Pub Date : 2025-04-23DOI: 10.1161/circresaha.124.326024
Mandy Kunze Guo,Corey A Scipione,Leandro C D Breda,Kamalben Prajapati,Sneha Raju,Steven R Botts,Majed Abdul-Samad,Sarvatit Patel,Garry Yu,Andrew C Dudley,Jason E Fish,Kathryn L Howe
{"title":"Tracking Endothelial Extracellular Vesicles in a Mouse Model of Atherosclerosis.","authors":"Mandy Kunze Guo,Corey A Scipione,Leandro C D Breda,Kamalben Prajapati,Sneha Raju,Steven R Botts,Majed Abdul-Samad,Sarvatit Patel,Garry Yu,Andrew C Dudley,Jason E Fish,Kathryn L Howe","doi":"10.1161/circresaha.124.326024","DOIUrl":"https://doi.org/10.1161/circresaha.124.326024","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"68 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866635","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}
BACKGROUNDCircular RNAs (circRNAs) have been gradually revealed to regulate the progression of heart disease in depth, showing their clinical significance. However, a mass of cardiac circRNAs still has not been functionally characterized. We aimed to explore the potential candidates that are involved in pathological cardiac hypertrophy.METHODSPublic substantial RNA-sequencing data of cardiac circRNAs were utilized to search the cardiac hypertrophy-related circRNAs. Cardiomyocyte hypertrophy in vitro was induced by Ang II (angiotensin II) treatment. Mice were subjected to Ang II infusion to induce cardiac hypertrophy in vivo. Gain-of-function and loss-of-function assays were conducted to detect the effect of RNAs or proteins in cardiac hypertrophy.RESULTSA circRNA derived from the cdyl (chromodomain Y-like) gene was screened out and named circCDYL. Our results showed that the expression of circCDYL in primary rat cardiomyocytes was significantly induced by Ang II. Gain-of-function and loss-of-function assays demonstrated that circCDYL effectively promoted cardiomyocyte hypertrophy in vitro. CircCDYL could encode a ≈100-aa truncated CDYL peptide (tCDYL-100), whose sequence highly overlaps that of full-length CDYL. The translation of tCDYL-100 was activated by N6-methylation of circCDYL under prohypertrophic stimulation. tCDYL-100 fulfilled the prohypertrophic of circCDYL. Mechanistically, tCDYL-100 competed with CDYL for binding REST (RE1-silencing transcription factor) and further disrupted the formation of REST-CDYL-EHMT2 (euchromatic histone-lysine N-methyltransferase 2) transcriptional repression complex, resulting in transcriptional activation of rhoa and nppb. Silence of circCDYL in mouse hearts could inhibit Ang II-induced cardiac hypertrophy, while forced expression of tCDYL-100 could cause cardiac hypertrophy.CONCLUSIONSIn summary, our study uncovered an important circRNA-derived peptide and a regulatory mechanism on transcription mediated by N6-methyladenosine-circRNA-histone methylation in pathological cardiac hypertrophy.
{"title":"Novel Truncated Peptide Derived From circCDYL Exacerbates Cardiac Hypertrophy.","authors":"Mengyang Li,Wei Ding,Xinyu Fang,Yu Wang,Peiyan Wang,Lin Ye,Shuo Miao,Lin Song,Xiang Ao,Qi Li,Jianxun Wang","doi":"10.1161/circresaha.124.325573","DOIUrl":"https://doi.org/10.1161/circresaha.124.325573","url":null,"abstract":"BACKGROUNDCircular RNAs (circRNAs) have been gradually revealed to regulate the progression of heart disease in depth, showing their clinical significance. However, a mass of cardiac circRNAs still has not been functionally characterized. We aimed to explore the potential candidates that are involved in pathological cardiac hypertrophy.METHODSPublic substantial RNA-sequencing data of cardiac circRNAs were utilized to search the cardiac hypertrophy-related circRNAs. Cardiomyocyte hypertrophy in vitro was induced by Ang II (angiotensin II) treatment. Mice were subjected to Ang II infusion to induce cardiac hypertrophy in vivo. Gain-of-function and loss-of-function assays were conducted to detect the effect of RNAs or proteins in cardiac hypertrophy.RESULTSA circRNA derived from the cdyl (chromodomain Y-like) gene was screened out and named circCDYL. Our results showed that the expression of circCDYL in primary