Circulation research最新文献

{"title":"Metabolomic Profiles and Changes During the 20 Years Preceding Heart Failure.","authors":"Jiangtao Li, Shusi Ding, Zhao Yang, Mingdan Wang, Xuan Deng, Xueting Sun, Wenting Lu, Pingping Jia, Yan Liu, Yuhan Zhang, Jun Cai, Lemin Zheng, Yue Qi, Jing Liu","doi":"10.1161/CIRCRESAHA.126.328542","DOIUrl":"10.1161/CIRCRESAHA.126.328542","url":null,"abstract":"<p><strong>Background: </strong>Longitudinal metabolomic studies can refine understanding of heart failure (HF) progression and enable precision prevention. This study aims to identify serum metabolites associated with HF risk via longitudinal metabolomic analysis, delineate their dynamic trajectories, and explore metabolite profiles in populations with different metabolic disorders.</p><p><strong>Methods: </strong>This study analyzed longitudinal serum metabolomic data from 4774 serum samples from 1728 HF-free participants in the Chinese Multi-Provincial Cohort Study Metabolomics Project at 4 time points over a 20-year follow-up. Intensity models and Cox proportional-hazards models identified metabolites associated with HF risk. Latent variable mixed-effects models evaluated metabolite trajectories.</p><p><strong>Results: </strong>Of the 784 detected metabolites, 23 were associated with HF risk at a false discovery rate-adjusted <i>P</i><0.05, including 9 not previously reported in relation to HF. The HF risk-associated metabolites exhibited 4 distinct trajectory clusters and corresponding biological trends. Most metabolites that showed positive associations with HF risk remained relatively stable throughout the 20-year follow-up period, whereas metabolites that were negatively associated with HF risk generally exhibited a declining trend. The levels of these 23 metabolites in the group who developed HF began to diverge from the levels in the non-HF group >5 years before clinical HF diagnosis, with most changes initiating 15 to 20 years before clinical manifestation. Populations with different metabolic disorders exhibited distinct metabolite profiles related to HF. The HF-associated metabolites were primarily involved in energy metabolism and the vasodilatory response among individuals with hypertension, lipotoxic effects and oxidative stress among those with obesity, and inflammatory processes and glucotoxic mechanisms among individuals with dysglycemia.</p><p><strong>Conclusions: </strong>This longitudinal metabolomic study identifies HF-associated metabolite profiles, characterizes their changes during the 20 years preceding clinical diagnosis, and reveals heterogeneity across individuals with different metabolic disorders, thereby informing future biomarker and intervention research.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e328542"},"PeriodicalIF":18.0,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13521254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148577377","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":"Methylmalonate Overload Despite Glycemic Control Drives Diabetic Heart Damage.","authors":"Shanjie Wang, Miao Yan, Yiying Zhang, Fan Tang, Ye Wang, Junchen Guo, Zhanchao Chen, Xiaoxuan Liu, Zhaoying Li, Rongze Lu, Yan Cui, Guanpeng Ma, Pengyan Wu, Yuanyuan Huang, Yige Liu, Zeng Wang, Xing Luo, Hengxuan Cai, Yanjiao Shen, Wen Ge, Zhuozhong Wang, Shuang Yang, Dongdong Sun, Shaohong Fang, Bo Yu","doi":"10.1161/CIRCRESAHA.125.327192","DOIUrl":"10.1161/CIRCRESAHA.125.327192","url":null,"abstract":"<p><strong>Background: </strong>Despite optimal glycemic control, the heart failure burden remains substantial in diabetic patients. Metabolic remodeling is involved in this process, yet our current understanding is still in its infancy. Methylmalonic acid (MMA) is conventionally viewed as a marker of cobalamin (Cbl) deficiency. Paradoxically, MMA elevation-related cardiovascular mortality is more pronounced in diabetic patients with normal or high Cbl levels. This study investigated the mechanisms and translational significance of this contradictory MMA accumulation in the diabetic heart.</p><p><strong>Methods: </strong>We analyzed serum Cbl, MMA, and cardiac biomarkers in 12 751 participants and characterized Mmut (methylmalonyl-CoA mutase; a key enzyme in MMA catabolism) expression in failing human hearts with diabetes. Cardiomyocyte-specific Mmut knockout and Mmut-overexpressing mice were subjected to high-fat diet/streptozotocin-induced diabetes. Molecular mechanisms were elucidated using ¹³C-isotope tracing, RNA sequencing, immunoprecipitation, and biolayer interferometry.