JCI insight最新文献

{"title":"Methylation-induced suppression of YAP/TAZ confers sensitivity to HDAC inhibitors in high grade IDH mutant gliomas.","authors":"Thomas K Sears, Matthew McCord, Wenxia Wang, Alicia Steffens, Kathleen McCortney, Rahul Chaliparambil, Jann N Sarkaria, Craig M Horbinski","doi":"10.1172/jci.insight.195385","DOIUrl":"https://doi.org/10.1172/jci.insight.195385","url":null,"abstract":"<p><p>IDH1/2 mutations (IDHmut) increase methylation of DNA and histones in gliomas. IDHmut inhibitors are effective against low-grade IDHmut gliomas, but new strategies against high grade IDHmut gliomas are needed. Although histone deacetylase inhibitors (HDACi) are ineffective against IDHwt glioblastoma (GBM), their potential in IDHmut gliomas has not been extensively studied. We previously established that IDHmut gliomas are more sensitive to HDACi than IDHwt GBM. Here we show that IDHmut is associated with greater sensitivity to HDACi only in glioma, not in IDHmut chondrosarcoma or cholangiocarcinoma. While HDACi induced more histone acetylation and gene regulation in IDHmut glioma than in IDHwt GBM, such acetylation was mostly within gene deserts, whereas IDHmut glioma promoters paradoxically lost histone acetylation. Two mediators of HDACi resistance, YAP and TAZ, were methylated and suppressed in IDHmut gliomas, but not in other IDHmut cancers. Inducing YAP or TAZ expression in IDHmut gliomas conferred resistance to HDACi. Finally, belinostat extended in vivo survival only in IDHmut glioma models, not in IDHmut GBM models. Our findings provide a mechanistic rationale for further studies of HDACi in IDHmut glioma patients, as well as the potential use of YAP/TAZ as a biomarker of HDACi sensitivity in cancers.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258227","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":"A systems approach to target discovery identifies the role of lncRNA-SPANXA2-OT1 in macrophage chemotaxis.","authors":"Prabhash Kumar Jha, Sarvesh Chelvanambi, Yuto Nakamura, Lucas Yuji Umesaki Itto, Aatira Vijay, Adrien Lupieri, Miguel Cantadori Barbeiro, Thanh-Dat Le, Caio Borges Nascimento, Taku Kasai, Mary C Whelan, Daiki Hosokawa, Dakota Becker-Greene, Sasha A Singh, Elena Aikawa, Shizuka Uchida, Masanori Aikawa","doi":"10.1172/jci.insight.191274","DOIUrl":"https://doi.org/10.1172/jci.insight.191274","url":null,"abstract":"<p><p>Coronary artery disease (CAD) is the leading cause of mortality worldwide, with macrophages playing a central role in shaping the inflammatory environment through cytokines, chemokines, and other mediators. Long noncoding RNAs (lncRNAs) are emerging as key regulators of cellular processes due to their interactions with DNA, RNA, microRNAs, and proteins, positioning them as promising therapeutic targets. Through integrative transcriptomic analysis, we identified SPANXA2-OT1 as a primate-specific lncRNA with a potential role in macrophage-mediated inflammation in CAD. Functional studies in primary human macrophages demonstrated that SPANXA2-OT1 is induced by inflammatory stimulation, localized to the cytoplasm, and exerts regulatory effects on chemokine expression and macrophage chemotaxis. Mechanistically, SPANXA2-OT1 acts as a molecular sponge for microRNA-338, thereby influencing the expression of interleukin-8 (IL-8), a critical mediator of monocyte recruitment and inflammatory signaling. Collectively, these findings establish SPANXA2-OT1 as a human-specific regulator of inflammatory pathways in CAD and highlight its translational potential as both a biomarker and therapeutic target.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258268","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":"Platelets impair the resolution of inflammation in atherosclerotic plaques in insulin-resistant mice after lipid-lowering.","authors":"Maria Laskou, Sofie Delbare, Michael Gildea, Ada Weinstock, Vitor De Moura Virginio, Maxwell La Forest, Franziska Krautter, Casey Donahoe, Letizia Amadori, Natalia Eberhardt, Tessa J Barrett, Chiara Giannarelli, Jeffrey S Berger, Edward A Fisher","doi":"10.1172/jci.insight.193593","DOIUrl":"https://doi.org/10.1172/jci.insight.193593","url":null,"abstract":"<p><p>Insulin resistance impairs benefits of lipid-lowering treatment as evidenced by higher cardiovascular risk in individuals with type 2 diabetes versus those without. Because platelet activity is higher in insulin-resistant patients and promotes atherosclerosis progression, we questioned whether platelets impair inflammation resolution in plaques during lipid-lowering. In mice with obesity and insulin resistance, we induced advanced plaques, then implemented lipid-lowering to promote atherosclerotic plaque inflammation-resolution. Concurrently, mice were treated with either platelet-depleting