Circulation research最新文献

{"title":"TMEM-ing the Tide: Gene Therapy Holds Promise for ARVC5.","authors":"Sandra Ratnavadivel,Matthew W Ellis,Farah Sheikh","doi":"10.1161/circresaha.125.326367","DOIUrl":"https://doi.org/10.1161/circresaha.125.326367","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"50 1","pages":"845-847"},"PeriodicalIF":20.1,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822610","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":"High-Throughput Echocardiography-Guided Induction of Myocardial Ischemia/Reperfusion in Mice.","authors":"Florian Sicklinger,Niklas Hartmann,Attila Kovacs,Carla Weinheimer,Jess Nigro,Tobias Thiemann,Junedh Amrute,David Schumacher,Moritz Kornardt,Laura M Wienecke,Lennart Rompel,Johannes Fischer,John Bachman,Olivia Bedard,Shibali Das,Tim C Kuhn,Mirko Völkers,Ralf P Brandes,Rafael Kramann,Nadia Rosenthal,Norbert Frey,Kory J Lavine,Florian Leuschner","doi":"10.1161/circresaha.125.326156","DOIUrl":"https://doi.org/10.1161/circresaha.125.326156","url":null,"abstract":"BACKGROUNDMouse models of myocardial ischemia with subsequent heart failure are common approaches to examine heart failure pathology and possible treatment strategies. We sought to establish a high-throughput approach for echocardiography-guided induction of myocardial ischemia/reperfusion (IR) in mice.METHODSAfter visualization of the left coronary artery with high-resolution ultrasound imaging and echocardiographic definition of the level of coronary occlusion, the left anterior descending artery was temporarily occluded with 2 micromanipulator-controlled needles. Functional and molecular changes were assessed and compared with commonly performed surgical techniques.RESULTSEchocardiography-guided induction of myocardial IR enabled standardized induction of myocardial IR injury with subsequent left ventricular remodeling. Incorporation of various quality control measures throughout the procedure ensured a high success rate and the absence of relevant postinterventional mortality in experienced hands. Compared with surgical approaches, echocardiography-guided induction of myocardial IR showed a quicker recovery time and induced a less pronounced inflammatory response characterized by decreased local and systemic neutrophil counts. Notably, infarct size and subsequent post-myocardial infarction cardiac dysfunction were comparable between methods. The novel procedure was successfully implemented at different academic institutions with imaging expertise and demonstrated high interinstitutional reproducibility.CONCLUSIONSEchocardiography-guided induction of myocardial IR enables high-throughput induction of myocardial IR injury with precise echocardiographic definition of the occlusion level and immediate evaluation of cardiac function during ischemia. The method provides a more clinically relevant assessment of IR sequelae and offers notable animal welfare advantages by eliminating the need for ventilation and thoracotomy, thereby mitigating potential surgery-related confounders.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"39 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819366","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":"Metabolic Coordination Structures Contribute to Diabetic Myocardial Dysfunction.","authors":"Teng Wu, Tongsheng Huang, Honglin Ren, Conghui Shen, Jiang Qian, Xinlu Fu, Shangyuan Liu, Chengshu Xie, Xi Lin, Junhong Wan, Shijie Xiong, Yuanjun Ji, Mengying Liu, Huiting Zheng, Ting Liang, Wenyi Liu, Yan Zou, Jingwei Li, Maoquan Yang, Zeyi Song, Peixuan Lan, Xinghui Li, Yandi Wu, Ming Yang, Hui Li, Xuezhe Huang, Hui Chen, Jing Tan, Weibin Cai","doi":"10.1161/CIRCRESAHA.124.326044","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.326044","url":null,"abstract":"<p><strong>Background: </strong>Individuals with diabetes are susceptible to cardiac dysfunction and heart failure, potentially resulting in mortality. Metabolic disorders frequently occur in patients with diabetes, and diabetes usually leads to remodeling of heart structure and cardiac dysfunction. However, the contribution and underlying mechanisms of metabolic and structural coupling in diabetic cardiac dysfunction remain elusive.</p><p><strong>Methods: </strong>Two mouse models of type 2 diabetes (T2DM) were used to assess alterations in glucose/lipid metabolism and cardiac structure. The potential metabolic-structural coupling molecule ACBP (acyl-coenzyme A-binding protein) was screened from 4 published datasets of T2DM-associated heart disease. In vivo loss-of-function and gain-of-function approaches were used to investigate the role of ACBP in diabetic cardiac dysfunction. The underlying mechanisms of metabolic and structural coupling were investigated by stable-isotope tracing metabolomics, coimmunoprecipitation coupled with mass spectrometry, and chromatin immunoprecipitation sequencing.