeb2os and Zeb2.RESULTSWe identified Zeb2os as a hypoxia-responsive long noncoding RNA that displays an inverse and oscillatory expression pattern with Zeb2 in both in vitro and in vivo models of cardiac injury. Functional experiments revealed that Zeb2os negatively regulates ZEB2 expression, impairing the cardiomyocyte dedifferentiation and metabolic remodeling necessary for effective repair. Adeno-associated virus-mediated delivery of Zeb2os resulted in preserved sarcomere structure, altered scar composition, reduced expression of regenerative genes, and diminished cardiac function following injury. In contrast, silencing of Zeb2os increased ZEB2 protein expression, suggesting a potential therapeutic strategy to enhance repair. Mechanistically, modulation of Zeb2os levels inversely regulated ZEB2 protein expression, whereas ZEB2 modulation did not affect Zeb2os levels, indicating a unidirectional regulatory axis between the 2 transcripts.CONCLUSIONSOur findings identify Zeb2os as a stress-responsive inhibitor of ZEB2 reactivation that limits cardiomyocyte plasticity and hinders repair following ischemic injury. Given its specific activity under ischemic conditions, targeting Zeb2os may represent a novel therapeutic strategy to enhance endogenous cardiac regeneration.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"296 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069966","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 : 2026-01-29DOI: 10.1161/circresaha.125.328023
Megha Talati,James West
{"title":"Recruited and Resident Macrophages Play a Distinct Role in Vascular Remodeling in Pulmonary Arterial Hypertension.","authors":"Megha Talati,James West","doi":"10.1161/circresaha.125.328023","DOIUrl":"https://doi.org/10.1161/circresaha.125.328023","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"72 1","pages":"e328023"},"PeriodicalIF":20.1,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073044","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 : 2026-01-29DOI: 10.1161/circresaha.125.327074
Yingzi Li,Joseph Loscalzo,Wusheng Xiao
Cardiopulmonary vascular diseases are the leading cause of death worldwide. Metabolic reprogramming and inflammation are 2 commonly shared hallmarks of such diseases. The bifunctional enzymes PFKFB (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases) 1 to 4 are well-known for their critical functions in glucose metabolism. Emerging evidence has indicated that PFKFB enzymes, particularly PFKFB3, are essential immunometabolic regulators and implicated in cardiopulmonary vascular and other pathologies. We here first summarize the structural basis for the catalytic function of PFKFB family enzymes, introduce the recent advances on the regulation of PFKFB3 expression and activity as well as its nonmetabolic functions, then elaborate on how dysregulation of PFKFBs influences physiological and pathological states of the cardiovascular and pulmonary systems, and finally touch on the current development of pharmacological inhibitors of PFKFB3 as potential therapeutics.
{"title":"Glucose Metabolic Enzyme PFKFB3 in Cardiopulmonary Vascular Health and Disease.","authors":"Yingzi Li,Joseph Loscalzo,Wusheng Xiao","doi":"10.1161/circresaha.125.327074","DOIUrl":"https://doi.org/10.1161/circresaha.125.327074","url":null,"abstract":"Cardiopulmonary vascular diseases are the leading cause of death worldwide. Metabolic reprogramming and inflammation are 2 commonly shared hallmarks of such diseases. The bifunctional enzymes PFKFB (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases) 1 to 4 are well-known for their critical functions in glucose metabolism. Emerging evidence has indicated that PFKFB enzymes, particularly PFKFB3, are essential immunometabolic regulators and implicated in cardiopulmonary vascular and other pathologies. We here first summarize the structural basis for the catalytic function of PFKFB family enzymes, introduce the recent advances on the regulation of PFKFB3 expression and activity as well as its nonmetabolic functions, then elaborate on how dysregulation of PFKFBs influences physiological and pathological states of the cardiovascular and pulmonary systems, and finally touch on the current development of pharmacological inhibitors of PFKFB3 as potential therapeutics.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"93 1","pages":"e327074"},"PeriodicalIF":20.1,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073212","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 : 2026-01-16Epub Date: 2025-12-04DOI: 10.1161/CIRCRESAHA.125.327403
Andrew N Carley, Santosh K Maurya, Chandan K Maurya, Yang Wang, Amy Webb, Azariyas A Challa, Tatiana Gromova, Thomas M Vondriska, Zhentao Zhang, Hua Zhu, Ahlke Heydemann, Kenneth C Bedi, Christos P Kyriakopoulos, Craig H Selzman, Stavros G Drakos, Kenneth B Margulies, E Douglas Lewandowski
Background: CPT1 (carnitine palmitoyltransferase 1) is a rate-limiting enzyme for long-chain fatty acid oxidation. In adult hearts, CPT1b predominates, while CPT1a is coexpressed at lower levels. Pathological stress on the heart induces CPT1a expression, coinciding with a reduction in fatty acid oxidation, yet the role of CPT1a in pathological remodeling is unknown.
