Catecholamine neurons in the rostral ventrolateral medulla (RVLM) have long been recognized as a crucial neuronal population involved in cardiovascular regulation. However, its function and related circuits in ventricular remodeling after myocardial ischemia/reperfusion injury (MIRI) remain unclear. In this study, we investigated the potential role of RVLM catecholaminergic neurons and the underlying mechanisms that drive MIRI and the development of post-MIRI ventricular remodeling. In vivo electrophysiological recordings revealed that the spontaneous spike rate of RVLM neurons increased throughout MIRI. Transneuronal tracing with neurotropic viruses indicated that the RVLM catecholaminergic neurons received glutamatergic projections from paraventricular nucleus (PVN). Specifically, these RVLM catecholaminergic neurons project directly to the spinal preganglionic neurons and then to the stellate ganglion, which are two critical neural nodes that regulate cardiovascular activity. In addition, inhibition of the neural circuit associated with RVLM catecholaminergic neurons suppresses cardiac sympathetic activity, thereby preventing MIRI and lessening the severity of ventricular remodeling at 4 weeks after MIRI. Our findings suggest that glutamatergic projections from PVN to RVLM catecholaminergic neurons are important yet distinctive mechanisms of the brain-to-heart axis in regulating MIRI and potentially mitigating ventricular remodeling and subsequent heart failure.
{"title":"The activation of catecholamine neurons in the rostral ventrolateral medulla drives ventricular remodeling after myocardial ischemia/reperfusion injury.","authors":"Shijin Xu,Rui Zhang,Shiyun Jin,Heyi Luo,Yiwen Hou,Shufang He,Zhou Shi,Ru Zhao,Zhenxin Chen,Bin Wang,Chen Chen,Qi Xue,Meiyan Sun,Sitong Fang,Guichang Zou,Wei Xiong,Ye Zhang","doi":"10.1007/s00395-025-01128-7","DOIUrl":"https://doi.org/10.1007/s00395-025-01128-7","url":null,"abstract":"Catecholamine neurons in the rostral ventrolateral medulla (RVLM) have long been recognized as a crucial neuronal population involved in cardiovascular regulation. However, its function and related circuits in ventricular remodeling after myocardial ischemia/reperfusion injury (MIRI) remain unclear. In this study, we investigated the potential role of RVLM catecholaminergic neurons and the underlying mechanisms that drive MIRI and the development of post-MIRI ventricular remodeling. In vivo electrophysiological recordings revealed that the spontaneous spike rate of RVLM neurons increased throughout MIRI. Transneuronal tracing with neurotropic viruses indicated that the RVLM catecholaminergic neurons received glutamatergic projections from paraventricular nucleus (PVN). Specifically, these RVLM catecholaminergic neurons project directly to the spinal preganglionic neurons and then to the stellate ganglion, which are two critical neural nodes that regulate cardiovascular activity. In addition, inhibition of the neural circuit associated with RVLM catecholaminergic neurons suppresses cardiac sympathetic activity, thereby preventing MIRI and lessening the severity of ventricular remodeling at 4 weeks after MIRI. Our findings suggest that glutamatergic projections from PVN to RVLM catecholaminergic neurons are important yet distinctive mechanisms of the brain-to-heart axis in regulating MIRI and potentially mitigating ventricular remodeling and subsequent heart failure.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"27 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578672","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 : 2025-07-06DOI: 10.1007/s00395-025-01125-w
Fábio Trindade,João Almeida-Coelho,Cláudia Sousa-Mendes,Francisca Saraiva,Maria L Arbonés,Adelino Leite-Moreira,Rui Vitorino,Inês Falcão-Pires
Aortic valve stenosis (AVS) is a growing healthcare burden. Aortic valve replacement (AVR) remains the only effective treatment to eliminate pressure overload and triggers myocardial reverse remodelling (RR), with regression of hypertrophy, fibrosis and diastolic function normalisation. However, many patients show an incomplete RR, being at higher risk of death. We aimed to uncover pathways and new therapeutic targets for incomplete RR through myocardial (phospho)proteomics. AVS patients were categorised based on left ventricle mass regression (LVM): complete RR (≥ 15%) or incomplete RR (≤ 5%). 83 myocardial proteins were dysregulated through LC-MS/MS. Gene ontology enrichment analysis identified inflammation, complement and immune system activation as priming events of an incomplete RR and a better mitochondrial function underscoring complete RR. Kinetic metabolic modelling corroborated the lower ATP production capacity of incomplete RR patients. To uncover therapeutic targets, kinases were predicted from phosphoproteome data. Casein kinase 2 and DYRK1A were among the most dysregulated kinases in RR. DYRK1A was found to be inversely correlated with LVM regression (r = - 0.62). DYRK1A functional role (passive, maximal tension and Ca2+ sensitivity) was evaluated in skinned cardiomyocytes from Dyrk1a+/- mice and from AVS patients upon incubation with this kinase. Cardiomyocytes from mutant mice showed increased myofilamentary stiffness in response to stretch. Also, the raised myofilamentary stiffness of cardiomyocytes isolated from incomplete RR was normalised upon incubation with DYRK1A. Better myocardial bioenergetics may underscore a complete LVM regression. In turn, complement and immune-inflammatory pathways activation prime an incomplete response to AVR. DYRK1A emerges as a surrogate target to treat myocardial stiffness-driven diastolic dysfunction.