rat cardiomyocytes was significantly induced by Ang II. Gain-of-function and loss-of-function assays demonstrated that circCDYL effectively promoted cardiomyocyte hypertrophy in vitro. CircCDYL could encode a ≈100-aa truncated CDYL peptide (tCDYL-100), whose sequence highly overlaps that of full-length CDYL. The translation of tCDYL-100 was activated by N6-methylation of circCDYL under prohypertrophic stimulation. tCDYL-100 fulfilled the prohypertrophic of circCDYL. Mechanistically, tCDYL-100 competed with CDYL for binding REST (RE1-silencing transcription factor) and further disrupted the formation of REST-CDYL-EHMT2 (euchromatic histone-lysine N-methyltransferase 2) transcriptional repression complex, resulting in transcriptional activation of rhoa and nppb. Silence of circCDYL in mouse hearts could inhibit Ang II-induced cardiac hypertrophy, while forced expression of tCDYL-100 could cause cardiac hypertrophy.CONCLUSIONSIn summary, our study uncovered an important circRNA-derived peptide and a regulatory mechanism on transcription mediated by N6-methyladenosine-circRNA-histone methylation in pathological cardiac hypertrophy.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"3 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846366","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 : 2025-04-17DOI: 10.1161/circresaha.124.324781
Mei Methawasin,Yanghai Zhang,Zachery R Gregorich,Yaqin He,Chunling Liu,Julia Muldoon,Zaynab Hourani,John E Smith,Henk Granzier,Wei Guo
BACKGROUNDRBM20 (RNA binding motif protein 20) cardiomyopathy is a severe form of dilated cardiomyopathy (DCM). Genetic variants in the nuclear localization signal of Rbm20 hinder its nuclear import and promote cytoplasmic pathogenic RNP (ribonucleoprotein) granules. We aimed to investigate whether reducing RNP granules by inhibiting Rbm20 expression could alleviate the DCM phenotype in Rbm20 S639G (Rbm20S639G) knock-in mice.METHODSWe downregulated Rbm20, utilizing antisense oligonucleotides (ASOs) that specifically inhibit Rbm20 expression. We administered Rbm20-ASOs in Rbm20S639G mice that carry a serine-to-glycine substitution in the nuclear localization signal of RBM20. The Rbm20-ASOs were administered subcutaneously at 25 mg/kg once a week for 8 weeks in both young (14-day-old) mice before the onset of DCM and adult (3-month-old) mice with established DCM phenotype. In vivo cardiac function was assessed by echocardiography. RNP granules were identified through fluorescent immunohistochemical staining, and the number and size of RNP granules were quantified using Cell Profiler software. Alternative splicing of RBM20 target genes was determined by reverse transcription polymerase chain reaction, and titin isoform expression was analyzed by gel electrophoresis. Cardiomyocyte Ca2+ release-reuptake kinetics and mouse electrocardiography were also studied.RESULTSThe results revealed that reducing the level of Rbm20 expression through treatment with ASOs significantly decreased the cytoplasmic RNP granules within the Rbm20S639G cardiomyocytes. ASO treatment reduced the severity of DCM developed when treatment was initiated before the onset of the disease. Importantly, ASO treatment reversed cardiac dysfunction and remodeling when treatment was commenced in mice with established DCM as shown by a significant improvement in ejection fraction and a decrease in the severity of left ventricular chamber dilation. Treatment with ASOs also effectively mitigated left ventricular hypertrophic remodeling and improved ECG parameters observed as normalized P wave and QRS durations. These beneficial effects occur without the restoration of mis-splicing of RBM20 target genes, including the primary target gene Ttn, and other genes such as Camk2d, Ryr2, and Ank3.CONCLUSIONSThe findings of this study demonstrated that RNP granules serve as a critical driver for RBM20 cardiomyopathy, and reduction of RNP granules through treatment with ASOs is a possible therapeutic option for RBM20 cardiomyopathy in patients carrying RBM20 genetic variants in the nuclear localization signal region.