</p><p><strong>Results: </strong>Elevated serum MMA was significantly associated with subclinical heart damage and adverse outcomes in diabetic adults, even in the absence of Cbl deficiency. Cardiac MMA overload and decreased protein expression of Mmut were observed in humans and mice with diabetes. Notably, MMA dysmetabolism preceded detectable cardiac dysfunction in diabetic mice and persisted even after glycemic normalization. Mechanistically, the hyperglycemic memory-associated molecule miR-499 binds to Mmut mRNA, suppressing its expression and driving MMA accumulation. Mmut deficiency amplified cardiac MMA overload and exacerbated disturbances in glycolipid metabolism and mitochondrial quality control, whereas adeno-associated virus-mediated Mmut overexpression attenuated cardiac MMA load and adverse remodeling in diabetic mice. Isotope tracing identified isoleucine and valine as the primary sources of cardiac MMA under diabetic conditions. Branched-chain amino acid-restricted diets alleviated diabetes-induced MMA accumulation and heart damage. Crucially, Cbl supplementation failed to alleviate MMA overload in diabetic mice, even at high doses or with activated forms. Strikingly, metformin, an established risk factor for Cbl deficiency, mitigated MMA-induced heart damage through dual mechanisms: activating AMPK (AMP-activated protein kinase)-dependent mitochondrial quality control to enhance tolerance to MMA, and directly promoting Mmut-Cbl cooperation to enhance MMA clearance.</p><p><strong>Conclusions: </strong>This study provides a foundation for understanding diabetes-related MMA dysmetabolism as a trigger for subclinical heart damage resistant to glycemic control and Cbl supplementation. Our findings challenge the prevailing clinical consensus regarding the impacts of Cbl and metformin use on MMA elevation in diabetic management.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e327192"},"PeriodicalIF":18.0,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599771","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":"Hepatic ChREBP Drives Cardiac Remodeling via ApoM Nontranscriptional Repression.","authors":"Shuang Zhang, Zhenzhen Zhang, Zihan Ma, Wen Wu, Lu Tang, Yanlu Han, Songning Chen, Tengteng Yan, Ye Chen, Junwu Liu, Dongdong Jian, Ji'e Yang, Likun Ma, Zequn Yin, Houzao Chen, Baofa Sun, Deling Kong, Junbo Ge, Yajun Duan","doi":"10.1161/CIRCRESAHA.125.327537","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.125.327537","url":null,"abstract":"<p><strong>Background: </strong>Pathological cardiac remodeling is a hallmark of numerous cardiovascular diseases and develops into heart failure. As a systemic disease, effective treatments for cardiac remodeling from a tissue crosstalk perspective are still significantly unmet.</p><p><strong>Methods: </strong>Hepatocyte-specific ChREBP (carbohydrate response element binding protein) knockout and overexpressed mice, global ApoM (apolipoprotein M) KO and adeno-associated virus-mediated hepatic ApoM knockdown or overexpressed mice, cardiomyocyte-specific ChREBP overexpressed mice, as well as S1PR1 (sphingosine-1-phosphate receptor 1) knockdown mice were used in isoproterenol- and transverse aortic constriction-induced cardiac remodeling models. RNA sequencing and LC-MS/MS analysis were used to detect changed pathways and the interaction between ChREBP and SURF4 (surfeit 4).</p><p><strong>Results: </strong>We found increased ChREBP expression in the liver, but not in the heart, especially in the cytosol of hepatocytes, but not the nucleus, in isoproterenol- or transverse aortic constriction-induced mice. Hepatocyte-specific ChREBP deficiency protected against isoproterenol- and transverse aortic constriction-induced cardiac remodeling. Mechanistically, hepatocyte ChREBP deficiency increased ApoM expression in the liver and its secretion, not by transcriptional regulation of ApoM, but by increasing its secretion through the release of SURF4. ApoM overexpression in the liver or ApoM-containing HDL (high-density lipoprotein) injection can both ameliorate cardiac remodeling through the sphingosine-1-phosphate/S1PR1 pathway in the heart.</p><p><strong>Conclusions: </strong>This work identifies the hepatic ChREBP-SURF4-ApoM axis as a critical pathway in cardiac remodeling, and induction of hepatic ApoM secretion constitutes a new promising approach for treating cardiac remodeling and heart failure.