or control antibodies for 3 weeks. Platelet activation and insulin resistance were unaffected by lipid-lowering. Both antibody-treated groups showed reduced plaque macrophages, but plaque cellular and structural composition differed. In platelet-depleted mice, scRNA seq revealed dampened inflammatory gene expression in plaque macrophages and an expansion of a subset of Fcgr4+ macrophages having features of inflammation-resolving, phagocytic cells. Necrotic core size was smaller and collagen content greater, resembling stable human plaques. Consistent with the mouse results, clinical data showed that patients with lower platelet counts had decreased pro-inflammatory signaling pathways in circulating non-classical monocytes after lipid-lowering. These findings highlight that platelets hinder inflammation-resolution in atherosclerosis during lipid-lowering treatment. Identifying novel platelet-targeted therapies following lipid-lowering treatment in individuals with insulin resistance may be a promising therapeutic approach to promote atherosclerotic plaque inflammation-resolution.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258279","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":"The role of TCF-1+CD8+ exhausted progenitors and TCF-1 in graft-versus-host responses.","authors":"Kevin Quann, Faruk Sacirbegovic, Sarah Rosenberger, Emily R McFerran, Kentin C Codispot, Laura Garcia-Dieguez, Alexander M Rowe, Wenzhong Wei, Dhanpat Jain, Jennifer M McNiff, Warren Shlomchik","doi":"10.1172/jci.insight.181568","DOIUrl":"10.1172/jci.insight.181568","url":null,"abstract":"<p><p>In allogeneic hematopoietic transplantation, donor αβ T cells attack recipient tissues, causing graft versus host disease (GVHD). A longstanding question has been how GVHD is maintained despite T cell exhaustion from chronic alloantigen stimulation. In other exhaustion models, CD8 responses are sustained by CD39loTim-3loToxhiTCF-1hi precursor exhausted T cells (TPEX). Here we characterize CD8+ TPEX in the B6(H-2b)→129(H-2b) GVHD model wherein responses against the minor histocompatibility antigen H60 can be tracked using MHCI-tetramers (TetH60). Early after transplant, TetH60+ CD8 cells were uniformly PD-1hiToxhi, whereas TetH60- cells also had PD-1loToxlo cells, indicative of more diverse antigen experiences. Among TetH60+ and TetH60- populations were CD39loTCF-1hi cells. Upon competitive retransplantation, TetH60+CD39loTCF-1hi cells outcompeted TetH60+CD39hiTCF-1lo cells and underwent self-renewal, whereas CD39hiTCF-1lo cells did not yield TCF-1hi cells. To test the role of TCF-1, we studied CD8 cells lacking long TCF-1 isoforms (p45-/-). P45-/- cells were outcompeted by WT cells when transplanted into 129 recipients, though they expanded similarly in syngeneic recipients. In the B6→C3H.SW(H-2b) model, p45-/- CD8 cells caused less weight loss than did WT CD8 cells; however, histopathologic GVHD was similar in both groups. P45-/- and WT CD8 cells also had similar graft versus leukemia activity. These results highlight the complex biology of TCF-1 in supporting alloreactive T cell function.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 19","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12507345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251072","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":"Unique epithelial proliferative transcriptomic signature in proton pump inhibitor-responsive pediatric eosinophilic esophagitis.","authors":"Somdutta Chakraborty, Ankit Sharma, Sahiti Marella, Christian F Rizza, Patrick A O'Brien, Varsha Ganesan, Gila Idelman, Susie Min, Mayee Chen, Talaya McCright-Gill, Nancy Gonzalez, Alexandros D Polydorides, Paul S Foster, Simon P Hogan, Mirna Chehade","doi":"10.1172/jci.insight.178595","DOIUrl":"10.1172/jci.insight.178595","url":null,"abstract":"<p><p>Clinical trials have identified 2 distinct eosinophilic esophagitis (EoE) treatment phenotypes: those that show proton pump inhibitor (PPI) responsiveness (PPI-R) and those that show PPI unresponsiveness (PPI-UR). Comprehensive clinical, endoscopic, and RNA-Seq analyses of patients with EoE prior to and following PPI therapy have not previously been performed to our knowledge. We showed that clinical, endoscopic, and histologic evaluation of esophageal biopsies from pediatric PPI-R and PPI-UR individuals with EoE prior to PPI therapy (diagnosis) were indistinguishable. RNA-Seq analyses revealed common immune and inflammatory transcriptional signatures in both PPI-R EoE and PPI-UR EoE esophageal biopsy samples at diagnosis and distinct signatures enriched for processes related to neuropeptide signaling and cell cycle and division. PPI therapy induced histologic, endoscopic, and transcriptional remission in PPI-R EoE, but not in PPI-UR EoE. Persistent disease in PPI-UR EoE was associated with the presence of Th2 inflammatory and dedifferentiated esophageal epithelial transcriptomic signatures, while PPI-R EoE revealed genes enriched in cellular responses to LPS, host defense against viruses, and type I IFN signaling. In silico analyses identified common and unique EoE disease gene drivers in PPI-R and PPI-UR EoE. These studies indicate that the 2 EoE phenotypes have unique transcriptomic elements that underlie the molecular nature of PPI-R and PPI-UR EoE disease.