{"title":"Myocardial phosphoproteomics unveils a key role of DYRK1A in aortic valve replacement-induced reverse remodelling.","authors":"Fábio Trindade,João Almeida-Coelho,Cláudia Sousa-Mendes,Francisca Saraiva,Maria L Arbonés,Adelino Leite-Moreira,Rui Vitorino,Inês Falcão-Pires","doi":"10.1007/s00395-025-01125-w","DOIUrl":"https://doi.org/10.1007/s00395-025-01125-w","url":null,"abstract":"Aortic valve stenosis (AVS) is a growing healthcare burden. Aortic valve replacement (AVR) remains the only effective treatment to eliminate pressure overload and triggers myocardial reverse remodelling (RR), with regression of hypertrophy, fibrosis and diastolic function normalisation. However, many patients show an incomplete RR, being at higher risk of death. We aimed to uncover pathways and new therapeutic targets for incomplete RR through myocardial (phospho)proteomics. AVS patients were categorised based on left ventricle mass regression (LVM): complete RR (≥ 15%) or incomplete RR (≤ 5%). 83 myocardial proteins were dysregulated through LC-MS/MS. Gene ontology enrichment analysis identified inflammation, complement and immune system activation as priming events of an incomplete RR and a better mitochondrial function underscoring complete RR. Kinetic metabolic modelling corroborated the lower ATP production capacity of incomplete RR patients. To uncover therapeutic targets, kinases were predicted from phosphoproteome data. Casein kinase 2 and DYRK1A were among the most dysregulated kinases in RR. DYRK1A was found to be inversely correlated with LVM regression (r = - 0.62). DYRK1A functional role (passive, maximal tension and Ca2+ sensitivity) was evaluated in skinned cardiomyocytes from Dyrk1a+/- mice and from AVS patients upon incubation with this kinase. Cardiomyocytes from mutant mice showed increased myofilamentary stiffness in response to stretch. Also, the raised myofilamentary stiffness of cardiomyocytes isolated from incomplete RR was normalised upon incubation with DYRK1A. Better myocardial bioenergetics may underscore a complete LVM regression. In turn, complement and immune-inflammatory pathways activation prime an incomplete response to AVR. DYRK1A emerges as a surrogate target to treat myocardial stiffness-driven diastolic dysfunction.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"20 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566513","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 : 2025-07-01DOI: 10.1007/s00395-025-01105-0
Lijiang Ma,Jacqueline E Tamis-Holland,Giuseppe Mocci,Kathryn Wolhuter,Nicole S Bryce,Swathy Sajja,Letizia Amadori,Payal Pradhan,Peik Sean Chong,Katyayani Sukhavasi,Haoxiang Cheng,Ling Li,Shichao Pang,Eric E Schadt,Heribert Schunkert,Moritz von Scheidt,Arno Ruusalepp,Pedro R Moreno,Ke Hao,Chiara Giannarelli,Clint L Miller,Jason C Kovacic,Johan L M Björkegren
Coronary artery disease (CAD) is a major cause of global morbidity and mortality. Macrophages play a central role in orchestrating this disease process. In 2016, we initiated the STARNET primary blood macrophage study, followed by the multi-ethnic NGS-PREDICT primary blood macrophage study in 2018. We applied integrative systems genetics analysis to explore and validate the role of macrophage gene regulatory co-expression networks (GRNs) in clinically significant CAD. This study included 318 CAD cases and 134 CAD-free controls in STARNET, and 95 CAD cases and 35 CAD-free controls in NGS-PREDICT. Primary leukocytes were isolated from blood and differentiated into macrophages in vitro, followed by RNA extraction and deep sequencing (RNAseq). In STARNET, we analyzed differentially expressed genes, inferred macrophage GRNs, assessed the phenotypic associations and functions of these GRNs, and determined their key driver genes. Integrative analysis of STARNET expression quantitative traits (eQTLs) with genotype data from genome-wide association studies was performed to determine the content of CAD candidate genes in these GRNs, and their contributions to CAD heritability. Five independent RNAseq datasets were used to retrospectively validate CAD-associated macrophage GRNs, followed by prospective validation in the NGS-PREDICT study. Using the STARNET datasets, we identified 23 macrophage GRNs. Of these, GRNGREEN stood out as being causally associated with CAD severity (SYNTAX score) and comprised 729 genes and 90 key drivers, with the top key driver being NEIL1. GRNGREEN accounted for 3.73% of CAD heritability and contained 34 candidate genes previously identified by GWAS of CAD. Functional analysis of GRNGREEN revealed a large portion of genes involved in the biological process of SRP-dependent co-translational protein targeting to the membrane. GRNGREEN replicated retrospectively in five independent human arterial wall RNAseq datasets, and prospectively in the NGS-PREDICT study. To prevent clinically significant CAD, GRNGREEN and its top key driver NEIL1 may be suitable therapeutic targets to modify SRP-dependent co-translational targeting of proteins to the endoplasmic reticulum in macrophages.
