Circulation research最新文献

{"title":"PCSK9 Regulates Cardiac Mitochondrial Cholesterol by Promoting TSPO Degradation.","authors":"Marion Laudette, Malin Lindbom, Mathieu Cinato, Per-Olof Bergh, Kristina Skålén, Arif Muhammad, Azra Miljanovic, Tomasz Czuba, Rosie Perkins, J Gustav Smith, Frank Lezoualc'h, Malin C Levin, Jan Borén","doi":"10.1161/CIRCRESAHA.124.325629","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.325629","url":null,"abstract":"<p><strong>Background: </strong>Cholesterol is critical for mitochondrial membrane structure and function. Given the emergence of mitochondria as a key factor in the pathogenesis of heart failure, mitochondrial cholesterol homeostasis may be crucial for maintaining mitochondrial properties and thus cardiac function. We previously showed that CM-<i>Pcsk9</i>^-/- mice (mice with cardiomyocyte-specific deletion of PCSK9 [proprotein convertase subtilisin-kexin type 9]) have impaired cardiomyocyte mitochondrial bioenergetics and heart function, paralleled by cardiomyocyte mitochondrial cholesterol accumulation and an increased number of mitochondria-endoplasmic reticulum contacts. However, the mechanisms linking PCSK9 to mitochondrial cholesterol homeostasis remain unclear. We hypothesized that PCSK9 acts on proteins involved in mitochondrial cholesterol trafficking in the heart to maintain cardiac mitochondrial function.</p><p><strong>Methods: </strong>By performing RNA sequencing and immunoblot on CM-<i>Pcsk9</i>^-/- and CM-<i>Pcsk9</i>^+/+ mouse hearts, we showed that TSPO (translocator protein) was increased by <i>Pcsk9</i> deficiency. To investigate the relationship between <i>TSPO</i> levels and heart function in humans, we compared the transcriptome of human left ventricles with high versus low <i>TSPO</i> levels. We used H9c2 (a rat cardiomyoblast cell line) cardiomyocytes to explore the mechanism linking PCSK9/TSPO to mitochondrial cholesterol content and function. The impact of reduced TSPO levels on cardiac function and mitochondrial oxidation in CM-<i>Pcsk9</i>^-/- mice was tested using adeno-associated virus serotype 9 short hairpin TSPO.</p><p><strong>Results: </strong>Both gene and protein levels of TSPO, a mitochondrial protein involved in cholesterol transport, were increased in CM-<i>Pcsk9</i>^-/- mouse hearts. Transcriptome analysis showed that high <i>TSPO</i> expression in human left ventricles was associated with impaired mitochondrial and cardiac function. We showed that PCSK9 induced TSPO degradation through a proteasomal mechanism that occurs in cardiomyocytes but not hepatocytes and contributes to maintaining normal mitochondrial cholesterol composition and function. At the molecular level, endoplasmic reticulum-resident PCSK9 interacted with GRP78, reducing GRP78-TSPO interactions and leading to TSPO misfolding and degradation by the ubiquitin-proteasome pathway. Importantly, gene therapy-induced downregulation of TSPO in CM-<i>Pcsk9</i>^-^/^- mice prevented mitochondrial cholesterol accumulation and improved cardiac function.</p><p><strong>Conclusions: </strong>These findings indicate that PCSK9 regulates mitochondrial cholesterol levels by modulating the TSPO degradation in the heart. Modulation of mitochondrial cholesterol by targeting TSPO may be a promising therapeutic approach for heart failure.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":16.5,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763074","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}

{"title":"Srsf3-Dependent APA Drives Macrophage Maturation and Limits Atherosclerosis.","authors":"Xian Yang, Xin Zhang, Yaru Tian, Jiaxuan Yang, Yunhui Jia, Yuhuai Xie, Lianping Cheng, Shenglai Chen, Linfeng Wu, Yihong Qin, Zhen Zhao, Dejian Zhao, Yuanyuan Wei","doi":"10.1161/CIRCRESAHA.124.326111","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.326111","url":null,"abstract":"<p><strong>Background: </strong>Circulating monocytes largely contribute to macrophage buildup in atheromata, which is crucial for clearing subendothelial LDLs (low-density lipoproteins) and dead cells; however, the transitional trajectory from monocytes to macrophages in atherosclerotic plaques and the underlying regulatory mechanism remain unclear. Moreover, the role of alternative polyadenylation, a posttranscriptional regulator of cell fate, in monocyte/macrophage fate decisions during atherogenesis is not entirely understood.