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817568","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":"Mitophagy Facilitates Cytosolic Proteostasis to Preserve Cardiac Function.","authors":"David R Rawnsley, Moydul Islam, Chen Zhao, Xumin Guan, Yasaman Kargar Gaz Kooh, Adelita Mendoza, Honora Navid, Minu Kumari, Phalgun Pandi, John T Murphy, Jess Nigro, Attila Kovacs, Lina Greenberg, Kartik Mani, Michael Greenberg, Nathaniel Huebsch, Xiucui Ma, Abhinav Diwan","doi":"10.1161/CIRCRESAHA.126.328328","DOIUrl":"10.1161/CIRCRESAHA.126.328328","url":null,"abstract":"<p><strong>Background: </strong>Protein quality control is critical for maintaining sarcomere structure and function in cardiomyocytes. Mutations in protein quality control pathway proteins, namely, CRYAB-R120G (arginine to glycine at position 120) and BAG3-P209L (proline to lysine at position 209), induce protein aggregates and cardiomyopathy in humans. Novel observations in yeast demonstrate mitochondrial uptake of cytosolic protein aggregates. We hypothesized that mitochondrial uptake of cytosolic protein aggregates, and their removal by mitophagy, a lysosomal degradative pathway, facilitates cytosolic protein quality control in cardiomyocytes.</p><p><strong>Methods: </strong>Mice with inducible cardiac myocyte-specific ablation of TRAF2 (TNF receptor-associated factor 2; TRAF2-icKO), which impairs mitophagy, were assessed for protein aggregates with biochemical fractionation and super-resolution imaging. Human-induced pluripotent stem cell-derived cardiomyocytes with <i>TRAF2</i> ablation or R120G knock-in to the <i>CRYAB</i> locus were assessed for protein aggregates and effects of mitophagy stimulation. Transgenic mice expressing R120G-CRYAB protein (R120G-transgenic mice) were subjected to adeno-associated virus 9-cTnT (cardiac troponin T) promoter-driven TRAF2 or PARKIN gain-of-function and TRAF2 loss of function in cardiomyocytes to determine the effect of mitophagy modulation on cardiac structure, function, and protein aggregate pathology.</p><p><strong>Results: </strong>TRAF2-icKO mice demonstrate accumulation of mitochondrial and cytosolic protein aggregates and DESMIN mislocalization to protein aggregates. <i>TRAF2</i> null human-induced pluripotent stem cell-derived cardiomyocytes demonstrate impaired mitophagy with accumulation of polyubiquitinated proteins and disrupted sarcomeres, which are rescued by both TRAF2 and PARKIN transduction. Isolated mitochondria take up cardiomyopathy-associated aggregate-prone cytosolic proteins, namely, R120G-CRYAB and P209L-BAG3. R120G-CRYAB mutant protein increasingly localizes to mitochondria in human and mouse cardiomyocytes. R120G-transgenic mice demonstrate upregulation of myocardial TRAF2 with increased mitophagy. Adult-onset inducible haplo-insufficiency of <i>TRAF2</i> resulted in accelerated mortality, left ventricular systolic dysfunction, and increased protein aggregates in R120G-transgenic mice. Conversely, adeno-associated virus 9-TRAF2 transduction in R120G-transgenic mice stimulated mitophagy, reduced mortality, attenuated LV systolic dysfunction, reduced cytosolic protein aggregates, and restored DESMIN localization.</p><p><strong>Conclusions: </strong>Stimulation of mitophagy in cardiomyocytes facilitates removal of cytosolic protein aggregates as a mechanism to ameliorate proteotoxic cardiomyopathy.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13519989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817549","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":"FAP-Directed CAR-NKT Cells for Multi-Target Suppression of Atherosclerotic Progression.","authors":"Enbo Zhu, Yan-Ruide Li, JaeMin Cho, Robert Kropp, Yunpei Zhang, Yas Sanaiha, Oh Jin Kwon, Yichen Zhu, Seul-Ki Park, Brian Arianpour, Melissa Justo, Peng Zhao, Shaolei Wang, Mingxia Gu, Peyman Benharash, Lili Yang, Tzung Hsiai","doi":"10.1161/CIRCRESAHA.126.328898","DOIUrl":"10.1161/CIRCRESAHA.126.328898","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13521603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148812236","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":"Regulated HSPG Signaling Directs Epicardial Behavior to Support Cardiac Formation.","authors":"Andia N Redpath, Irina-Elena Lupu, Louis Haffreingue, Quang M Dang, Ian R McCracken, Tamara Carsana, Toin H van Kuppevelt, Joaquim Miguel Vieira, Nicola Smart","doi":"10.1161/CIRCRESAHA.125.327330","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.125.327330","url":null,"abstract":"<p><strong>Background: </strong>Pathways controlling cardiac cell behavior share a common dependency on heparan sulfate proteoglycans (HSPGs), which tightly regulate signaling at extracellular locations. This signaling is essential for cardiac development, yet how HSPGs are regulated in the forming heart is unknown. The epicardium is a rich source of HSPG-dependent signaling and cellular progenitors. We hypothesized that extracellular heparan sulfate modifiers, 6-<i>O</i>-endosulfatases, orchestrate progenitor cell behavior to support cardiogenesis.