Circulation research最新文献

{"title":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000770","DOIUrl":"https://doi.org/10.1161/RES.0000000000000770","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"139 8","pages":"e000770"},"PeriodicalIF":18.0,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036591","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":"Gut Dysbiosis Promotes Myocardial Hypertrophy via GBP2b/GBP1 in Chronic Colitis.","authors":"Yadong Wang, Jian Li, Junqing An, Vu L Ngo, Shuhan Wang, Zhenkai Hao, Chao Li, Hirohito Abo, Ye Ding, Jun Zou","doi":"10.1161/CIRCRESAHA.126.329058","DOIUrl":"10.1161/CIRCRESAHA.126.329058","url":null,"abstract":"<p><strong>Background: </strong>Patients with inflammatory bowel disease are at increased risk of cardiovascular disease, yet the mechanisms linking chronic intestinal inflammation to cardiac dysfunction remain poorly understood. Inflammatory bowel disease is characterized by profound gut microbiota dysbiosis, which we hypothesize drives systemic immune dysregulation and contributes to cardiac dysfunction.</p><p><strong>Methods: </strong>A chronic colitis mouse model was used to assess gut microbiota dysbiosis, systemic immune cell metabolism, and cardiac remodeling. Cardiac outcomes were evaluated by echocardiography, histology, and molecular analyses. Mechanisms were examined using fecal microbiota transplantation, immune cell depletion, exosome transfer, bone marrow chimeras, RNA sequencing, coimmunoprecipitation, confocal microscopy, and siRNA-mediated gene silencing.</p><p><strong>Results: </strong>Chronic dextran sulfate sodium colitis induced cardiac dysfunction, hypertrophy, and fibrosis in mice. These changes were accompanied by sustained gut microbiota dysbiosis, metabolic reprogramming, and mitochondrial dysfunction in circulating immune cells. Fecal microbiota transfer experiments demonstrated that colitis-associated microbiota were sufficient to reprogram systemic immune cells and promote cardiac dysfunction. Immune cell depletion studies identified macrophages as key mediators of colitis-associated cardiac injury. Colitis increased systemic lipopolysaccharide translocation; bone marrow chimera experiments demonstrated that hematopoietic TLR4 (toll-like receptor 4) signaling was required for immune cell metabolic remodeling and cardiac dysfunction during chronic colitis. Transcriptomic analysis identified GBP2b (guanylate-binding protein 2b/GBP1, hereafter referred to as GBP1) as a key downstream effector of lipopolysaccharide TLR4 signaling. Upon lipopolysaccharide stimulation, GBP1 localized to mitochondria, where it interacted with DRP1 (dynamin-related protein 1) and FIS1 (fission 1 protein) to promote mitochondrial fission, oxidative stress, and enhanced immune cell migration into the heart. In addition, GBP1 was secreted via exosomes, which were taken up by cardiomyocytes and contributed to hypertrophic remodeling and cardiac dysfunction.</p><p><strong>Conclusions: </strong>These findings establish the lipopolysaccharide TLR4-GBP1 axis as a key driver of colitis-associated cardiovascular dysfunction and highlight this pathway as a promising therapeutic target for reducing cardiovascular risk in patients with inflammatory bowel disease.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e329058"},"PeriodicalIF":18.0,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13580750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863668","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":"Hepatic ChREBP Drives Cardiac Remodeling via ApoM Non-transcriptional 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":"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 (KO) or 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- or transverse aortic constriction-induced cardiac remodeling models. RNA sequencing and liquid chromatography - tandem mass spectrometry (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 or 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 high-density lipoprotein (HDL) injection can both ameliorate cardiac remodeling through the S1P (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":"e327537"},"PeriodicalIF":18.0,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13608343/pdf/","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":"OA","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, Kenneth 