</p><p><strong>Methods: </strong>To identify monocyte/macrophage subtypes in atherosclerotic lesions and the effect of alternative polyadenylation on these subtypes and atherogenesis, single-cell RNA sequencing, 3'-end sequencing, flow cytometric, and histopathologic analyses were performed on plaques obtained from <i>Apoe</i>^<i>-/-</i> mouse arteries with or without myeloid deletion of <i>Srsf3</i> (serine/arginine-rich splicing factor 3). Cell fractionation, polysome profiling, L-azidohomoalanine metabolic labeling assay, and metabolomic profiling were conducted to disclose the underlying mechanisms. Reprogramming of widespread alternative polyadenylation patterns was estimated in human plaques via bulk RNA sequencing.</p><p><strong>Results: </strong>We identified a subset of lesional cells in a monocyte-to-macrophage transitional state, which exhibited high expression of chemokines in mice. <i>Srsf3</i> deletion caused a maturation delay of these transitional cells and phagocytic impairment of lesional macrophages, aggravating atherosclerosis. Mechanistically, <i>Srsf3</i> deficiency shortened 3' untranslated regions of mitochondria-associated Aars2 (alanyl-tRNA synthetase 2), disrupting its translation. The resultant impairment of protein synthesis in mitochondria led to mitochondrial dysfunction with declined NAD⁺ levels, activation of the integrated stress response, and metabolic reprogramming in macrophages. Administering an NAD⁺ precursor nicotinamide mononucleotide or the integrated stress response inhibitor partially restored <i>Srsf3</i>-deficient macrophage maturation, and nicotinamide mononucleotide treatment mitigated the proatherosclerotic effects of <i>Srsf3</i> deficiency. Consistently, <i>Srsf3</i> downregulation, global 3' untranslated region shortening, and accumulation of these transitional macrophages were associated with atherosclerosis progression in humans.</p><p><strong>Conclusions: </strong>Our study reveals that Srsf3-dependent generation of long 3' untranslated region is required for efficient mitochondrial translation, which promotes mature phagocytic macrophage formation, thereby playing a protective role in atherosclerosis.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":16.5,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751194","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}

{"title":"Cardiomyocyte PRL2 Promotes Cardiac Hypertrophy via Directly Dephosphorylating AMPKα2.","authors":"Xue Han, Qiaojuan Shi, Yu Tu, Jiajia Zhang, Mengyang Wang, Weiqi Li, Yanan Liu, Ruyi Zheng, Jiajia Wei, Shiju Ye, Yanmei Zhang, Bozhi Ye, Yi Wang, Huazhong Ying, Guang Liang","doi":"10.1161/CIRCRESAHA.124.325262","DOIUrl":"10.1161/CIRCRESAHA.124.325262","url":null,"abstract":"<p><strong>Background: </strong>Pathological cardiac hypertrophy can result in heart failure. Protein dephosphorylation plays a primary role in the mediation of various cellular processes in cardiomyocytes. Here, we investigated the effects of a protein tyrosine phosphatase, PRL2 (phosphatase of regenerative liver 2), on pathological cardiac hypertrophy.</p><p><strong>Methods: </strong>The PRL2 knockout mice were subjected to angiotensin II infusion or transverse aortic constriction to induce myocardial hypertrophy and cardiac dysfunction. RNA-sequencing analysis was performed to explore the underlying mechanisms. Mass spectrometry and bio-layer interferometry assays were used to identify AMPKα2 (AMP-activated protein kinase α2) as an interacting protein of PRL2. Mutant plasmids of AMPKα2 were used to clarify how PRL2 interacts and dephosphorylates AMPKα2.</p><p><strong>Results: </strong>A significant upregulation of PRL2 was observed in hypertrophic myocardium tissues in mice and patients with heart failure. PRL2 deficiency alleviated cardiac hypertrophy, fibrosis, and dysfunction in mice challenged with angiotensin II infusion or transverse aortic constriction. Transcriptomic and biochemical analyses showed that PRL2 knockout or silence maintained AMPK^T172 phosphorylation and subsequent mitochondrial integrity in angiotensin II-challenged heart tissues or cardiomyocytes. Mass spectrometry-based interactome assay indicated AMPKα2 subunit as the substrate of PRL2. Mechanistically, PRL2 binds to the C-terminal domain of AMPKα2 and then dephosphorylates AMPKα2^T172 via its active site C46. Adeno-associated virus 9-mediated deficiency of cardiomyocyte PRL2 also protected cardiac mitochondrial function and showed cardioprotective effects in angiotensin II-challenged mice, but these benefits were not observed in AMPKα2^-/- mice.