</p><p><strong>Methods: </strong>We used single-cell RNA sequencing, microscopy, and flow cytometry-based single-molecule RNA ISH to systematically profile 6-<i>O</i>-endosulfatases and target HSPGs in the embryonic mouse heart. Subsequently, we utilized knockout and knockdown models that identified gene associations and a role for the main epicardial 6-<i>O</i>-endosulfatase isoform, <i>Sulf1</i>. Transcriptional regulation of <i>Sulf1</i> was assessed using ATAC and CUT&RUN sequencing, luciferase assays, and siRNA, and the impact on epicardial cell behavior was confirmed in vivo and using in vitro functional assays.</p><p><strong>Results: </strong>Despite identical function, we find that <i>Sulf1</i> is expressed in the embryonic epicardium, while <i>Sulf2</i> is expressed broadly throughout the myocardium. We show that epicardial SULF1 dynamically regulates HSPG sulfation to fine-tune the magnitude and duration of signaling to impact cell fate and cardiac morphogenesis. Single-cell genomics and lineage tracing studies reveal <i>Sulf1</i> to be strongly coexpressed with key transcriptional regulator <i>Wt1</i> (Wilms tumor 1) in the epicardium, with reduction of both coinciding with epithelial-to-mesenchymal transition and quiescence. CUT&RUN-seq revealed transcriptional control of <i>Sulf1</i> by WT1, which directly impacts essential HSPG-dependent downstream signaling. Ligand-receptor interaction predictions and functional assays indicated that FGF (fibroblast growth factor)-2 and TGF-β (transforming growth factor β)-driven processes were governed by this regulatory interaction.</p><p><strong>Conclusions: </strong>Our study highlights, for the first time, essential fine-tuning of HSPG-dependent signaling to modulate key processes in heart formation, offering potential insights for therapeutically targeting congenital heart disease and enhancing epicardial proregenerative behaviors.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148812261","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":"Single-Molecule Imaging Reveals ERK-Dependent Spatial Translation in Cardiomyocytes.","authors":"Itai Erlich, Guy Douvdevany, Rami Haddad, Benjamin L Prosser, Izhak Kehat","doi":"10.1161/CIRCRESAHA.126.329033","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.126.329033","url":null,"abstract":"<p><strong>Background: </strong>Translational control of gene expression is crucial in cardiomyocytes, particularly in response to hypertrophic stimuli. The ERK (extracellular signal-regulated kinase) pathway plays a key role in inducing cardiac hypertrophy and regulating specific protein translation. However, it remains unclear how this specificity is achieved, and the spatiotemporal regulation of protein translation is not fully understood.</p><p><strong>Methods: </strong>We used SINAP (single-molecule imaging of nascent peptide) reporters to visualize and analyze the translation dynamics in single adult rat ventricular cardiomyocytes and tracked active translation sites at high spatiotemporal resolution. We also examined the effects of adrenergic stimulation and the role of the ERK pathway in translation localization.</p><p><strong>Results: </strong>Our findings revealed that translation sites are primarily localized near Z-lines in cardiomyocytes, with some sites being highly dynamic and moving during translation. The 3' untranslated regions did not significantly change the localization of translation. Many translation sites colocalized with microtubules, and their movement predominantly occurred along microtubular tracks. Adrenergic stimulation led to a transient shift in translation activity toward the perinuclear region, peaking at 12 hours and requiring ERK pathway activity for this localization change. This shift is part of the hypertrophic response and is required for early translation of genes such as <i>Nppa</i>.