{"title":"A macrophage gene-regulatory network linked to clinical severity of coronary artery disease : The STARNET and NGS-PREDICT primary blood macrophage studies.","authors":"Lijiang Ma,Jacqueline E Tamis-Holland,Giuseppe Mocci,Kathryn Wolhuter,Nicole S Bryce,Swathy Sajja,Letizia Amadori,Payal Pradhan,Peik Sean Chong,Katyayani Sukhavasi,Haoxiang Cheng,Ling Li,Shichao Pang,Eric E Schadt,Heribert Schunkert,Moritz von Scheidt,Arno Ruusalepp,Pedro R Moreno,Ke Hao,Chiara Giannarelli,Clint L Miller,Jason C Kovacic,Johan L M Björkegren","doi":"10.1007/s00395-025-01105-0","DOIUrl":"https://doi.org/10.1007/s00395-025-01105-0","url":null,"abstract":"Coronary artery disease (CAD) is a major cause of global morbidity and mortality. Macrophages play a central role in orchestrating this disease process. In 2016, we initiated the STARNET primary blood macrophage study, followed by the multi-ethnic NGS-PREDICT primary blood macrophage study in 2018. We applied integrative systems genetics analysis to explore and validate the role of macrophage gene regulatory co-expression networks (GRNs) in clinically significant CAD. This study included 318 CAD cases and 134 CAD-free controls in STARNET, and 95 CAD cases and 35 CAD-free controls in NGS-PREDICT. Primary leukocytes were isolated from blood and differentiated into macrophages in vitro, followed by RNA extraction and deep sequencing (RNAseq). In STARNET, we analyzed differentially expressed genes, inferred macrophage GRNs, assessed the phenotypic associations and functions of these GRNs, and determined their key driver genes. Integrative analysis of STARNET expression quantitative traits (eQTLs) with genotype data from genome-wide association studies was performed to determine the content of CAD candidate genes in these GRNs, and their contributions to CAD heritability. Five independent RNAseq datasets were used to retrospectively validate CAD-associated macrophage GRNs, followed by prospective validation in the NGS-PREDICT study. Using the STARNET datasets, we identified 23 macrophage GRNs. Of these, GRNGREEN stood out as being causally associated with CAD severity (SYNTAX score) and comprised 729 genes and 90 key drivers, with the top key driver being NEIL1. GRNGREEN accounted for 3.73% of CAD heritability and contained 34 candidate genes previously identified by GWAS of CAD. Functional analysis of GRNGREEN revealed a large portion of genes involved in the biological process of SRP-dependent co-translational protein targeting to the membrane. GRNGREEN replicated retrospectively in five independent human arterial wall RNAseq datasets, and prospectively in the NGS-PREDICT study. To prevent clinically significant CAD, GRNGREEN and its top key driver NEIL1 may be suitable therapeutic targets to modify SRP-dependent co-translational targeting of proteins to the endoplasmic reticulum in macrophages.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"27 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533504","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 : 2025-06-25DOI: 10.1007/s00395-025-01126-9
Johnathan D Tune,Dirk J Duncker,Adam G Goodwill,Cooper M Warne,Salman I Essajee,Selina M Tucker,Steven A Romero,Shawn B Bender,Daniel A Beard,C Alberto Figueroa,Oana Sorop,Daphne Merkus,Gregory M Dick
This study tested the hypothesis that K+ serves as an in vivo signal coupling coronary blood flow with the oxidative requirements of the myocardium. Experiments were performed in swine in which coronary parameters and arterial and coronary venous [K+] were measured under baseline conditions, during exogenous administration of K+ (1-5 mM; n = 4), during increases in myocardial oxygen consumption (MVO2) to dobutamine (n = 7) and exercise (n = 6), alterations in coronary perfusion pressure (CPP; n = 8), and systemic hypoxemia (PaO2 to ~ 30 mmHg; n = 7). Exogenous intracoronary K+ increased blood flow (~ 20%) in direct proportion to the coronary venous [K+] up to the lethal limit of ~ 10 mM. Dobutamine increased coronary flow and MVO2 ~ threefold but the coronary venous-arterial [K+] gradient (i.e., a surrogate index of myocardial release of K+ into the coronary circulation) did not change. Similarly, exercise increased coronary flow and MVO2 ~ 2.5-fold without a change in the coronary venous-arterial [K+] gradient. The coronary venous-arterial [K+] gradient did not change over the CPP range of 140-40 mmHg. Hypoxemia increased coronary blood flow ~ twofold and coronary vascular resistance was weakly associated with < 0.5 mM change in the coronary venous-arterial [K+] gradient. Intracoronary glibenclamide dose-dependently (1-3 mg/min; n = 4) increased coronary resistance but did not affect the coronary venous-arterial [K+] gradient. Intracoronary pinacidil dose-dependently (0.3-3.0 µg/kg/min; n = 3) increased coronary blood flow but did not affect the coronary venous-arterial [K+] gradient. Similarly, intravenous glibenclamide (3 mg/kg; n = 6) increased coronary resistance but did not affect the coronary venous-arterial [K+] gradient in exercising swine. These findings fail to support the concept that myocardial interstitial [K+] couples coronary blood flow to MVO2 during physiologic increases in cardiac work or when oxygen delivery is constrained.