</p><p><strong>Conclusions: </strong>This study reveals that PRL2, as a novel AMPK-regulating phosphatase, promotes mitochondrial instability and hypertrophic injury in cardiomyocytes and provides PLR2 as a potential target for future drug development treating heart failure.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"645-663"},"PeriodicalIF":16.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413548","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}

{"title":"ASH2L Deficiency in Smooth Muscle Drives Pulmonary Vascular Remodeling.","authors":"Jing Zhang, Xia Gu, Tian-Le Cheng, Yong-Jia Qi, Dao-Yan Liu, Na Wu, Da-Peng Wang, Yu Huang, Zhi-Ming Zhu, Ye Fan","doi":"10.1161/CIRCRESAHA.124.325539","DOIUrl":"10.1161/CIRCRESAHA.124.325539","url":null,"abstract":"<p><strong>Background: </strong>Histone H3 lysine 4 methylation is one of the most abundant epigenetic modifications, which has been recently linked to vascular remodeling in pulmonary hypertension (PH). SET1/MLL methyltransferase complexes comprise the main enzymes responsible for methylating H3 lysine 4, yet their roles in vascular remodeling and PH are not fully understood. We aim to assess the contribution of ASH2L, a core SET1/MLL family member, to the pathogenesis of PH.</p><p><strong>Methods: </strong>Human pulmonary artery specimens and primary vascular cells, smooth muscle cell (SMC)-specific <i>ASH2L</i>-deficient mice, rats with SMC-specific ASH2L overexpression, mass spectrometry, immunoprecipitation, and chromatin immunoprecipitation were used to define the role of ASH2L in PH.</p><p><strong>Results: </strong>Analysis of bulk RNA-sequencing data sets from human lung vessels identified ASH2L as the only differentially expressed SET1/MLL family member in PH compared with healthy controls. Decreased ASH2L expression in human pulmonary arteries correlated with the clinical severity of PH, which contrasted with elevated H3 lysine 4 methylation and was primarily localized to SMCs. Depletion of ASH2L promoted whereas its restoration ameliorated SMC proliferation and vascular remodeling in PH. Mechanistically, we revealed that ASH2L functioned independently of the canonical H3 lysine 4 trimethylation-based transcriptional activation, while it formed a protein complex with KLF5 and FBXW7, thereby accelerating the ubiquitin-proteasomal degradation of KLF5. NOTCH3 was discovered as a new downstream target of KLF5, and the loss of ASH2L promoted the recruitment of KLF5 to the NOTCH3 promoter, thus enhancing NOTCH3 expression. Pharmacological blockage of KLF5 attenuated PH in chronic hypoxia-exposed SMC-specific <i>ASH2L</i>-deficient mice and sugen/hypoxia-challenged rats.</p><p><strong>Conclusions: </strong>This study demonstrated that ASH2L deficiency causatively affects SMC proliferation and lung vascular remodeling that is partially mediated through KLF5-dependent NOTCH3 transcription. Activating ASH2L or targeting KLF5 might represent potential therapeutic strategies for PH.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"719-734"},"PeriodicalIF":16.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491024","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}

{"title":"Biophysical and Biochemical Roles of Shear Stress on Endothelium: A Revisit and New Insights.","authors":"Chak Kwong Cheng, Nanping Wang, Li Wang, Yu Huang","doi":"10.1161/CIRCRESAHA.124.325685","DOIUrl":"10.1161/CIRCRESAHA.124.325685","url":null,"abstract":"<p><p>Hemodynamic shear stress, the frictional force exerted by blood flow on the endothelium, mediates vascular homeostasis. This review examines the biophysical nature and biochemical effects of shear stress on endothelial cells, with a particular focus on its impact on cardiovascular pathophysiology. Atherosclerosis develops preferentially at arterial branches and curvatures, where disturbed flow patterns are most prevalent. The review also highlights