Methods: CPT1 isoform expression was assayed in the myocardium of patients with heart failure with nonischemic cardiomyopathy and a preclinical mouse model of heart failure. Mice were subjected to afterload stress via transverse aortic constriction (TAC) or sham surgery (sham) with cardiac-specific CPT1a knockdown or cardiac-specific, adeno-associated virus serotype 9 (AAV9)-mediated CPT1a overexpression (AAV9.cTnT [cardiac troponin T].Cpt1a) versus empty virus or PBS infusions as controls. MicroRNA 370, known to suppress hepatic CPT1a, was assayed and overexpressed to determine if microRNA 370 regulates cardiac CPT1a expression.
Results: CPT1a protein was elevated and microRNA 370 reduced in the myocardium of male and female patients with nonischemic cardiomyopathy, as well as in failing mouse hearts. AAV9-mediated microRNA 370 overexpression in mouse hearts suppressed CPT1a expression and attenuated the response of CPT1a to TAC. Preventing CPT1a upregulation in response to TAC in cardiac-specific CPT1a knockout mice exacerbated adverse remodeling, severe dysfunction, and increased mortality. In contrast, CPT1a overexpression (2.8-fold) attenuated impaired ejection fraction (by 54%) versus control TAC hearts (P<0.05). Delivery of AAV9.cTnT.Cpt1a 4 weeks after TAC surgery led to significant rescue of ejection fraction and mitigated the exacerbated dysfunction of cardiac-specific CPT1a knockout mice TAC hearts. RNA-seq revealed a novel function of CPT1a in suppressing hypertrophic, profibrotic, and cell death gene programs in both sham and TAC hearts, irrespective of changes in fatty acid oxidation, with reduced histone acetylation.
Conclusions: The effects of CPT1a in the heart extend beyond fatty acid oxidation including noncanonical regulation of gene programs. CPT1a upregulation occurs in nonischemic cardiomyopathy and is a critical cardioprotective adaptation to pathological stress.
{"title":"CPT1a Expression Is a Critical Cardioprotective Response to Pathological Stress That Enables Rescue by Gene Transfer.","authors":"Andrew N Carley, Santosh K Maurya, Chandan K Maurya, Yang Wang, Amy Webb, Azariyas A Challa, Tatiana Gromova, Thomas M Vondriska, Zhentao Zhang, Hua Zhu, Ahlke Heydemann, Kenneth C Bedi, Christos P Kyriakopoulos, Craig H Selzman, Stavros G Drakos, Kenneth B Margulies, E Douglas Lewandowski","doi":"10.1161/CIRCRESAHA.125.327403","DOIUrl":"10.1161/CIRCRESAHA.125.327403","url":null,"abstract":"<p><strong>Background: </strong>CPT1 (carnitine palmitoyltransferase 1) is a rate-limiting enzyme for long-chain fatty acid oxidation. In adult hearts, CPT1b predominates, while CPT1a is coexpressed at lower levels. Pathological stress on the heart induces CPT1a expression, coinciding with a reduction in fatty acid oxidation, yet the role of CPT1a in pathological remodeling is unknown.</p><p><strong>Methods: </strong>CPT1 isoform expression was assayed in the myocardium of patients with heart failure with nonischemic cardiomyopathy and a preclinical mouse model of heart failure. Mice were subjected to afterload stress via transverse aortic constriction (TAC) or sham surgery (sham) with cardiac-specific CPT1a knockdown or cardiac-specific, adeno-associated virus serotype 9 (AAV9)-mediated CPT1a overexpression (AAV9.cTnT [cardiac troponin T].Cpt1a) versus empty virus or PBS infusions as controls. MicroRNA 370, known to suppress hepatic CPT1a, was assayed and overexpressed to determine if microRNA 370 regulates cardiac CPT1a expression.</p><p><strong>Results: </strong>CPT1a protein was elevated and microRNA 370 reduced in the myocardium of male and female patients with nonischemic cardiomyopathy, as well as in failing mouse hearts. AAV9-mediated microRNA 370 overexpression in mouse hearts suppressed CPT1a expression and attenuated the response of CPT1a to TAC. Preventing CPT1a upregulation in response to TAC in cardiac-specific CPT1a knockout mice exacerbated adverse remodeling, severe dysfunction, and increased mortality. In contrast, CPT1a overexpression (2.8-fold) attenuated impaired ejection fraction (by 54%) versus control TAC hearts (<i>P</i><0.05). Delivery of AAV9.cTnT.Cpt1a 4 weeks after TAC surgery led to significant rescue of ejection fraction and mitigated the exacerbated dysfunction of cardiac-specific CPT1a knockout mice TAC hearts. RNA-seq revealed a novel function of CPT1a in suppressing hypertrophic, profibrotic, and cell death gene programs in both sham and TAC hearts, irrespective of changes in fatty acid oxidation, with reduced histone acetylation.