{"title":"Potassium as an electro-metabolic signal for local coronary vasodilation.","authors":"Johnathan D Tune,Dirk J Duncker,Adam G Goodwill,Cooper M Warne,Salman I Essajee,Selina M Tucker,Steven A Romero,Shawn B Bender,Daniel A Beard,C Alberto Figueroa,Oana Sorop,Daphne Merkus,Gregory M Dick","doi":"10.1007/s00395-025-01126-9","DOIUrl":"https://doi.org/10.1007/s00395-025-01126-9","url":null,"abstract":"This study tested the hypothesis that K+ serves as an in vivo signal coupling coronary blood flow with the oxidative requirements of the myocardium. Experiments were performed in swine in which coronary parameters and arterial and coronary venous [K+] were measured under baseline conditions, during exogenous administration of K+ (1-5 mM; n = 4), during increases in myocardial oxygen consumption (MVO2) to dobutamine (n = 7) and exercise (n = 6), alterations in coronary perfusion pressure (CPP; n = 8), and systemic hypoxemia (PaO2 to ~ 30 mmHg; n = 7). Exogenous intracoronary K+ increased blood flow (~ 20%) in direct proportion to the coronary venous [K+] up to the lethal limit of ~ 10 mM. Dobutamine increased coronary flow and MVO2 ~ threefold but the coronary venous-arterial [K+] gradient (i.e., a surrogate index of myocardial release of K+ into the coronary circulation) did not change. Similarly, exercise increased coronary flow and MVO2 ~ 2.5-fold without a change in the coronary venous-arterial [K+] gradient. The coronary venous-arterial [K+] gradient did not change over the CPP range of 140-40 mmHg. Hypoxemia increased coronary blood flow ~ twofold and coronary vascular resistance was weakly associated with < 0.5 mM change in the coronary venous-arterial [K+] gradient. Intracoronary glibenclamide dose-dependently (1-3 mg/min; n = 4) increased coronary resistance but did not affect the coronary venous-arterial [K+] gradient. Intracoronary pinacidil dose-dependently (0.3-3.0 µg/kg/min; n = 3) increased coronary blood flow but did not affect the coronary venous-arterial [K+] gradient. Similarly, intravenous glibenclamide (3 mg/kg; n = 6) increased coronary resistance but did not affect the coronary venous-arterial [K+] gradient in exercising swine. These findings fail to support the concept that myocardial interstitial [K+] couples coronary blood flow to MVO2 during physiologic increases in cardiac work or when oxygen delivery is constrained.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"20 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478761","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 : 2025-06-19DOI: 10.1007/s00395-025-01124-x
Y Xiao,X Hu,C F Rudolphi,E E Nollet,R Nederlof,Q Wang,D Bakker,Panagiota Efstathia Nikolaou,J C Knol,R R Goeij-de Haas,A A Henneman,T V Pham,C R Jimenez,A E Grootemaat,N N van der Wel,S E Girardin,N Kaludercic,J van der Velden,Z Onódi,P Leszek,Z V Varga,P Ferdinandy,B Preckel,N C Weber,M W Hollmann,F Di Lisa,C J Zuurbier
NLRX1 is the only NOD-like innate immune receptor that localises to mitochondria. We previously demonstrated that NLRX1 deletion increased infarct size in isolated mouse hearts subjected to ischemia-reperfusion injury (IRI); however, underlying mechanisms are yet to be identified. Given the crucial role played by mitochondria in cardiac IRI, we here hypothesise that NLRX1 affects key mechanisms of cardiac IRI. Cardiac IRI was evaluated in isolated C57BL/6J (WT) and NLRX1 knock out (KO) mouse hearts. The following known modulators of IRI were explored in isolated hearts, isolated mitochondria; or permeabilised cardiac fibres: 1) mTOR/RISK/autophagy regulation, 2) AMPK and mitochondrial energy production, and 3) mitochondrial permeability transition pore (mPTP) opening. NLRX1 deletion increased IRI, and cardiac NLRX1 was decreased after IRI in mouse and pig hearts. NLRX1 ablation caused decreased mTOR and RISK pathway (Akt, ERK, and S6K) activation following IR, without affecting autophagy/inflammation/oxidative stress markers. The RISK activator Urocortin dissipated NLRX1 effects on mTOR, RISK pathway and IRI, indicating that increased cardiac IRI with NLRX1 deletion is, at least partly, due to impaired RISK activation. The energy sensor AMPK was activated in NLRX1 KO hearts, possibly due to slowed mitochondrial respiratory responses (impaired mitochondrial permeability) towards palmitoylcarnitine in permeabilised cardiac fibres. NLRX1 deletion completely abolished calcium-induced mPTP opening, and cyclosporine A (CsA) effects on mPTP, both before and after IR, and was associated with increased mitochondrial calcium content after IR. Mitochondrial sub-fractionation studies localised NLRX1 to the inner mitochondrial membrane. NLRX1 deletion associated with decreased phosphorylation of mitochondrial Got2, Cx43, Myl2, Ndufb7 and MICOS10. The mPTP inhibitor CsA abolished IRI differences between KO and WT hearts, suggesting that the permanent closure of mPTP due to NLRX1 deletion contributed to the increased IR sensitivity of NLRX1 KO hearts. This is the first demonstration that the mitochondrial NLRX1 is a novel factor required for mPTP opening and contributes to cardioprotection against acute IRI through RISK pathway activation and prevention of permanent mPTP closure.