{"title":"Reducing Granules Without Splicing Restoration Alleviates RBM20 Cardiomyopathy.","authors":"Mei Methawasin,Yanghai Zhang,Zachery R Gregorich,Yaqin He,Chunling Liu,Julia Muldoon,Zaynab Hourani,John E Smith,Henk Granzier,Wei Guo","doi":"10.1161/circresaha.124.324781","DOIUrl":"https://doi.org/10.1161/circresaha.124.324781","url":null,"abstract":"BACKGROUNDRBM20 (RNA binding motif protein 20) cardiomyopathy is a severe form of dilated cardiomyopathy (DCM). Genetic variants in the nuclear localization signal of Rbm20 hinder its nuclear import and promote cytoplasmic pathogenic RNP (ribonucleoprotein) granules. We aimed to investigate whether reducing RNP granules by inhibiting Rbm20 expression could alleviate the DCM phenotype in Rbm20 S639G (Rbm20S639G) knock-in mice.METHODSWe downregulated Rbm20, utilizing antisense oligonucleotides (ASOs) that specifically inhibit Rbm20 expression. We administered Rbm20-ASOs in Rbm20S639G mice that carry a serine-to-glycine substitution in the nuclear localization signal of RBM20. The Rbm20-ASOs were administered subcutaneously at 25 mg/kg once a week for 8 weeks in both young (14-day-old) mice before the onset of DCM and adult (3-month-old) mice with established DCM phenotype. In vivo cardiac function was assessed by echocardiography. RNP granules were identified through fluorescent immunohistochemical staining, and the number and size of RNP granules were quantified using Cell Profiler software. Alternative splicing of RBM20 target genes was determined by reverse transcription polymerase chain reaction, and titin isoform expression was analyzed by gel electrophoresis. Cardiomyocyte Ca2+ release-reuptake kinetics and mouse electrocardiography were also studied.RESULTSThe results revealed that reducing the level of Rbm20 expression through treatment with ASOs significantly decreased the cytoplasmic RNP granules within the Rbm20S639G cardiomyocytes. ASO treatment reduced the severity of DCM developed when treatment was initiated before the onset of the disease. Importantly, ASO treatment reversed cardiac dysfunction and remodeling when treatment was commenced in mice with established DCM as shown by a significant improvement in ejection fraction and a decrease in the severity of left ventricular chamber dilation. Treatment with ASOs also effectively mitigated left ventricular hypertrophic remodeling and improved ECG parameters observed as normalized P wave and QRS durations. These beneficial effects occur without the restoration of mis-splicing of RBM20 target genes, including the primary target gene Ttn, and other genes such as Camk2d, Ryr2, and Ank3.CONCLUSIONSThe findings of this study demonstrated that RNP granules serve as a critical driver for RBM20 cardiomyopathy, and reduction of RNP granules through treatment with ASOs is a possible therapeutic option for RBM20 cardiomyopathy in patients carrying RBM20 genetic variants in the nuclear localization signal region.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"49 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846365","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}
BACKGROUNDPulmonary venous remodeling is a key pathological feature of pulmonary hypertension associated with left heart disease (PH-LHD). This study aims to investigate the role of regulatory T (Treg) cells in this process.METHODSWe used mouse models with transverse aortic constriction and cell depletion of Foxp3-DTR/tdTomato mice to examine Treg cells' function around pulmonary veins in PH-LHD in vivo. To confirm the effect of Nlrc3-/- Treg cells on PH-LHD, we utilized 3 mouse models: Nlrc3 knockout mice, athymic mice, and endothelial cell lineage tracing Cdh5CreERT2+/--mT/mG+/- mice. The interaction proteins and signaling pathways of Treg cells during endothelial-to-mesenchymal transition were elucidated by protein docking prediction, coimmunoprecipitation and cocultivation of Treg cells with venous endothelial cells.RESULTSTreg cells were abundant around pulmonary veins of transverse aortic constriction-induced PH-LHD and were essential for promoting inflammation resolution and inhibiting pulmonary venous remodeling. Nlrc3 expression was reduced in mice and patients with PH-LHD. NLRC3 (nucleotide-oligomerization domain-like receptor family CARD domain containing 3) deficiency inhibited Treg cell proliferation and impaired their immunosuppressive and endothelial-to-mesenchymal transition-protective effects. Mechanistically, NLRC3 interacted with TRAM (TRIF-related adaptor molecule) and regulated IRF3/NF-κB (nuclear factor-κB) p65 signaling in CD4+ T cells. NLRC3-deficient Treg cells promoted IL (interleukin)-18 expression through IRF3/NF-κB p65 signaling, and thus IL-18 secretion activated endothelial RTK (receptor tyrosine kinase) signaling, favoring endothelial-to-mesenchymal transition progression in pulmonary veins and PH-LHD progress. This process was reversible with IL-18 binding protein in vivo.CONCLUSIONSNLRC3 is crucial for Treg cells to prevent pulmonary venous remodeling in PH-LHD, primarily by modulating IL-18 secretion, which inhibits endothelial-to-mesenchymal transition and thereby improves disease progression and prognosis.