</p><p><strong>Conclusions: </strong>Our high-resolution single-cell study demonstrates that protein translation in cardiomyocytes is dynamic and responsive to hypertrophic stimuli in an ERK-dependent manner. The localized translation mechanism allows cardiomyocytes to rapidly adapt to changing environments by preferentially translating mRNAs in the perinuclear region. These findings provide new insights into the spatial regulation of translation in cardiomyocytes and its role in cardiac hypertrophy.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788485","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":"Desmoplakin Loss Leads to PKC- and Src-Mediated Contractile Dysfunction in Cardiomyocytes.","authors":"Ilhan Gokhan, Margaret McKay, Xia Li, Michele Zanetti, Jonathan M Granger, Jack M Sendek, Alex J Mora Pagan, Ken S Campbell, Fadi G Akar, Stuart G Campbell","doi":"10.1161/CIRCRESAHA.125.327676","DOIUrl":"10.1161/CIRCRESAHA.125.327676","url":null,"abstract":"<p><strong>Background: </strong>Mutations in <i>DSP</i>, which encodes the protein desmoplakin, lead to cardiomyopathy with unusually high penetrance that presents with arrhythmias, fibro-fatty infiltration, and eventually heart failure. However, the precise mechanism of contractile dysfunction and dilation is incompletely understood. Here, we investigate the pathogenesis of <i>DSP</i>-R451G, a missense mutation that results in complete degradation of desmoplakin protein.</p><p><strong>Methods: </strong>We use 3 complementary models to characterize desmoplakin-linked cardiomyopathy: induced pluripotent stem cell-derived engineered heart tissue expressing R451G desmoplakin, a heterozygous <i>Dsp</i>^WT/R451G knock-in mouse, and left-ventricular biopsy specimens. Tissue-engineered constructs are used to characterize contractility, calcium handling, sarcomere length, and cell signaling. These results are corroborated in the R451G mouse. To expand the generalizability of the findings, we compare them to those from human heart biopsies bearing 3 different desmoplakin mutations.</p><p><strong>Results: </strong>Using induced pluripotent stem cell-derived engineered heart tissue and isolated mouse ventricular cardiomyocytes, we recapitulate a disease phenotype consistent with desmoplakin cardiomyopathy and identify shortened resting sarcomere length as a pathogenic mechanism for contractile dysfunction. Phosphorylation of Src and protein kinase C underlies sarcomere shortening in mutant tissues, and pharmacological inhibition of these kinases rescues sarcomere length. Notably, these sarcomeric and biochemical hallmarks are also present in human hearts bearing 3 different desmoplakin mutations. We next identify redistribution of mechanical force at cardiomyocyte junctions as a proximal factor that may promote mechanoactivation of proto-oncogene tyrosine-protein kinase Src. Finally, we rescue sarcomere length and contractile function in <i>DSP</i>-mutant engineered heart tissue with dasatinib, a Food and Drug Administration-approved receptor tyrosine kinase inhibitor.</p><p><strong>Conclusions: </strong>Our study reveals a mechanism by which a desmosomal mutation affects cardiomyocyte function at the sarcomere level through activation of key signaling pathways that have not previously been implicated in desmoplakin cardiomyopathy.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788897","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":"FPR1-Driven Neutrophil-Endothelial Cell Axis Promotes Angiogenesis in PAOD.","authors":"Fengyang Li, Peishen Zhao, Tianshu Wei, Yuqin Zha, Xinhao Zhao, Owen L Woodman, Yuguo Chen, Xiaojun Zhou, Cheng Xue Qin","doi":"10.1161/CIRCRESAHA.126.328454","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.126.328454","url":null,"abstract":"<p><strong>Background: </strong>Peripheral artery occlusive disease (PAOD) is characterized by limb ischemia, heightened inflammation, and a substantial risk of mortality and amputation. Coordinated regulation of inflammation resolution and angiogenesis represents a promising therapeutic strategy. Given the established roles of FPRs (formyl peptide receptors) in inflammation resolution, we investigated their contribution to the integrated control of inflammation and angiogenesis in PAOD.</p><p><strong>Methods: </strong>Using a murine hindlimb ischemia model and clinical blood samples, we identified FPR1 as a key regulator of PAOD. We evaluated hindlimb perfusion recovery and inflammatory responses in <i>Fpr1</i>-deficient mice. The therapeutic potential of an FPR1 agonist was assessed, and RNA sequencing was used to elucidate underlying mechanisms. FPR1‑dependent angiogenic responses were further confirmed in vivo using neutrophil‑specific <i>Fpr1</i>-knockout mice and in vitro using neutrophils isolated from <i>Fpr1</i>-deficient mice and individuals carrying the <i>FPR1 rs867228</i> variant.