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 4 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 different desmoplakin mutations. We next identify the 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":"e327676"},"PeriodicalIF":18.0,"publicationDate":"2026-09-25","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":"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 (crystallin alpha B with arginine to glycine at position 120) and BAG3-P209L (Bcl-2-associated athanogene 3 with 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 [inducible conditional knockout]), 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":"e328328"},"PeriodicalIF":18.0,"publicationDate":"2026-09-25","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":"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":"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":"e328454"},"PeriodicalIF":18.0,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13608278/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathogenic B-T Cell Axis Driven by BAFF Induces Endothelial Apoptosis in SLE-PAH.","authors":"Xuehan Jiang, Leyao Ma, Yutong Li, Xiaoyue Deng, Qizhi Yuan, Junwei Zhang, Huiyuan Hu, Yidan Gao, Xingbei Dong, Yuhuan Tao, Wenjia Zhang, Junyan Qian, Yanjiang Xing, Yufei Hu, Hong Zhang, Jiuliang Zhao, Qian Wang, Xiaofeng Zeng, Yuanhua Yang, Wanlu Song, Mengtao Li, Peiran Yang, Chen Wang","doi":"10.1161/CIRCRESAHA.126.328338","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.126.328338","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary arterial hypertension (PAH) is a fatal complication of systemic lupus erythematosus (SLE), yet the mechanisms linking autoimmune dysregulation to progressive pulmonary vascular remodeling are poorly defined, leading to inadequate therapies. This study investigated BAFF (B-cell activating factor), a key cytokine in SLE, as a potential driver of SLE-PAH pathogenesis.</p><p><strong>Methods: </strong>BAFF expression was assessed in patients with SLE-PAH and animal models. Humanized BAFF-transgenic mice were generated to investigate the effects of BAFF elevation on serological, hemodynamic, and histological parameters of SLE and PAH. Single-cell RNA sequencing, flow cytometry, histological analyses, and cell-based experiments were performed to elucidate cellular and molecular mechanisms. The therapeutic efficacy of the BAFF-neutralizing antibody Belimumab was tested in 2 distinct SLE-PAH animal models.</p><p><strong>Results: </strong>BAFF was significantly upregulated in both SLE-PAH patient cohorts and animal models. Humanized BAFF-transgenic mice exhibited systemic B-cell hyperactivation and pulmonary infiltration and spontaneously developed hallmark features of both SLE and PAH. Single-cell transcriptomic analysis of lung tissues revealed that BAFF overexpression drove the increase of a novel, disease-specific S<i>100a6</i>⁺ mature B-cell subset, which orchestrated a pathogenic immune cascade by activating a cytotoxic <i>Gzmk</i>⁺ CD8⁺ T-cell population via MHC-I (major histocompatibility complex class I)-mediated antigen presentation and CD80-CD28 costimulation. This B-T cell crosstalk triggered apoptosis of a susceptible endothelial cell subpopulation through Fas/Fas ligand signaling, ultimately culminating in pulmonary vascular remodeling. The BAFF-neutralizing antibody Belimumab effectively ameliorated both autoimmune and cardiopulmonary manifestations in 2 distinct SLE-PAH animal models, while improving survival.</p><p><strong>Conclusions: </strong>These findings establish BAFF as a key mediator in SLE-PAH, driving a previously unrecognized pathogenic immune axis connecting dysregulated B cells to T-cell-mediated endothelial injury. BAFF inhibition may represent a therapeutic strategy for SLE-PAH.