{"title":"Treg Cells Attenuate Pulmonary Venous Remodeling in PH-LHD via NLRC3 Signaling.","authors":"Gulinigeer Zhakeer,Yanxi Zeng,Guangxi E,Nuerbiyemu Maimaitiaili,Peinan Ju,Hongyun Yao,Yefei Shi,Ming Zhai,Ke Li,Jianhui Zhuang,Yunshan Cao,Qing Yu,Wenhui Peng","doi":"10.1161/circresaha.124.325201","DOIUrl":"https://doi.org/10.1161/circresaha.124.325201","url":null,"abstract":"BACKGROUNDPulmonary venous remodeling is a key pathological feature of pulmonary hypertension associated with left heart disease (PH-LHD). This study aims to investigate the role of regulatory T (Treg) cells in this process.METHODSWe used mouse models with transverse aortic constriction and cell depletion of Foxp3-DTR/tdTomato mice to examine Treg cells' function around pulmonary veins in PH-LHD in vivo. To confirm the effect of Nlrc3-/- Treg cells on PH-LHD, we utilized 3 mouse models: Nlrc3 knockout mice, athymic mice, and endothelial cell lineage tracing Cdh5CreERT2+/--mT/mG+/- mice. The interaction proteins and signaling pathways of Treg cells during endothelial-to-mesenchymal transition were elucidated by protein docking prediction, coimmunoprecipitation and cocultivation of Treg cells with venous endothelial cells.RESULTSTreg cells were abundant around pulmonary veins of transverse aortic constriction-induced PH-LHD and were essential for promoting inflammation resolution and inhibiting pulmonary venous remodeling. Nlrc3 expression was reduced in mice and patients with PH-LHD. NLRC3 (nucleotide-oligomerization domain-like receptor family CARD domain containing 3) deficiency inhibited Treg cell proliferation and impaired their immunosuppressive and endothelial-to-mesenchymal transition-protective effects. Mechanistically, NLRC3 interacted with TRAM (TRIF-related adaptor molecule) and regulated IRF3/NF-κB (nuclear factor-κB) p65 signaling in CD4+ T cells. NLRC3-deficient Treg cells promoted IL (interleukin)-18 expression through IRF3/NF-κB p65 signaling, and thus IL-18 secretion activated endothelial RTK (receptor tyrosine kinase) signaling, favoring endothelial-to-mesenchymal transition progression in pulmonary veins and PH-LHD progress. This process was reversible with IL-18 binding protein in vivo.CONCLUSIONSNLRC3 is crucial for Treg cells to prevent pulmonary venous remodeling in PH-LHD, primarily by modulating IL-18 secretion, which inhibits endothelial-to-mesenchymal transition and thereby improves disease progression and prognosis.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"15 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841188","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 : 2025-04-11DOI: 10.1161/circresaha.124.325310
Sarah Costantino,Shafeeq A Mohammed,Samuele Ambrosini,Marialucia Telesca,Alessandro Mengozzi,Kaivalya Walavalkar,Era Gorica,Melissa Herwig,Loek van Heerebeek,Junyan Xia,Gergely Karsai,Thorsten Hornemann,Omer Dzemali,Raffaella Santoro,Qian Li,Frank Ruschitzka,Nazha Hamdani,Francesco Paneni
BACKGROUNDCardiometabolic heart failure with preserved ejection fraction (cHFpEF) is a highly prevalent and deadly condition. Histone 3 trimethylation at lysine 36 (H3k36me3)-a chromatin signature induced by the histone methyltransferase SETD2 (SET domain containing 2)-correlates with changes in gene expression in human failing hearts; however, its role remains poorly understood. This study investigates the role of SETD2 in cHFpEF.METHODSChromatin immunoprecipitation sequencing and RNA sequencing were used to investigate H3k36me3-related transcriptional regulation. Mice with cardiomyocyte-specific deletion of SETD2 (c-SETD2-/-) were generated and subjected to high-fat diet feeding and L-NAME treatment for 15 weeks to induce cHFpEF. Cardiac function and exercise tolerance were assessed by echocardiography and treadmill exhaustion test. A selective pharmacological inhibitor of SETD2, EZM0414, was also tested in cHFpEF mice. Mechanistic experiments were performed in cultured cardiomyocytes exposed to palmitic acid. SETD2 signaling and the effects of EZM0414 were also investigated in cardiomyocytes from patients with cHFpEF and control donors.RESULTSSETD2 was upregulated in cHFpEF