{"title":"The innate immune receptor NLRX1 is a novel required modulator for mPTP opening: implications for cardioprotection.","authors":"Y Xiao,X Hu,C F Rudolphi,E E Nollet,R Nederlof,Q Wang,D Bakker,Panagiota Efstathia Nikolaou,J C Knol,R R Goeij-de Haas,A A Henneman,T V Pham,C R Jimenez,A E Grootemaat,N N van der Wel,S E Girardin,N Kaludercic,J van der Velden,Z Onódi,P Leszek,Z V Varga,P Ferdinandy,B Preckel,N C Weber,M W Hollmann,F Di Lisa,C J Zuurbier","doi":"10.1007/s00395-025-01124-x","DOIUrl":"https://doi.org/10.1007/s00395-025-01124-x","url":null,"abstract":"NLRX1 is the only NOD-like innate immune receptor that localises to mitochondria. We previously demonstrated that NLRX1 deletion increased infarct size in isolated mouse hearts subjected to ischemia-reperfusion injury (IRI); however, underlying mechanisms are yet to be identified. Given the crucial role played by mitochondria in cardiac IRI, we here hypothesise that NLRX1 affects key mechanisms of cardiac IRI. Cardiac IRI was evaluated in isolated C57BL/6J (WT) and NLRX1 knock out (KO) mouse hearts. The following known modulators of IRI were explored in isolated hearts, isolated mitochondria; or permeabilised cardiac fibres: 1) mTOR/RISK/autophagy regulation, 2) AMPK and mitochondrial energy production, and 3) mitochondrial permeability transition pore (mPTP) opening. NLRX1 deletion increased IRI, and cardiac NLRX1 was decreased after IRI in mouse and pig hearts. NLRX1 ablation caused decreased mTOR and RISK pathway (Akt, ERK, and S6K) activation following IR, without affecting autophagy/inflammation/oxidative stress markers. The RISK activator Urocortin dissipated NLRX1 effects on mTOR, RISK pathway and IRI, indicating that increased cardiac IRI with NLRX1 deletion is, at least partly, due to impaired RISK activation. The energy sensor AMPK was activated in NLRX1 KO hearts, possibly due to slowed mitochondrial respiratory responses (impaired mitochondrial permeability) towards palmitoylcarnitine in permeabilised cardiac fibres. NLRX1 deletion completely abolished calcium-induced mPTP opening, and cyclosporine A (CsA) effects on mPTP, both before and after IR, and was associated with increased mitochondrial calcium content after IR. Mitochondrial sub-fractionation studies localised NLRX1 to the inner mitochondrial membrane. NLRX1 deletion associated with decreased phosphorylation of mitochondrial Got2, Cx43, Myl2, Ndufb7 and MICOS10. The mPTP inhibitor CsA abolished IRI differences between KO and WT hearts, suggesting that the permanent closure of mPTP due to NLRX1 deletion contributed to the increased IR sensitivity of NLRX1 KO hearts. This is the first demonstration that the mitochondrial NLRX1 is a novel factor required for mPTP opening and contributes to cardioprotection against acute IRI through RISK pathway activation and prevention of permanent mPTP closure.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"38 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320364","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}
Ferroptosis is an important cause of cardiomyocyte loss and cardiac dysfunction. Cathelicidin-related antimicrobial peptide (CRAMP) is an endogenous polypeptide that regulates oxidative stress in the body and is involved in ferroptosis. However, its specific role and mechanism in ferroptosis are unclear. To analyze the role of CRAMP in ferroptosis, we first analyzed its expression in infarcted myocardial tissues, and verified its role in ferroptosis in vitro through overexpression and knock-down techniques. The activity and expression of cathepsin L (CTSL) and its effect on ferroptosis were analyzed to verify whether CTSL participated in ferroptosis as a downstream of CRAMP. Protein disulfide isomerase family A member 4 (PDIA4) was screened as an interacting protein of CTSL by using the database, and the role of PDIA4 in ferroptosis was analyzed by gene knockdown and overexpression. Finally, the regulatory mechanism of CRAMP in ferroptosis was verified in vivo by mouse myocardial infarction model. CRAMP levels were reduced in both infarcted cardiac tissues and cardiomyocytes exposed to ferroptosis inducers. The overexpression of CRAMP or pretreatment of LL-37 alleviated cardiomyocyte ferroptosis, whereas CRAMP knockdown exacerbated cell death. Under ferroptotic stress, the expression of CTSL was elevated. CRAMP inhibited ferroptosis by antagonizing the CTSL activity. Abnormal increase in CTSL activity and levels caused PDIA4 to decrease. Overexpression of PDIA4 inhibited ferroptosis induced by CTSL, while knocking down PDIA4 counteracted the protection of CRAMP. In vivo, both CRAMP overexpression and administration of CRAMP peptide significantly ameliorated myocardial injury and improved cardiac function. CRAMP increases PDIA4 levels by inhibiting the activity of CTSL and antagonizes ferroptosis in cardiomyocytes. Targeting CRAMP offers innovative therapeutic strategies and insights for the prevention and management of myocardial injury.
{"title":"Antimicrobial peptide CRAMP/LL-37 mediates ferroptosis resistance in cardiomyocytes by inhibiting cathepsin L.","authors":"Zhantao Liu,Qingsong Zhang,Dan Su,Hong Chen,Bowen Wang,Lin Ye,Peiyan Wang,Jingnan Wu,Wencan Jia,Lijun Liu,Jianxun Wang,Shuo Miao","doi":"10.1007/s00395-025-01122-z","DOIUrl":"https://doi.org/10.1007/s00395-025-01122-z","url":null,"abstract":"Ferroptosis is an important cause of cardiomyocyte loss and cardiac dysfunction. Cathelicidin-related antimicrobial peptide (CRAMP) is an endogenous polypeptide that regulates oxidative stress in the body and is involved in ferroptosis. However, its specific role and mechanism in ferroptosis are unclear. To analyze the role of CRAMP in ferroptosis, we first analyzed its expression in infarcted myocardial tissues, and verified its role in ferroptosis in vitro through overexpression and knock-down techniques. The activity and expression of cathepsin L (CTSL) and its effect on ferroptosis were analyzed to verify whether CTSL participated in ferroptosis as a downstream of CRAMP. Protein disulfide isomerase family A member 4 (PDIA4) was screened as an interacting protein of CTSL by using the database, and the role of PDIA4 in ferroptosis was analyzed by gene knockdown and overexpression. Finally, the regulatory mechanism of CRAMP in ferroptosis was verified in vivo by mouse myocardial infarction model. CRAMP levels were reduced in both infarcted cardiac tissues and cardiomyocytes exposed to ferroptosis inducers. The overexpression of CRAMP or pretreatment of LL-37 alleviated cardiomyocyte ferroptosis, whereas CRAMP knockdown exacerbated cell death. Under ferroptotic stress, the expression of CTSL was elevated. CRAMP inhibited ferroptosis by antagonizing the CTSL activity. Abnormal increase in CTSL activity and levels caused PDIA4 to decrease. Overexpression of PDIA4 inhibited ferroptosis induced by CTSL, while knocking down PDIA4 counteracted the protection of CRAMP. In vivo, both CRAMP overexpression and administration of CRAMP peptide significantly ameliorated myocardial injury and improved cardiac function. CRAMP increases PDIA4 levels by inhibiting the activity of CTSL and antagonizes ferroptosis in cardiomyocytes. Targeting CRAMP offers innovative therapeutic strategies and insights for the prevention and management of myocardial injury.