</p><p><strong>Conclusions: </strong>The effects of CPT1a in the heart extend beyond fatty acid oxidation including noncanonical regulation of gene programs. CPT1a upregulation occurs in nonischemic cardiomyopathy and is a critical cardioprotective adaptation to pathological stress.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e327403"},"PeriodicalIF":16.2,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12811910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145667357","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 : 2026-01-16Epub Date: 2026-01-15DOI: 10.1161/RES.0000000000000744
{"title":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000744","DOIUrl":"https://doi.org/10.1161/RES.0000000000000744","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"138 2","pages":"e000744"},"PeriodicalIF":16.2,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984439","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 : 2026-01-15DOI: 10.1161/circresaha.125.327929
Anja Karlstaedt
{"title":"Fatty Acid Transport at the Heart of Metabolic Adaptation.","authors":"Anja Karlstaedt","doi":"10.1161/circresaha.125.327929","DOIUrl":"https://doi.org/10.1161/circresaha.125.327929","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"10 1","pages":"e327929"},"PeriodicalIF":20.1,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971795","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}
BACKGROUNDDirect cardiac reprogramming offers a promising therapeutic strategy for heart regeneration by converting endogenous fibroblasts to functional induced cardiomyocytes (iCMs) that integrate into the myocardium to restore heart structure and function. While ECM (extracellular matrix) plays critical roles in cardiac disease and repair, the dynamic changes and transcriptional regulation underlying ECM remodeling during reprogramming remain poorly understood.METHODSWe investigated ECM dynamics during iCM reprogramming using integrated transcriptomic, proteomic, and epigenetic analyses, focusing on cell type-specific ECM components. A loss-of-function screen was used to identify critical ECM components and regulators, including Itga8 (integrin alpha-8) and Grhl3 (grainyhead-like protein 3 homolog), respectively, as reprogramming barriers. Mechanistic studies integrated RNA sequencing, mass spectrometry, and Cleavage Under Targets and Tagmentation to define Grhl3-dependent regulation. Functional outcomes were evaluated in vitro using decellularized ECM and in vivo using a myocardial infarction model with genetic lineage tracing.RESULTSCardiac reprogramming induced dynamic ECM remodeling, with significant changes in collagen, fibrillar proteins, and integrins. Itga8 was identified as a pivotal ECM component that restricts iCM conversion via the TGF-β (transforming growth factor-β)/SMAD pathway. Grhl3 emerged as a key transcriptional regulator for ECM components, including Itga8. ECM derived from Grhl3-deficient fibroblasts enhanced iCM induction, while Grhl3 depletion also reduced fibroblast activation and increased cellular plasticity. These effects synergized with TF (transcription factor)-mediated reprogramming to improve iCM efficiency, structural organization, and functional maturation. In vivo, removing Grhl3 enhanced fibroblast-to-cardiomyocyte conversion, reduced scar formation, and improved cardiac function after myocardial infarction.CONCLUSIONSOur findings establish ECM adaptation as a critical determinant of cardiac reprogramming and identify Grhl3 as a promising therapeutic target to advance myocardial repair strategies.