mouse hearts, and its chromatin mark H3k36me3 was involved in lipid metabolism and highly enriched on the promoter of the Srebf1 gene, encoding for SREBP1 (sterol regulatory binding protein 1). SETD2 activation in cHFpEF led to SREBP1 upregulation, triglyceride accumulation, and lipotoxic damage. Of note, cardiomyocyte-specific deletion of SETD2 in mice prevented heart failure with preserved ejection fraction-related hypertrophy, diastolic dysfunction, and lung congestion while improving exercise tolerance. SETD2 deletion blunted H3K36me3 enrichment on Srebf1 promoter, thus leading to a marked rewiring of the cardiac lipidome and restoration of autophagic flux. In vivo treatment with the SETD2 inhibitor EZM0414 recapitulated the effects of SETD2 deletion. Silencing of SETD2 in palmitic acid-treated cardiomyocytes prevented SREBP1 upregulation, whereas SETD2 overexpression mirrored lipotoxic damage. Finally, SETD2 was upregulated in left ventricle specimens from patients with cHFpEF while EZM0414 attenuated cardiomyocyte stiffness.CONCLUSIONSTargeting SETD2 might prevent lipotoxic injury in cHFpEF.
{"title":"Chromatin Rewiring by SETD2 Drives Lipotoxic Injury in Cardiometabolic HFpEF.","authors":"Sarah Costantino,Shafeeq A Mohammed,Samuele Ambrosini,Marialucia Telesca,Alessandro Mengozzi,Kaivalya Walavalkar,Era Gorica,Melissa Herwig,Loek van Heerebeek,Junyan Xia,Gergely Karsai,Thorsten Hornemann,Omer Dzemali,Raffaella Santoro,Qian Li,Frank Ruschitzka,Nazha Hamdani,Francesco Paneni","doi":"10.1161/circresaha.124.325310","DOIUrl":"https://doi.org/10.1161/circresaha.124.325310","url":null,"abstract":"BACKGROUNDCardiometabolic heart failure with preserved ejection fraction (cHFpEF) is a highly prevalent and deadly condition. Histone 3 trimethylation at lysine 36 (H3k36me3)-a chromatin signature induced by the histone methyltransferase SETD2 (SET domain containing 2)-correlates with changes in gene expression in human failing hearts; however, its role remains poorly understood. This study investigates the role of SETD2 in cHFpEF.METHODSChromatin immunoprecipitation sequencing and RNA sequencing were used to investigate H3k36me3-related transcriptional regulation. Mice with cardiomyocyte-specific deletion of SETD2 (c-SETD2-/-) were generated and subjected to high-fat diet feeding and L-NAME treatment for 15 weeks to induce cHFpEF. Cardiac function and exercise tolerance were assessed by echocardiography and treadmill exhaustion test. A selective pharmacological inhibitor of SETD2, EZM0414, was also tested in cHFpEF mice. Mechanistic experiments were performed in cultured cardiomyocytes exposed to palmitic acid. SETD2 signaling and the effects of EZM0414 were also investigated in cardiomyocytes from patients with cHFpEF and control donors.RESULTSSETD2 was upregulated in cHFpEF mouse hearts, and its chromatin mark H3k36me3 was involved in lipid metabolism and highly enriched on the promoter of the Srebf1 gene, encoding for SREBP1 (sterol regulatory binding protein 1). SETD2 activation in cHFpEF led to SREBP1 upregulation, triglyceride accumulation, and lipotoxic damage. Of note, cardiomyocyte-specific deletion of SETD2 in mice prevented heart failure with preserved ejection fraction-related hypertrophy, diastolic dysfunction, and lung congestion while improving exercise tolerance. SETD2 deletion blunted H3K36me3 enrichment on Srebf1 promoter, thus leading to a marked rewiring of the cardiac lipidome and restoration of autophagic flux. In vivo treatment with the SETD2 inhibitor EZM0414 recapitulated the effects of SETD2 deletion. Silencing of SETD2 in palmitic acid-treated cardiomyocytes prevented SREBP1 upregulation, whereas SETD2 overexpression mirrored lipotoxic damage. Finally, SETD2 was upregulated in left ventricle specimens from patients with cHFpEF while EZM0414 attenuated cardiomyocyte stiffness.CONCLUSIONSTargeting SETD2 might prevent lipotoxic injury in cHFpEF.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"108 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822607","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 : 2025-04-11DOI: 10.1161/circresaha.124.325550