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"91 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295699","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 : 2025-05-14DOI: 10.1007/s00395-025-01115-y
Mengnan Wang,Benedikt Preckel,Coert J Zuurbier,Nina C Weber
Heart failure (HF) is a life-threatening cardiovascular disease associated with high mortality, diminished quality of life, and a significant economic burden on both patients and society. The pathogenesis of HF is closely related to the endothelium, where endothelial ion channels play an important role in regulating intracellular Ca2+ signals. These ion channels are essential to maintain vascular function, including endothelium-dependent vascular tone, inflammation response, and oxidative stress. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown promising cardiovascular benefits in HF patients, reducing mortality risk and hospitalization in several large clinical trials. Clinical and preclinical studies indicate that the cardioprotective effects of SGLT2i in HF are mediated by endothelial nitric oxide (NO) pathways, as well as by reducing inflammation and reactive oxygen species in cardiac endothelial cells. Additionally, SGLT2i may confer endothelial protection by lowering intracellular Ca2+ level through the inhibition of sodium-hydrogen exchanger 1 (NHE1) and sodium-calcium exchanger (NCX) in endothelial cells. In this review, we discuss present knowledge regarding the expression and role of Ca2+-related ion channels in endothelial cells in HF, focusing on the effects of SGLT2i on endothelial NHE1, NCX as well as on vascular tone.
{"title":"Effects of SGLT2 inhibitors on ion channels in heart failure: focus on the endothelium.","authors":"Mengnan Wang,Benedikt Preckel,Coert J Zuurbier,Nina C Weber","doi":"10.1007/s00395-025-01115-y","DOIUrl":"https://doi.org/10.1007/s00395-025-01115-y","url":null,"abstract":"Heart failure (HF) is a life-threatening cardiovascular disease associated with high mortality, diminished quality of life, and a significant economic burden on both patients and society. The pathogenesis of HF is closely related to the endothelium, where endothelial ion channels play an important role in regulating intracellular Ca2+ signals. These ion channels are essential to maintain vascular function, including endothelium-dependent vascular tone, inflammation response, and oxidative stress. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown promising cardiovascular benefits in HF patients, reducing mortality risk and hospitalization in several large clinical trials. Clinical and preclinical studies indicate that the cardioprotective effects of SGLT2i in HF are mediated by endothelial nitric oxide (NO) pathways, as well as by reducing inflammation and reactive oxygen species in cardiac endothelial cells. Additionally, SGLT2i may confer endothelial protection by lowering intracellular Ca2+ level through the inhibition of sodium-hydrogen exchanger 1 (NHE1) and sodium-calcium exchanger (NCX) in endothelial cells. In this review, we discuss present knowledge regarding the expression and role of Ca2+-related ion channels in endothelial cells in HF, focusing on the effects of SGLT2i on endothelial NHE1, NCX as well as on vascular tone.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"25 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945457","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 : 2025-05-09DOI: 10.1007/s00395-025-01114-z
Wei Ni, Xiaofeng Ge, Yang Liu, Jingyu Chen, Lin Wang, Linjian Chen, Zhaokai Li, Peng Zhang, Shufen Huang, Junhui Xu, Le Zhang, Xiabin Fan, Gang Wang, Wei Huang, Yuanchao Ye, Jiancang Zhou, Cuilian Dai, Binbin Liu
Macrophage depletion exacerbates pressure overload-induced heart failure, but therapeutic translation is hindered by macrophage subset heterogeneity. The functional role of CD163+ macrophages in heart failure remains unclear. Transverse aortic constriction (TAC) was employed to induce pressure overload. Cd163−/− mice exhibited significantly aggravated TAC-induced left ventricular systolic dysfunction, as demonstrated by reduced ejection fraction, fractional shortening, and global longitudinal strain, compared to wild-type (WT) controls. RNA sequencing of cardiac tissues revealed significant differential gene expression between TAC-treated WT and Cd163−/− mice, especially in pathways governing mitochondrial bioenergetics and homeostasis. Transmission electron microscopy confirmed greater accumulation of dysfunctional mitochondria in cardiomyocytes of Cd163−/− mice relative to WT following TAC. Additionally, the proportion of CD163+ macrophages among cardiac macrophages increased post-TAC. Serum IL-10 levels and cardiac macrophage IL-10 expression were significantly diminished in Cd163−/− mice compared to WT after TAC. IL-10 supplementation effectively reversed the TAC-induced impairment in left ventricular systolic function in both WT and Cd163−/− mice, and reduced NADH/NAD+ ratios, reduced mitochondrial dysfunction, and improved mitochondrial membrane potential in Cd163−/− mice. Cross-sectional clinical data supported these findings, showing decreased IL-10 levels as a significant risk factor for heart failure in hypertensive patients (odds ratio: 0.397; 95% CI 0.203–0.775; p = 0.007). Collectively, these results highlight the protective role of CD163+ macrophages against pressure overload-induced left ventricular dysfunction and mitochondrial dysfunction through IL-10-dependent pathways.