{"title":"Grhl3 Downregulation Facilitates ECM Adaptation for Fibroblast to iCM Commitment.","authors":"Xin Wu,Lanbing Liu,Yuanru Huang,Yi Ling,Fang Luo,Dongyu Gu,Mengxin Liu,Zhenhua Jia,Zhangyi Yu,Xiangjie Kong,Hong Ma,Yanggan Wang,Li Wang","doi":"10.1161/circresaha.125.327726","DOIUrl":"https://doi.org/10.1161/circresaha.125.327726","url":null,"abstract":"BACKGROUNDDirect cardiac reprogramming offers a promising therapeutic strategy for heart regeneration by converting endogenous fibroblasts to functional induced cardiomyocytes (iCMs) that integrate into the myocardium to restore heart structure and function. While ECM (extracellular matrix) plays critical roles in cardiac disease and repair, the dynamic changes and transcriptional regulation underlying ECM remodeling during reprogramming remain poorly understood.METHODSWe investigated ECM dynamics during iCM reprogramming using integrated transcriptomic, proteomic, and epigenetic analyses, focusing on cell type-specific ECM components. A loss-of-function screen was used to identify critical ECM components and regulators, including Itga8 (integrin alpha-8) and Grhl3 (grainyhead-like protein 3 homolog), respectively, as reprogramming barriers. Mechanistic studies integrated RNA sequencing, mass spectrometry, and Cleavage Under Targets and Tagmentation to define Grhl3-dependent regulation. Functional outcomes were evaluated in vitro using decellularized ECM and in vivo using a myocardial infarction model with genetic lineage tracing.RESULTSCardiac reprogramming induced dynamic ECM remodeling, with significant changes in collagen, fibrillar proteins, and integrins. Itga8 was identified as a pivotal ECM component that restricts iCM conversion via the TGF-β (transforming growth factor-β)/SMAD pathway. Grhl3 emerged as a key transcriptional regulator for ECM components, including Itga8. ECM derived from Grhl3-deficient fibroblasts enhanced iCM induction, while Grhl3 depletion also reduced fibroblast activation and increased cellular plasticity. These effects synergized with TF (transcription factor)-mediated reprogramming to improve iCM efficiency, structural organization, and functional maturation. In vivo, removing Grhl3 enhanced fibroblast-to-cardiomyocyte conversion, reduced scar formation, and improved cardiac function after myocardial infarction.CONCLUSIONSOur findings establish ECM adaptation as a critical determinant of cardiac reprogramming and identify Grhl3 as a promising therapeutic target to advance myocardial repair strategies.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"39 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968383","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 : 2026-01-15DOI: 10.1161/circresaha.125.325798
E Dale Abel,Rexford S Ahima,Ethan J Anderson,David D Berg,Jeffrey S Berger,Saumya Das,Mark W Feinberg,Edward A Fisher,Michael S Garshick,Chiara Giannarelli,Ira J Goldberg,Naomi M Hamburg,Sangwon F Kim,Filipe A Moura,Chiadi E Ndumele,Jonathan D Newman,Marc S Sabatine,Elizabeth Selvin,Ravi Shah
Despite major advances in medical therapies and prevention strategies, the risk of cardiovascular complications in patients with both type I and type II diabetes remains substantially elevated. In 2019, the American Heart Association sought applications for a Strategically Focused Research Network on Cardiometabolic Health and Type 2 Diabetes. In 2020, 4 centers were named, including Brigham and Women's Hospital, Johns Hopkins University, New York University, and the University of Iowa. These centers performed basic, translational, and clinical studies to provide insights to explain the over 2-fold risk of cardiovascular complications in diabetes. Clinical studies and studies in cells and animals aimed to uncover new mechanisms responsible for disease development. Studies using human populations sought to uncover new biomarkers to prognosticate risk. In this review, we discuss several key issues and current and developing methods to understand why diabetes drives atherosclerotic cardiovascular disease and heart failure. Both human data and experimental models are considered. We integrate a review of these topics with work from the Strategically Focused Research Network and conclude with suggestions for identifying novel risk factors and future experimental research.