the range of shear stress across diverse human arteries and its temporal variations, including aging-related alterations. This review presents a summary of the critical mechanosensors and flow-sensitive effectors that respond to shear stress, along with the downstream cellular events that they regulate. The review evaluates experimental models for studying shear stress in vitro and in vivo, as well as their potential limitations. The review discusses strategies targeting shear stress, including pharmacological approaches, physiological means, surgical interventions, and gene therapies. Furthermore, the review addresses emerging perspectives in hemodynamic research, including single-cell sequencing, spatial omics, metabolomics, and multiomics technologies. By integrating the biophysical and biochemical aspects of shear stress, this review offers insights into the complex interplay between hemodynamics and endothelial homeostasis at the preclinical and clinical levels.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 7","pages":"752-772"},"PeriodicalIF":16.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728976","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}

{"title":"Cardiac Fibrosis in the Multi-Omics Era: Implications for Heart Failure.","authors":"Rachad Ghazal, Min Wang, Duan Liu, Daniel J Tschumperlin, Naveen L Pereira","doi":"10.1161/CIRCRESAHA.124.325402","DOIUrl":"10.1161/CIRCRESAHA.124.325402","url":null,"abstract":"<p><p>Cardiac fibrosis, a hallmark of heart failure and various cardiomyopathies, represents a complex pathological process that has long challenged therapeutic intervention. High-throughput omics technologies have begun revolutionizing our understanding of the molecular mechanisms driving cardiac fibrosis and are providing unprecedented insights into its heterogeneity and progression. This review provides a comprehensive analysis of how techniques-encompassing genomics, epigenomics, transcriptomics, proteomics, and metabolomics-are providing insight into our understanding of cardiac fibrosis. Genomic studies have identified novel genetic variants and regulatory networks associated with fibrosis susceptibility and progression, and single-cell transcriptomics has unveiled distinct cardiac fibroblast subpopulations with unique molecular signatures. Epigenomic profiling has revealed dynamic chromatin modifications controlling fibroblast activation states, and proteomic analyses have identified novel biomarkers and potential therapeutic targets. Metabolomic studies have uncovered important alterations in cardiac energetics and substrate utilization during fibrotic remodeling. The integration of these multi-omic data sets has led to the identification of previously unrecognized pathogenic mechanisms and potential therapeutic targets, including cell-type-specific interventions and metabolic modulators. We discuss how these advances are driving the development of precision medicine approaches for cardiac fibrosis while highlighting current challenges and future directions in translating multi-omic insights into effective therapeutic strategies. This review provides a systems-level perspective on cardiac fibrosis that may inform the development of more effective, personalized therapeutic approaches for heart failure and related cardiovascular diseases.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 7","pages":"773-802"},"PeriodicalIF":16.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728979","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}

{"title":"Taxing Hearts: <i>TAX1BP3</i> Loss Stirs Up TRPV4 Channels in Arrhythmogenic Cardiomyopathy.","authors":"Sandra Ratnavadivel, Afaf Jreije, Farah Sheikh","doi":"10.1161/CIRCRESAHA.124.325502","DOIUrl":"10.1161/CIRCRESAHA.124.325502","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 7","pages":"685-687"},"PeriodicalIF":16.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728985","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}