</p><p><strong>Results: </strong>Diabetic mouse hearts exhibit enhanced lipid metabolism and impaired ultrastructure with marked cardiac systolic and diastolic dysfunction. Analysis of 4 T2DM public datasets revealed that <i>Acbp</i> was a significant lipid metabolism gene whose expression was upregulated. Consistently, ACBP expression levels were markedly elevated in the hearts of patients with diabetes and diabetic mice. Moreover, we constructed cardiomyocyte-specific <i>Acbp</i> knockout mice that exhibited attenuation of T2DM-induced cardiac remodeling and cardiac dysfunction, including attenuation of cardiac hypertrophy, fibrosis, ultrastructural damage, and enhanced cardiomyocyte contractility and cardiac function. Conversely, cardiac-specific <i>Acbp</i> overexpression via adeno-associated virus type 9, which encodes <i>Acbp</i> under the cTnT (cardiac troponin T) promoter, recapitulated cardiac dysfunction. Mechanistically, cardiac-specific <i>Acbp</i> knockout enhances glucose utilization in diabetic cardiomyocytes, suggesting a potential compensatory mechanism for insufficient ATP levels, highlighting its metabolic role. In addition, combined with mass spectrometry analysis revealed that ACBP binds MyBPC3 (myosin-binding protein C3) in T2DM individuals, which potentially prevents MyBPC3 from assisting the formation of cross-bridge structures between myosin and actin, thereby impairing myocardial contraction. Importantly, chromatin immunoprecipitation sequencing revealed that peroxisome proliferator-activated receptor γ regulates the transcriptional activity of <i>Acbp</i>.</p><p><strong>Conclusions: </strong>Our findings demonstrated that ACBP mediates the bidirectional regulation of cardiomyocyte metabolic and structural associations and identified a promising therapeutic target for ameliorating cardiac dysfunction in patients with T2DM.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":16.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794815","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":"Piezo1 in PASMCs: Critical for Hypoxia-Induced Pulmonary Hypertension Development.","authors":"Fenja Knoepp, Shariq Abid, Amal Houssaini, Larissa Lipskaia, Mira Yasemin Gökyildirim, Emmanuelle Born, Elisabeth Marcos, Malika Arhatte, Edyta Glogowska, Nora Vienney, Andreas Günther, Simone Kraut, Ingrid Breitenborn-Mueller, Karin Quanz, Dagmar Fenner-Nau, Geneviève Derumeaux, Norbert Weissmann, Eric Honoré, Serge Adnot","doi":"10.1161/CIRCRESAHA.124.325475","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.325475","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary hypertension (PH) is a life-threatening and progressive yet incurable disease. The hallmarks of PH comprise (1) sustained contraction and (2) excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs). A major stimulus to which PASMCs are exposed during PH development is altered mechanical stress, originating from increased blood pressure, changes in blood flow velocity, and a progressive stiffening of pulmonary arteries. Mechanosensitive ion channels, including Piezo1, perceive such mechanical stimuli and translate them into a variety of cellular responses, including contractility or proliferation. Thus, the objective of the present study was to elucidate the specific role of Piezo1 in PASMCs for PH development and progression.</p><p><strong>Methods: </strong>The cell-type specific function of Piezo1 in PH was assessed in (1) PASMCs and lung tissues from patients with PH and (2) 2 mouse strains characterized by smooth muscle cell-specific, conditional Piezo1 knockout. Taking advantage of these strains, the smooth muscle cell-specific role of Piezo1 in PH development and progression was assessed in isolated, perfused, and ventilated mouse lungs, wire myography, and proliferation assays. Finally, in vivo function of smooth muscle cell-specific Piezo1 knockout was evaluated upon induction of chronic hypoxia-induced PH in these mice with insights into pulmonary vascular cell senescence.</p><p><strong>Results: </strong>Compared with healthy controls, PASMCs from patients with PH featured an elevated Piezo1 expression and increased proliferative phenotype. Smooth muscle cell-specific Piezo1 deletion, as confirmed via quantitative real-time polymerase chain reaction and patch clamp recordings, prevented the hypoxia-induced increase in PASMC proliferation in mice. Moreover, Piezo1 knockout reduced hypoxic pulmonary vasoconstriction in isolated, perfused, and ventilated mouse lungs, endothelial-denuded pulmonary arteries, and hemodynamic measurements in vivo. Consequently, Piezo1-deficient mice were considerably protected against chronic hypoxia-induced PH development with ameliorated right heart hypertrophy and improved hemodynamic function. In addition, distal pulmonary capillaries were preserved in the Piezo1-knockout mice, associated with a lower number of senescent endothelial cells.</p><p><strong>Conclusions: </strong>This study provides evidence that Piezo1 expressed in PASMCs is critically involved in the pathogenesis of PH by controlling pulmonary vascular tone, arterial remodeling, and associated lung capillary rarefaction due to endothelial cell senescence.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":16.5,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779323","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":"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}