{"title":"A Road Map to Understanding Cardiovascular Disease in Diabetes: From the AHA Strategically Focused Research Network in Cardiometabolic Health and Type 2 Diabetes.","authors":"E Dale Abel,Rexford S Ahima,Ethan J Anderson,David D Berg,Jeffrey S Berger,Saumya Das,Mark W Feinberg,Edward A Fisher,Michael S Garshick,Chiara Giannarelli,Ira J Goldberg,Naomi M Hamburg,Sangwon F Kim,Filipe A Moura,Chiadi E Ndumele,Jonathan D Newman,Marc S Sabatine,Elizabeth Selvin,Ravi Shah","doi":"10.1161/circresaha.125.325798","DOIUrl":"https://doi.org/10.1161/circresaha.125.325798","url":null,"abstract":"Despite major advances in medical therapies and prevention strategies, the risk of cardiovascular complications in patients with both type I and type II diabetes remains substantially elevated. In 2019, the American Heart Association sought applications for a Strategically Focused Research Network on Cardiometabolic Health and Type 2 Diabetes. In 2020, 4 centers were named, including Brigham and Women's Hospital, Johns Hopkins University, New York University, and the University of Iowa. These centers performed basic, translational, and clinical studies to provide insights to explain the over 2-fold risk of cardiovascular complications in diabetes. Clinical studies and studies in cells and animals aimed to uncover new mechanisms responsible for disease development. Studies using human populations sought to uncover new biomarkers to prognosticate risk. In this review, we discuss several key issues and current and developing methods to understand why diabetes drives atherosclerotic cardiovascular disease and heart failure. Both human data and experimental models are considered. We integrate a review of these topics with work from the Strategically Focused Research Network and conclude with suggestions for identifying novel risk factors and future experimental research.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"100 1","pages":"e325798"},"PeriodicalIF":20.1,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971835","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 : 2026-01-14DOI: 10.1161/circresaha.125.326772
Nicolas Hense,Andrea Gogels,Bilal Mir,Emiel P C van der Vorst,Guillaume Falgayrac,Mara Terliesner,Isabel Goncalves,Ljubica Matic,Andreas Edsfeldt,Jiangming Sun,Ulf Hedin,Sikander Hayat,Jessica Thiel,Maria Alejandra Ramirez-Torres,Mirna Barsoum,Alexander Rauch,Martina Rauner,Alexander Gombert,Christian Preisinger,Heidi Noels,Nikolaus Marx,Claudia Goettsch
BACKGROUNDCardiovascular calcification is a significant predictor and contributor to cardiovascular diseases. Vascular smooth muscle cell (SMC)-derived extracellular vesicles (EVs) play a crucial role in microcalcification formation. EVs can originate from the endosomal system, and PIKFYVE (1-phosphatidylinositol 3-phosphate 5-kinase), a lipid kinase, plays a key role in endomembrane maturation. We hypothesize that PIKFYVE inhibition will modulate EV cargo and, thereby, arterial calcification.METHODSHuman coronary artery SMCs were cultured in osteogenic media to induce calcification. PIKFYVE inhibition was achieved using the pharmacological inhibitor apilimod and siRNA. We characterized the SMC phenotype and EVs through proteomics, transcriptomics, and kinomics. Ldlr-deficient mice fed a high-fat, high-cholesterol diet received apilimod for 5 weeks.RESULTSCalcified human arteries and SMCs exhibited increased PIKFYVE protein expression compared with controls. In calcifying SMCs, phosphatidylinositol 3-phosphate levels were reduced but restored by apilimod. Apilimod prevented matrix mineralization and collagen deposition in calcifying SMCs, accompanied by reduced procollagen 1A1 secretion. Apilimod inhibited TNAP (tissue-nonspecific alkaline phosphatase) at mRNA, protein, and activity levels. EVs released from apilimod-treated calcifying SMCs exhibited lower mineral cargo, reduced aggregation potential, and diminished TNAP cargo. Phenotypic omics analyses revealed that apilimod induced a shift toward an adipocyte-like SMC phenotype, marked by upregulation of adipogenic TFs (transcription factors), fatty acid metabolism genes, and increased fatty acid uptake. Reactivation of YAP (Yes-associated protein)-TEAD (transcriptional enhancer factor) signaling partially reversed these phenotypic changes. In vivo, apilimod reduced vascular calcification and plaque TNAP activity but increased plaque lipid accumulation.CONCLUSIONSPharmacological inhibition of PIKFYVE disrupts YAP-TEAD signaling, thereby reducing arterial calcification by limiting the calcification potential of EVs and suppressing osteogenic SMC programming, but also induces an adipocyte-like SMC phenotype with lipid accumulation. These findings emphasize the need to consider SMC phenotypic plasticity and potential adverse effects when developing therapeutic strategies for arterial calcification.