{"title":"CD163+ macrophages attenuate pressure overload-induced left ventricular systolic dysfunction and cardiac mitochondrial dysfunction via interleukin-10","authors":"Wei Ni, Xiaofeng Ge, Yang Liu, Jingyu Chen, Lin Wang, Linjian Chen, Zhaokai Li, Peng Zhang, Shufen Huang, Junhui Xu, Le Zhang, Xiabin Fan, Gang Wang, Wei Huang, Yuanchao Ye, Jiancang Zhou, Cuilian Dai, Binbin Liu","doi":"10.1007/s00395-025-01114-z","DOIUrl":"https://doi.org/10.1007/s00395-025-01114-z","url":null,"abstract":"<p>Macrophage depletion exacerbates pressure overload-induced heart failure, but therapeutic translation is hindered by macrophage subset heterogeneity. The functional role of CD163<sup>+</sup> macrophages in heart failure remains unclear. Transverse aortic constriction (TAC) was employed to induce pressure overload. <i>Cd163</i><sup>−/−</sup> mice exhibited significantly aggravated TAC-induced left ventricular systolic dysfunction, as demonstrated by reduced ejection fraction, fractional shortening, and global longitudinal strain, compared to wild-type (WT) controls. RNA sequencing of cardiac tissues revealed significant differential gene expression between TAC-treated WT and <i>Cd163</i><sup>−/−</sup> mice, especially in pathways governing mitochondrial bioenergetics and homeostasis. Transmission electron microscopy confirmed greater accumulation of dysfunctional mitochondria in cardiomyocytes of <i>Cd163</i><sup>−/−</sup> mice relative to WT following TAC. Additionally, the proportion of CD163<sup>+</sup> macrophages among cardiac macrophages increased post-TAC. Serum IL-10 levels and cardiac macrophage IL-10 expression were significantly diminished in <i>Cd163</i><sup>−/−</sup> mice compared to WT after TAC. IL-10 supplementation effectively reversed the TAC-induced impairment in left ventricular systolic function in both WT and <i>Cd163</i><sup>−/−</sup> mice, and reduced NADH/NAD<sup>+</sup> ratios, reduced mitochondrial dysfunction, and improved mitochondrial membrane potential in <i>Cd163</i><sup>−/−</sup> mice. Cross-sectional clinical data supported these findings, showing decreased IL-10 levels as a significant risk factor for heart failure in hypertensive patients (odds ratio: 0.397; 95% CI 0.203–0.775; p = 0.007). Collectively, these results highlight the protective role of CD163<sup>+</sup> macrophages against pressure overload-induced left ventricular dysfunction and mitochondrial dysfunction through IL-10-dependent pathways.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"75 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926602","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}
Our prior research demonstrated that chronic intermittent hypobaric hypoxia (CIHH) pretreatment confers cardioprotection against ischemia/reperfusion (I/R) injury in rats. However, the precise mechanisms underlying CIHH's cardioprotective effects remain insufficiently understood. This study aims to elucidate the upstream signaling pathways and dynamic regulation of BKCa channels in mediating CIHH-induced cardioprotection through coronary artery vasodilation in rats. Male Sprague-Dawley rats, matched by age and body weight, were assigned to control (Con) and CIHH groups. The CIHH group underwent 35 days of hypobaric hypoxia exposure simulating an altitude of 4000 m, for 5 h daily. Hearts were isolated, perfused using the Langendorff system, and subjected to 30 min of ischemia, followed by 60 or 120 min of reperfusion. Compared to the Con group, CIHH significantly improved left ventricular function recovery, reduced infarct size, and increased coronary flow (CF). Microvessel recording, co-immunoprecipitation, and whole-cell patch clamp techniques demonstrated that CIHH augmented CF by promoting coronary vasodilation, attributed to the inhibition of muscle RING-finger protein-1 (MuRF1)-mediated degradation of the BKCa-β1 subunit. Moreover, CIHH inhibited IKKα-induced phosphorylation and ubiquitin-mediated degradation of IκBα, thereby enhancing its cytoplasmic binding to NF-κB p65 in coronary smooth muscle cells. This process attenuated NF-κB p65 nuclear translocation and the subsequent inflammation-induced expression of MuRF1. The observed increase in coronary vasodilation, driven by the suppression of NF-κB/MuRF1-mediated BKCa-β1 degradation, contributes to enhanced CF and cardioprotection against I/R injury following CIHH.