{"title":"β-Hydroxybutyrate Facilitates Postinfarction Cardiac Repair via Targeting PHD2.","authors":"Cheng Wang, Wenjing Xu, Shushu Jiang, Yichen Wu, Jiangcheng Shu, Xinyuan Gao, Kai Huang","doi":"10.1161/CIRCRESAHA.124.325179","DOIUrl":"10.1161/CIRCRESAHA.124.325179","url":null,"abstract":"<p><strong>Background: </strong>Acute myocardial infarction (MI) remains one of the major causes of death worldwide, and innovative treatment strategies for MI represent a major challenge in cardiovascular medicine. Caloric restriction (CR) is the most potent nonpharmacological intervention known to prevent age-related disorders and extend lifespan. CR reduces glycolysis and elevates ketone body metabolism. However, whether and how CR or ketone body prevents the progression of MI remains poorly defined.</p><p><strong>Methods: </strong>Mice treated with CR and β-hydroxybutyrate (β-OHB) underwent MI induced by ligation of the left anterior descending coronary artery. Cardiac function was assessed by echocardiographic measurements. Histological analysis, fluorescence-activated cell sorting, and immunofluorescence were used to assess myocardial neovascularization and macrophage filtration. The interaction and modification of β-OHB on PHD2 were analyzed by molecular docking, cellular thermal shift assay, liquid chromatography with tandem mass spectrometry, and coimmunoprecipitation. Macrophage-specific PHD2 K239R and K385R knock-in mice were used to determine the functional significance of β-OHB/PHD2 axis in vivo.</p><p><strong>Results: </strong>Twelve weeks of CR markedly rescued postinfarction cardiac function by enhancing neovascularization. CR significantly increased circulating and cardiac ketone bodies, including β-OHB and acetoacetate. We identified β-OHB but not acetoacetate selectively targeted macrophages to stimulate VEGF (vascular endothelial growth factor) production in the peri-infarct area to promote neovascularization and cardiac repair. Mechanistically, β-OHB binds to and induces lysine β-hydroxybutyrylation of PHD2 at lysines 239 and 385, thus blocking its function in the hydroxylation of HIF-1α (hypoxia-inducible factor 1α) and resulting in enhanced HIF1α-dependent VEGF transcription and secretion. More importantly, specific PHD2 lys239 and lys385 mutations in macrophages abolished the preventive effects of exogenous β-OHB on MI in mice.</p><p><strong>Conclusions: </strong>These data reveal a novel regulation of lysine β-hydroxybutyrylation on PHD2 and demonstrate a promising and therapeutic role for β-OHB/PHD2 in effectively accelerating neovascularization and preserving heart function after cardiac ischemia.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"704-718"},"PeriodicalIF":16.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432711","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}

{"title":"Endothelial PPARδ Ablation Exacerbates Vascular Hyperpermeability via STAT1/CXCL10 Signaling in Acute Lung Injury.","authors":"Huiling Hong, Yalan Wu, Yangxian Li, Yumeng Han, Xiaoyun Cao, Vivian Wei Yan Wu, Thomas Ting Hei Chan, Jingying Zhou, Qin Cao, Kathy O Lui, Chun-Kwok Wong, Zhiyu Dai, Xiao Yu Tian","doi":"10.1161/CIRCRESAHA.124.325855","DOIUrl":"10.1161/CIRCRESAHA.124.325855","url":null,"abstract":"<p><strong>Background: </strong>Vascular hyperpermeability is one of the hallmarks of acute lung injury, contributing to excessive inflammation and respiratory failure. The PPARδ (peroxisome proliferator-activated receptor delta) is an anti-inflammatory transcription factor, although its role in endothelial barrier function remains unclear. Here, we studied the essential role of PPARδ in maintaining vascular endothelial barrier integrity during lung inflammation and investigated the underlying mechanisms.</p><p><strong>Methods: </strong>Endothelial cell (EC)-selective PPARδ knockout mice (Ppard^EC-KO) and littermate control mice (Ppard^EC-WT) received lipopolysaccharide injection to induce acute lung injury. Lung inflammation, pulmonary vascular leakage, and mouse mortality were monitored. Single-cell RNA sequencing was performed on sorted mouse lung ECs.