{"title":"1-Phosphatidylinositol 3-Phosphate 5-Kinase Inhibition by Apilimod Promotes an Adipocyte-Like Vascular Smooth Muscle Cell Phenotype and Prevents Arterial Calcification.","authors":"Nicolas Hense,Andrea Gogels,Bilal Mir,Emiel P C van der Vorst,Guillaume Falgayrac,Mara Terliesner,Isabel Goncalves,Ljubica Matic,Andreas Edsfeldt,Jiangming Sun,Ulf Hedin,Sikander Hayat,Jessica Thiel,Maria Alejandra Ramirez-Torres,Mirna Barsoum,Alexander Rauch,Martina Rauner,Alexander Gombert,Christian Preisinger,Heidi Noels,Nikolaus Marx,Claudia Goettsch","doi":"10.1161/circresaha.125.326772","DOIUrl":"https://doi.org/10.1161/circresaha.125.326772","url":null,"abstract":"BACKGROUNDCardiovascular calcification is a significant predictor and contributor to cardiovascular diseases. Vascular smooth muscle cell (SMC)-derived extracellular vesicles (EVs) play a crucial role in microcalcification formation. EVs can originate from the endosomal system, and PIKFYVE (1-phosphatidylinositol 3-phosphate 5-kinase), a lipid kinase, plays a key role in endomembrane maturation. We hypothesize that PIKFYVE inhibition will modulate EV cargo and, thereby, arterial calcification.METHODSHuman coronary artery SMCs were cultured in osteogenic media to induce calcification. PIKFYVE inhibition was achieved using the pharmacological inhibitor apilimod and siRNA. We characterized the SMC phenotype and EVs through proteomics, transcriptomics, and kinomics. Ldlr-deficient mice fed a high-fat, high-cholesterol diet received apilimod for 5 weeks.RESULTSCalcified human arteries and SMCs exhibited increased PIKFYVE protein expression compared with controls. In calcifying SMCs, phosphatidylinositol 3-phosphate levels were reduced but restored by apilimod. Apilimod prevented matrix mineralization and collagen deposition in calcifying SMCs, accompanied by reduced procollagen 1A1 secretion. Apilimod inhibited TNAP (tissue-nonspecific alkaline phosphatase) at mRNA, protein, and activity levels. EVs released from apilimod-treated calcifying SMCs exhibited lower mineral cargo, reduced aggregation potential, and diminished TNAP cargo. Phenotypic omics analyses revealed that apilimod induced a shift toward an adipocyte-like SMC phenotype, marked by upregulation of adipogenic TFs (transcription factors), fatty acid metabolism genes, and increased fatty acid uptake. Reactivation of YAP (Yes-associated protein)-TEAD (transcriptional enhancer factor) signaling partially reversed these phenotypic changes. In vivo, apilimod reduced vascular calcification and plaque TNAP activity but increased plaque lipid accumulation.CONCLUSIONSPharmacological inhibition of PIKFYVE disrupts YAP-TEAD signaling, thereby reducing arterial calcification by limiting the calcification potential of EVs and suppressing osteogenic SMC programming, but also induces an adipocyte-like SMC phenotype with lipid accumulation. These findings emphasize the need to consider SMC phenotypic plasticity and potential adverse effects when developing therapeutic strategies for arterial calcification.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"55 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971796","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}
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：