</p><p><strong>Results: </strong>We identified FPR1 as a pivotal regulator in PAOD. <i>Fpr1</i> deficiency led to exaggerated inflammation and impaired angiogenesis, whereas FPR1 activation by a biased agonist, Cmpd17b, attenuated inflammation and improved perfusion recovery through a neutrophil‑dependent mechanism. Mechanistically, the Cmpd17b shifted neutrophil signaling away from Ca²⁺‑dependent proinflammatory pathways toward IL‑10 (interleukin-10) and VEGF-A (vascular endothelial growth factor‑A) production. Further analysis revealed that FPR1 activation in neutrophils promotes CCL2 (C-C motif chemokine ligand 2) release, which may upregulate HMOX1 (heme oxygenase 1) in endothelial cells to enhance angiogenesis. We also demonstrated that <i>FPR1 rs867228</i> confers protection in human PAOD by favoring pro-resolving responses and enhancing CCL2-mediated angiogenesis.</p><p><strong>Conclusions: </strong>FPR1 is a central regulator of inflammation and angiogenesis in PAOD. Biased FPR1 activation engages a neutrophil/CCL2-endothelial/HMOX1 axis to resolve inflammation and promote angiogenesis, supporting its therapeutic potential in PAOD.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788451","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":"Desmoplakin Mutations in Cardiac Fibroblasts Cause TGFβ1-Mediated Pathological Fibrogenesis in Desmoplakin Cardiomyopathy Via Beclin-1 Regulation.","authors":"Chuanyu Wei, Weinian Shou, Shing-Fai Chan, Ardan M Saguner, Corinna Brunckhorst, Firat Duru, Joseph E Marine, Cynthia A James, Hugh Calkins, Daniel P Judge, Huei-Sheng Vincent Chen","doi":"10.1161/CIRCRESAHA.124.325512","DOIUrl":"10.1161/CIRCRESAHA.124.325512","url":null,"abstract":"<p><strong>Background: </strong>Pathological fibrosis is a major finding in cardiovascular diseases and can result in arrhythmia and heart failure. Desmosome gene mutations can lead to arrhythmogenic cardiomyopathy. Among arrhythmogenic cardiomyopathies, pathogenic DSP (desmoplakin) variants cause a distinctive cardiomyopathy with excessive cardiac fibrosis that could precede ventricular dysfunction. <i>DSP</i> variants are also linked to other fibrotic diseases. Whether DSP plays any role in pathological fibrosis remains unknown.</p><p><strong>Methods: </strong>Mesenchymal stromal cells (MSCs) are resident fibroblast-like cells that are responsible for fibrogenesis in most organs, including the heart. We first used RNA-seq genome-wide analyses to generate cardiac fibroblast-like, induced pluripotent stem cell-derived MSCs from normal donors and patients with arrhythmogenic cardiomyopathy with <i>DSP</i> mutations. We then studied the fibrogenic responses of cardiac MSCs to TGFβ1 (transforming growth factor β1) using Western/Co-IP, autophagy assays, gene knockdowns/over-expressions, genomic analyses, mouse DSP knockdown models, immunostaining, and qPCR.</p><p><strong>Results: </strong>TGFβ1 induced excessive accumulation of VIM (vimentin)/fibrillar collagens and over-activated fibrotic genes in <i>DSP</i>-mutant MSCs when compared with normal MSCs. In normal MSCs, VIMs bind to wild-type DSP during normal fibrogenesis after TGFβ1. <i>DSP</i>-mutant MSCs exhibited a haplo-insufficient phenotype with increased DSP-unbound VIMs that sequestered BECN1 (beclin-1) from activating autophagy and CAV1 (caveolin-1)-mediated endocytosis. Decreased autophagy caused collagen accumulation, and diminished CAV1 endocytosis resulted in abnormal CAV1 plaque formation that over-activated fibrotic genes (<i>COL1A1</i>, <i>COL3A1</i>, and fibronectin [<i>FN</i>]) via heightened p38 activity after TGFβ1. Genome-wide analysis and DSP knockdown in mouse fibroblasts confirmed this novel role of <i>DSP</i> mutations in pathological fibrosis. Overexpression of VIM-binding domains of DSP could suppress pathological fibrosis by increasing collagen autophagic degradation and decreasing fibrotic gene expression.</p><p><strong>Conclusions: </strong>Our data reveal that DSP deficiency in MSCs/fibroblasts leads to exaggerated fibrogenesis in DSP-cardiomyopathy by decreasing BECN1 availability for autophagy and CAV1-endocytosis. Overexpression of VIM binding domains of DSP could be a new strategy to treat pathological fibrosis.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788494","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}