</p><p><strong>Results: </strong>Ppard^EC-KO mice exhibited aggravated lung inflammation, characterized by increased leukocyte infiltration, elevated production of proinflammatory cytokines, and higher mortality rates. The enhanced inflammatory responses were associated with increased protein leakage, interstitial edema, and impaired endothelial barrier structure, leading to vascular hyperpermeability in Ppard^EC-KO mice. Mechanistically, with single-cell RNA sequencing, we identified the emergence of an interferon-activated capillary EC population marked by CXCL10 (C-X-C motif chemokine 10) expression following lipopolysaccharide challenge. PPARδ silencing significantly increased CXCL10 expression in ECs through activating STAT1 (Signal transducer and activator of transcription 1). Notably, CXCL10 treatment induced degradation of tight junction proteins ZO-1 (zonula occludens protein 1) and claudin-5 through the ubiquitin-proteasome system, disrupting membrane junction continuity in ECs. Administration of anti-CXCL10 antibody or CXCL10 receptor antagonist AMG487 suppressed both lipopolysaccharide-induced lung inflammation and vascular leakage in Ppard^EC-KO mice.</p><p><strong>Conclusions: </strong>These results highlighted a novel anti-inflammatory role of PPARδ in ECs by suppressing CXCL10-mediating vascular hyperpermeability. Targeting the CXCL10 signaling shows therapeutic potential against vascular injury in acute lung injury.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"735-751"},"PeriodicalIF":16.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490462","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}

{"title":"<i>TAX1BP3</i> Causes TRPV4-Mediated Autosomal Recessive Arrhythmogenic Cardiomyopathy.","authors":"Robin M Perelli, Enya R Dewars, Heidi Cope, Alexander S Behura, Anna Q Ponek, Angelina M Sala, Zhushan Zhang, Padmapriya Muralidharan, Mary E Moya-Mendez, Amy Berkman, Gabrielle G Monaco, Molly C Sullivan, Jordan E Ezekian, Qixin Yang, Bo Sun, Leonie M Kurzlechner, Tulsi Asokan, Andrew M Breglio, M Jay Campbell, Zebulon Z Spector, Catherine W Rehder, Paul C Tang, Cynthia A James, Hugh Calkins, Vandana Shashi, Andrew P Landstrom","doi":"10.1161/CIRCRESAHA.124.325180","DOIUrl":"10.1161/CIRCRESAHA.124.325180","url":null,"abstract":"<p><strong>Background: </strong>Arrhythmogenic cardiomyopathy (ACM) is one of the leading causes of sudden cardiac death in children, young adults, and athletes and is characterized by the fibro-fatty replacement of the myocardium, predominantly of the right ventricle. Sixty percent of patients with ACM have a known genetic cause, but for the remainder, the pathogenesis is unknown. This lack of mechanistic understanding has slowed the development of disease-modifying therapies, and children with ACM have a high degree of morbidity and mortality.</p><p><strong>Methods: </strong>Induced pluripotent stem cells (iPSCs) from 3 family members were differentiated into cardiac myocytes (CMs). Calcium imaging was conducted by labeling calcium with CAL-520 and confocal imaging to capture calcium sparks after iPSC-CMs were electrically paced. A cardiac-specific, inducible knockout mouse (<i>Tax1bp3^-/-</i>) was made and intracardiac electrophysiology studies conducted to observe arrhythmia inducibility following pacing.</p><p><strong>Results: </strong>We identified a kindred with multiple members affected by ACM cosegregating with biallelic variants in the gene <i>TAX1BP3</i>, which encodes the protein TAX1BP3 (Tax1-binding protein 3). iPSC-CMs derived from this kindred demonstrated increased intracellular lipid droplets, induction of TRPV4 (transient receptor potential vanilloid type 4) expression, and inducible TRPV4 current. This was associated with depletion of the intracellular sarcoplasmic reticulum Ca²⁺ store and increased RyR2 (ryanodine receptor 2)-mediated store Ca²⁺ leak and delayed afterdepolarizations, a known mechanism of Ca²⁺-mediated arrhythmogenesis. Similarly, <i>Tax1bp3</i> cardiac-specific knockout mice had increased Ca²⁺ leak and were predisposed to ventricular arrhythmias compared with wild-type mice. Ca²⁺ leak in both the iPSC-CMs and mouse ventricular myocytes was rescued by small molecule TRPV4 inhibition. This strategy also effectively reduced Ca²⁺ leak in a PKP2 (plakophilin 2) p.His773AlafsX8 iPSC-CM model of ACM.</p><p><strong>Conclusions: </strong>We conclude that <i>TAX1BP3</i> is associated with rare autosomal recessive ACM through TRPV4-mediated Ca²⁺ leak from RyR2. Further, TRPV4 current inhibition has the potential to be a new therapeutic target for ACM.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"667-684"},"PeriodicalIF":16.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440050","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}