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029624","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":"Neural Mechanisms of Heart-Lung Crosstalk in Chronic Heart Failure.","authors":"Juan Hong, Samuel Gillman, Peter R Pellegrino, Gang Zhao, Rongguo Ren, Steven J Lisco, Irving H Zucker, Dong Wang, Han-Jun Wang","doi":"10.1161/CIRCRESAHA.126.328216","DOIUrl":"10.1161/CIRCRESAHA.126.328216","url":null,"abstract":"<p><strong>Background: </strong>The cardiac sympathetic afferent reflex and pulmonary spinal afferent reflex amplify sympathetic activity and may contribute to chronic heart failure. We hypothesized that cardiac injury triggers a cardiac nerve-mediated cytokine uptake cascade that propagates neural inflammation in thoracic dorsal root ganglia (DRGs) and drives reciprocal cardiopulmonary afferent sensitization through suppression of voltage-gated potassium channels after myocardial infarction (MI).</p><p><strong>Methods: </strong>MI was induced in rats by coronary ligation. Molecular profiling, immunofluorescence, tissue clearing, and functional assays were used to assess neuroinflammation and reflex responses.</p><p><strong>Results: </strong>Post-MI, thoracic DRGs showed macrophage infiltration, glial activation, cytokine upregulation, and reduced voltage-gated potassium channel expression. Bulk RNA-sequencing identified enrichment of macrophage activation-related genes, and in vitro studies confirmed that proinflammatory cytokines and activated macrophages suppressed voltage-gated potassium channels and increased DRG neuron excitability. Epicardial injection of biotinylated TNF-α (tumor necrosis factor-α) demonstrated cardiac afferent-mediated cytokine transport to DRGs, inducing macrophage infiltration via a cytokine receptor-dependent mechanism. Anti-inflammatory interventions, including oral minocycline, systemic macrophage depletion, and local epidural delivery of thermo-responsive hydrogel-forming dexamethasone prodrug (ProGel-Dex), significantly reduced DRG neuroinflammation, restored voltage-gated potassium channel levels, and attenuated exaggerated cardiac sympathetic afferent reflex and pulmonary spinal afferent reflex responses. Minocycline and ProGel-Dex also improved cardiac chamber dilation in the post-MI rats.</p><p><strong>Conclusions: </strong>These findings identify a neural inflammatory cascade involving cytokine uptake, glial activation, and macrophage activation as a contributor to cardiopulmonary afferent sensitization after MI. Targeting DRG inflammation, particularly with sustained dexamethasone delivery using ProGel-Dex, offers a prospect of precision medicine to dampen pathological sympathetic activation and improve cardiac outcomes in chronic heart failure.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030075","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":"Multilaboratory, Blinded, Randomized Trial of Five Cerebroprotectants in Ischemic Stroke","authors":"Cenk Ayata,Anil K. Chauhan,David C. Hess,Bingren Hu,Enrique C. Leira,Lauren Sansing,Huaxin Sheng,Takahiko Imai,Xuyan Jin,Sanem A. Aykan,Andreia Morais,Abhishek B. Jha,Aditi Jain,Daniel Thedens,Rakesh B. Patel,Mariia Kumskova,Mohammad B. Khan,Krishnan M. Dhandapani,Pradip K. Kamat,Ali S. Arbab,Yamileck Olivas Garcia,Yasin Asadi,Chunli Liu,Kaley Sauer,Yingxin Chen,Ligia S.B. Boisserand,Pinar Caglayan,Qinyue Stacy Guan,Fahmeed Hyder,J. Martin,Sanjana Gade,Basavaraju G. Sanganahalli,Sandeep Kumar Mishra,Wei Yang,Haichen Wang,Shasha Zhang,William Wetsel,G. Allan Johnson,Karni Bedirian,Shu-Hsiang Wang,Marcio A. Diniz,Kirsten Lynch,Michael Bienkowski,Arthur W. Toga,Karisma Nagarkatti,Jessica Lamb,Patrick Lyden","doi":"10.1161/circresaha.126.329467","DOIUrl":"https://doi.org/10.1161/circresaha.126.329467","url":null,"abstract":"BACKGROUND: Negative clinical trials foster therapeutic nihilism and public skepticism, especially if they follow optimistic preclinical results. One way to increase the likelihood of successful clinical trials is to enhance the preclinical testing of new treatments. Recently, multicenter preclinical testing networks have gained attention as one tool to enhance rigor and reduce the likelihood of erroneously recommending a new candidate treatment for advancement to clinical trial testing. METHODS: The SPAN (Stroke Preclinical Assessment Network) consists of 6 research laboratories performing the experiments and 1 coordinating center at which treatments are prepared in a blinded manner, subjects are randomized, and statistical analysis is performed. We conducted a rigorous trial that included both sexes, multiple comorbidities, randomization, concealment of treatment status, blinded outcome assessments, prespecified sample