{"title":"A new mechanism of high-altitude adaptation reducing myocardium infarction: inhibiting inflammation-induced ubiquitin degradation of BKCa to enhance coronary vasodilation.","authors":"Sen Wang,Yu Zhang,Wei-Cheng Yuan,Can-Yang Qi,Hua-Xing Zhang,Tian-Qi Wang,Hui-Jie Liu,Hai-Shuang Li,Yan-Ming Tian,Sheng Wang,Sui-Bing Miao,Li-Ping Zhang,Hui Guo,Xiang-Jian Zhang,Yi Zhang,Huijie Ma,Yue Guan","doi":"10.1007/s00395-025-01113-0","DOIUrl":"https://doi.org/10.1007/s00395-025-01113-0","url":null,"abstract":"Our prior research demonstrated that chronic intermittent hypobaric hypoxia (CIHH) pretreatment confers cardioprotection against ischemia/reperfusion (I/R) injury in rats. However, the precise mechanisms underlying CIHH's cardioprotective effects remain insufficiently understood. This study aims to elucidate the upstream signaling pathways and dynamic regulation of BKCa channels in mediating CIHH-induced cardioprotection through coronary artery vasodilation in rats. Male Sprague-Dawley rats, matched by age and body weight, were assigned to control (Con) and CIHH groups. The CIHH group underwent 35 days of hypobaric hypoxia exposure simulating an altitude of 4000 m, for 5 h daily. Hearts were isolated, perfused using the Langendorff system, and subjected to 30 min of ischemia, followed by 60 or 120 min of reperfusion. Compared to the Con group, CIHH significantly improved left ventricular function recovery, reduced infarct size, and increased coronary flow (CF). Microvessel recording, co-immunoprecipitation, and whole-cell patch clamp techniques demonstrated that CIHH augmented CF by promoting coronary vasodilation, attributed to the inhibition of muscle RING-finger protein-1 (MuRF1)-mediated degradation of the BKCa-β1 subunit. Moreover, CIHH inhibited IKKα-induced phosphorylation and ubiquitin-mediated degradation of IκBα, thereby enhancing its cytoplasmic binding to NF-κB p65 in coronary smooth muscle cells. This process attenuated NF-κB p65 nuclear translocation and the subsequent inflammation-induced expression of MuRF1. The observed increase in coronary vasodilation, driven by the suppression of NF-κB/MuRF1-mediated BKCa-β1 degradation, contributes to enhanced CF and cardioprotection against I/R injury following CIHH.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"115 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915151","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 : 2025-05-07DOI: 10.1007/s00395-025-01111-2
Jiankun Zhu, Xinjia Ruan, MariaSanta C. Mangione, Pablo Parra, Guo Chen, Xiaoping Su, Xiang Luo, Dian J. Cao
Our previous work demonstrated that the DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) negatively affects post-infarct repair by promoting pro-inflammatory macrophages. However, whether cGAS and its downstream partner STING (Stimulator of Interferon Genes) regulate neutrophil production and function in the context of acute myocardial ischemia remains unclear. This study investigated the role of the cGAS-STING pathway in neutropoiesis (neutrophil production and differentiation) and examined whether ischemia primes neutrophils in the bone marrow via this pathway, enhancing their functionality and contributing to cardiac inflammatory injury. Using myocardial infarction (MI) models in wild-type (WT), Cgas−/−, and Sting−/− mice, we analyzed neutrophils from the bone marrow, peripheral blood, and infarcted tissue. Additionally, we generated neutrophil-specific conditional knockouts of Cgas and performed adoptive transfer experiments with Cgas-deficient neutrophils. RNA sequencing revealed that ischemia increased neutrophil production in the bone marrow and activated pathways involved in cytokine signaling, phagocytosis, chemotaxis, and degranulation. Inhibiting the cGAS-STING pathway reduced neutrophil production by decreasing lineage committed neutrophil precursors including early neutrophil precursors (eNP) and preNeu and downregulated ischemia-induced pathways. Neutrophil conditional Cgas deletion or adoptive transfer of Cgas-deficient neutrophils improved survival but did not significantly impact ischemia-induced remodeling. In conclusion, we demonstrate for the first time that ischemia enhanced neutrophil functionality before recruitment to infarcted tissue, and the cGAS-STING pathway played an important role in neutrophil production and priming. Furthermore, our findings demonstrate a neutrophil-specific role of cGAS in promoting cardiac rupture and mortality in MI. This study provides a more comprehensive understanding of the cGAS-STING pathway in acute ischemia and may support the translation of cGAS-STING modulators, an emerging therapeutic field.
{"title":"The cGAS-STING pathway promotes acute ischemia-induced neutropoiesis and neutrophil priming in the bone marrow","authors":"Jiankun Zhu, Xinjia Ruan, MariaSanta C. Mangione, Pablo Parra, Guo Chen, Xiaoping Su, Xiang Luo, Dian J. Cao","doi":"10.1007/s00395-025-01111-2","DOIUrl":"https://doi.org/10.1007/s00395-025-01111-2","url":null,"abstract":"<p>Our previous work demonstrated that the DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) negatively affects post-infarct repair by promoting pro-inflammatory macrophages. However, whether cGAS and its downstream partner STING (Stimulator of Interferon Genes) regulate neutrophil production and function in the context of acute myocardial ischemia remains unclear. This study investigated the role of the cGAS-STING pathway in neutropoiesis (neutrophil production and differentiation) and examined whether ischemia primes neutrophils in the bone marrow via this pathway, enhancing their functionality and contributing to cardiac inflammatory injury. Using myocardial infarction (MI) models in wild-type (WT), <i>Cgas</i><sup>−/−</sup>, and <i>Sting</i><sup>−/−</sup> mice, we analyzed neutrophils from the bone marrow, peripheral blood, and infarcted tissue. Additionally, we generated neutrophil-specific conditional knockouts of <i>Cgas</i> and performed adoptive transfer experiments with <i>Cgas</i>-deficient neutrophils. RNA sequencing revealed that ischemia increased neutrophil production in the bone marrow and activated pathways involved in cytokine signaling, phagocytosis, chemotaxis, and degranulation. Inhibiting the cGAS-STING pathway reduced neutrophil production by decreasing lineage committed neutrophil precursors including early neutrophil precursors (eNP) and preNeu and downregulated ischemia-induced pathways. Neutrophil conditional <i>Cgas</i> deletion or adoptive transfer of <i>Cgas</i>-deficient neutrophils improved survival but did not significantly impact ischemia-induced remodeling. In conclusion, we demonstrate for the first time that ischemia enhanced neutrophil functionality before recruitment to infarcted tissue, and the cGAS-STING pathway played an important role in neutrophil production and priming. Furthermore, our findings demonstrate a neutrophil-specific role of cGAS in promoting cardiac rupture and mortality in MI. This study provides a more comprehensive understanding of the cGAS-STING pathway in acute ischemia and may support the translation of cGAS-STING modulators, an emerging therapeutic field.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"63 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920309","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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