Yen Chin Koay,Bailey McIntosh,Yann Huey Ng,Yang Cao,XiaoSuo Wang,Yanchuang Han,Saki Tomita,Angela Yu Bai,Benjamin Hunter,Ashish Misra,Christopher M Loughrey,Paul G Bannon,Sean Lal,Aldons J Lusis,David M Kaye,Mark Larance,John F O'Sullivan
BACKGROUNDHeart failure with preserved ejection fraction (HFpEF) has overtaken heart failure with reduced ejection fraction as the leading type of heart failure globally and is marked by high morbidity and mortality rates, yet with only a single approved pharmacotherapy: SGLT2i (sodium-glucose co-transporter 2 inhibitor). A prevailing theory for the mechanism underlying SGLT2i is nutrient deprivation signaling, of which ketogenesis is a hallmark. However, it is unclear whether the canonical ketogenic enzyme, HMGCS2 (3-hydroxy-3-methylglutaryl-coenzyme A synthase 2), plays any cardiac role in HFpEF pathogenesis or therapeutic response.METHODSWe used human myocardium, human HFpEF and heart failure with reduced ejection fraction transcardiac blood sampling, an established murine model of HFpEF, ex vivo Langendorff perfusion, stable isotope tracing in isolated cardiomyocytes, targeted metabolomics, proteomics, lipidomics, and a novel cardiomyocyte-specific conditional HMGCS2-deficient model that we generated.RESULTSWe demonstrate, for the first time, the intrinsic capacity of the human heart to produce ketones via HMGCS2. We found that increased acetylation of HMGCS2 led to a decrease in the enzyme's specific activity. However, this was overcome by an increase in the steady-state levels of protein. Oxidized form of nicotinamide adenine dinucleotide repletion restored HMGCS2 function via deacetylation, increased fatty acid oxidation, and rescued cardiac function in HFpEF. Critically, using a conditional, cardiomyocyte-specific HMGCS2 knockdown murine model, we revealed that the oxidized form of nicotinamide adenine dinucleotide is unable to rescue HFpEF in the absence of cardiomyocyte HMGCS2.CONCLUSIONSThe canonical ketogenic enzyme, HMGCS2, mediates the therapeutic effects of the oxidized form of nicotinamide adenine dinucleotide repletion in HFpEF by restoring normal lipid metabolism and mitochondrial function.
{"title":"Heart Has Intrinsic Ketogenic Capacity that Mediates NAD+ Therapy in HFpEF.","authors":"Yen Chin Koay,Bailey McIntosh,Yann Huey Ng,Yang Cao,XiaoSuo Wang,Yanchuang Han,Saki Tomita,Angela Yu Bai,Benjamin Hunter,Ashish Misra,Christopher M Loughrey,Paul G Bannon,Sean Lal,Aldons J Lusis,David M Kaye,Mark Larance,John F O'Sullivan","doi":"10.1161/circresaha.124.325550","DOIUrl":"https://doi.org/10.1161/circresaha.124.325550","url":null,"abstract":"BACKGROUNDHeart failure with preserved ejection fraction (HFpEF) has overtaken heart failure with reduced ejection fraction as the leading type of heart failure globally and is marked by high morbidity and mortality rates, yet with only a single approved pharmacotherapy: SGLT2i (sodium-glucose co-transporter 2 inhibitor). A prevailing theory for the mechanism underlying SGLT2i is nutrient deprivation signaling, of which ketogenesis is a hallmark. However, it is unclear whether the canonical ketogenic enzyme, HMGCS2 (3-hydroxy-3-methylglutaryl-coenzyme A synthase 2), plays any cardiac role in HFpEF pathogenesis or therapeutic response.METHODSWe used human myocardium, human HFpEF and heart failure with reduced ejection fraction transcardiac blood sampling, an established murine model of HFpEF, ex vivo Langendorff perfusion, stable isotope tracing in isolated cardiomyocytes, targeted metabolomics, proteomics, lipidomics, and a novel cardiomyocyte-specific conditional HMGCS2-deficient model that we generated.RESULTSWe demonstrate, for the first time, the intrinsic capacity of the human heart to produce ketones via HMGCS2. We found that increased acetylation of HMGCS2 led to a decrease in the enzyme's specific activity. However, this was overcome by an increase in the steady-state levels of protein. Oxidized form of nicotinamide adenine dinucleotide repletion restored HMGCS2 function via deacetylation, increased fatty acid oxidation, and rescued cardiac function in HFpEF. Critically, using a conditional, cardiomyocyte-specific HMGCS2 knockdown murine model, we revealed that the oxidized form of nicotinamide adenine dinucleotide is unable to rescue HFpEF in the absence of cardiomyocyte HMGCS2.CONCLUSIONSThe canonical ketogenic enzyme, HMGCS2, mediates the therapeutic effects of the oxidized form of nicotinamide adenine dinucleotide repletion in HFpEF by restoring normal lipid metabolism and mitochondrial function.