sizes, and comprehensive data tracking. Five promising treatments were evaluated: BPN-27332, a lipoxygenase inhibitor; uric acid, a potent natural scavenger of free radicals; tatCN19o, a peptide inhibitor of activated CaMKII (Ca 2+ /CaM–dependent protein kinase II); GSK2256294, an inhibitor of sEH (soluble epoxide hydrolase); and NVX-058, an oxygen-carrying compound. A behavioral battery was selected as the end point for the primary analysis. The primary analysis used the modified intention-to-treat population. RESULTS: In total, 1768 rodents (882 females and 886 males) were enrolled: 441 young healthy mice, 444 aging mice, 450 mice with obesity-induced hyperglycemia and metabolic syndrome, and 433 spontaneously hypertensive rats. Data missing due to death before 30 days of follow-up were imputed from the same treatment group, animal model, sex, and stage. Although none of the candidates met the prespecified efficacy boundary, GSK2256294 showed an odds ratio for benefit of 1.28 (95% CI, 0.99–1.65), which was significant at P &lt;0.05. CONCLUSIONS: The second SPAN study reaffirms the importance and feasibility of rigorous, multilaboratory preclinical testing networks to potentially reduce false positives in the development pipeline.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"222 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020318","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":"Calpain-Dependent Protein Degradation Contributes to CASQ2-R33Q CPVT.","authors":"Laura Ramos-Hernández, Demetrio J Santiago, Rocío F Serrano-Blanco, Andrea Cancemi, Lorena Esteban-Martínez, Emilio Camafeita, Marina López-Olañeta, Deni Kukavica, Ana Guío-Carrión, Jesús M Vázquez, Miguel Torres, Silvia G Priori, Enrique Lara-Pezzi","doi":"10.1161/CIRCRESAHA.126.329035","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.126.329035","url":null,"abstract":"<p><strong>Background: </strong>Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease associated with cardiac arrest in children and young adults. The recessive form of CPVT is caused by loss-of-function mutations in the genes encoding <i>CASQ2</i> and <i>TRDN</i>, which, together with <i>JCTN</i>, regulate the release of calcium ions from the sarcoplasmic reticulum through the RyR2 (ryanodine receptor). The <i>CASQ2</i> R33Q mutation causes calcium mishandling and ventricular tachycardia through triggered activity. The homozygous mouse model <i>Casq2^R33Q/R33Q</i> closely replicates the clinical phenotype of patients with CPVT. In this model, CASQ2 (calsequestrin 2), TRDN (triadin), and JCTN (junctin) levels are markedly reduced; however, the mechanisms underlying this reduction and their contribution to CPVT are incompletely understood.</p><p><strong>Methods: </strong>We used a combination of proteomics, animal models, and experimental methods to identify the molecular mechanisms responsible for the decrease of couplon proteins in <i>Casq2^R33Q/R33Q</i> mice and to explore their functional contribution to the disease.</p><p><strong>Results: </strong><i>Casq2^R33Q/R33Q</i> hearts showed activation of endoplasmic reticulum stress, the unfolded protein response, and alterations in major proteolytic pathways. Inhibition of the proteasome or autophagy in neonatal cardiomyocytes and adult mice partially restored CASQ2 but not TRDN levels, suggesting distinct degradation mechanisms. In contrast, calpain inhibition restored CASQ2 and TRDN protein levels, decreased triggered activity in isolated cardiomyocytes, and reduced ventricular tachycardia episodes in vivo in <i>Casq2^R33Q/R33Q</i> mice. Biochemical assays showed that TRDN is a direct calpain substrate. TRDN degradation preceded CASQ2 loss, and TRDN overexpression using modified RNA in cardiomyocytes or an adeno-associated viral vector in vivo increased CASQ2 levels in mutant mice, supporting an upstream role for TRDN destabilization.</p><p><strong>Conclusions: </strong>Couplon protein loss in CPVT associated with CASQ2-R33Q is mediated by coordinated but distinct proteolytic pathways, with calpain-dependent TRDN degradation representing a key pathogenic event that promotes CASQ2 destabilization and arrhythmogenesis.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015909","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}