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"50 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822601","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 : 2025-04-10DOI: 10.1161/circresaha.125.326364
Yanki Yarman,Xuefei Zhao,Peisong Ma
{"title":"Nuclear Receptors in Platelet Activation and Thrombosis in Hypercholesterolemia.","authors":"Yanki Yarman,Xuefei Zhao,Peisong Ma","doi":"10.1161/circresaha.125.326364","DOIUrl":"https://doi.org/10.1161/circresaha.125.326364","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"116 1","pages":"827-829"},"PeriodicalIF":20.1,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822613","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 : 2025-04-10DOI: 10.1161/circresaha.125.326366
James A Oo,Timothy Warwick,Matthias S Leisegang
{"title":"Long Noncoding RNA MIR181A1HG Takes a Proinflammatory Driver's Seat in Atherosclerosis by Hijacking FOXP1.","authors":"James A Oo,Timothy Warwick,Matthias S Leisegang","doi":"10.1161/circresaha.125.326366","DOIUrl":"https://doi.org/10.1161/circresaha.125.326366","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"38 1","pages":"884-886"},"PeriodicalIF":20.1,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822611","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 : 2025-04-10DOI: 10.1161/circresaha.124.323578
Heidi M Schmidt,Kelsey E Jarrett,Thomas Q de Aguiar Vallim,Elizabeth J Tarling
Clearance of circulating plasma LDL (low-density lipoprotein) cholesterol by the liver requires hepatic LDLR (low-density lipoprotein receptor). Complete absence of functional LDLR manifests in severe hypercholesterolemia and premature atherosclerotic cardiovascular disease. Since the discovery of the LDLR 50 years ago by Brown and Goldstein, all approved lipid-lowering medications have been aimed at increasing the abundance and availability of LDLR on the surface of hepatocytes to promote the removal of LDL particles from the circulation. As such a critical regulator of circulating and cellular cholesterol, it is not surprising that LDLR activity is tightly regulated. Despite over half a century's worth of study, there are still many facets of LDLR biology that remain unexplored. This review will focus on pathways that regulate the LDLR and emerging concepts of LDLR biology.
{"title":"Pathways and Molecular Mechanisms Governing LDL Receptor Regulation.","authors":"Heidi M Schmidt,Kelsey E Jarrett,Thomas Q de Aguiar Vallim,Elizabeth J Tarling","doi":"10.1161/circresaha.124.323578","DOIUrl":"https://doi.org/10.1161/circresaha.124.323578","url":null,"abstract":"Clearance of circulating plasma LDL (low-density lipoprotein) cholesterol by the liver requires hepatic LDLR (low-density lipoprotein receptor). Complete absence of functional LDLR manifests in severe hypercholesterolemia and premature atherosclerotic cardiovascular disease. Since the discovery of the LDLR 50 years ago by Brown and Goldstein, all approved lipid-lowering medications have been aimed at increasing the abundance and availability of LDLR on the surface of hepatocytes to promote the removal of LDL particles from the circulation. As such a critical regulator of circulating and cellular cholesterol, it is not surprising that LDLR activity is tightly regulated. Despite over half a century's worth of study, there are still many facets of LDLR biology that remain unexplored. This review will focus on pathways that regulate the LDLR and emerging concepts of LDLR biology.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"60 1","pages":"902-919"},"PeriodicalIF":20.1,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822617","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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