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 19","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12513502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251024","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":"Intranodal expansion of follicular T helper cells in patients with multiple sclerosis.","authors":"Joona Sarkkinen, Eliisa Kekäläinen, Leo Hannolainen, Ada Junquera, Johannes Dunkel, Maria F Perdomo, Mikko I Mäyränpää, Sini M Laakso","doi":"10.1172/jci.insight.188125","DOIUrl":"10.1172/jci.insight.188125","url":null,"abstract":"<p><p>The efficacy of anti-CD20 therapies places B cells and their interaction with T cells at the center of attention for multiple sclerosis (MS) pathogenesis. Follicular T helper cells (Tfh), which guide B cell maturation in germinal centers within lymph nodes (LNs), are elevated in the circulation and cerebrospinal fluid of patients with MS (pwMS). However, the LN spatial landscape has remained largely without investigation for pwMS. Using cyclic immunofluorescence, we assessed cell abundance and spatial connections in FFPE LNs of 33 pwMS and 35 non-MS controls. The presence of EBV was analyzed through EBER immunostaining and multiplex quantitative PCR. Our analysis showed that Tfh cells were expanded in LNs of pwMS and accumulated especially in the mantle zone and B cell follicles compared with controls. The Tfh/T follicular regulator ratio was increased in pwMS, while B cell ratios were similar between the cohorts. The interaction of Tfh cells with follicular B cells was higher in pwMS. Interestingly, Tfh accumulation was also observed in 5 prediagnostic MS cases. No signs of EBV latency were detected in either group. These findings highlight LNs as a site of early and persistent immune activation in pwMS, with therapeutic implications to be further addressed.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 19","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12513493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251066","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":"Icosapent ethyl-induced lipoprotein remodeling and its impact on cardiovascular disease risk markers in normolipidemic individuals.","authors":"Lauri Äikäs, Petri T Kovanen, Martina B Lorey, Reijo Laaksonen, Minna Holopainen, Hanna Ruhanen, Reijo Käkelä, Matti Jauhiainen, Martin Hermansson, Katariina Öörni","doi":"10.1172/jci.insight.193637","DOIUrl":"10.1172/jci.insight.193637","url":null,"abstract":"<p><p>BACKGROUNDIcosapent ethyl (IPE), an ethyl ester of eicosapentaenoic acid (EPA), reduces cardiovascular disease (CVD), but the mechanism remains elusive. We examined the effect of IPE supplementation on lipoprotein subclasses, lipidomes, and pro-atherogenic properties.METHODSUsing 3 independent metabolomic platforms, we examined the effect of high-dose IPE supplementation for 28 days on fatty acid profiles, lipoprotein subclasses, lipidomes, and pro-atherogenic properties in normolipidemic volunteers (n = 38).RESULTSIPE supplementation increased lipoprotein EPA on average 4-fold within 7 days, returning to baseline after a 7-day washout. Notably, the incorporation displayed marked interindividual variance, negatively correlating with baseline levels. We identified persistent participant-specific lipoprotein fingerprints despite uniform IPE-induced lipidome remodeling across all lipoprotein classes. This remodeling resulted in reductions in saturated, monounsaturated, and n-6 polyunsaturated fatty acids, resulting in reduced clinical risk markers, including triglyceride, remnant cholesterol, and apolipoprotein B (apoB) levels and 10-year CVD risk score. Of the pro-atherogenic properties tested, IPE significantly reduced apoB lipoprotein binding to proteoglycans, which correlated with lower apoB particle concentration, cholesterol content, and specific lipid species in LDL, including phosphatidylcholine 38:3 previously associated with CVD.CONCLUSIONThese findings highlight IPE's rapid, uniform remodeling of lipoproteins and reduced proteoglycan binding, likely contributing to previously observed CVD risk reduction. Persistent interindividual lipidome signatures underscore the potential for personalized therapeutic approaches in atherosclerotic CVD treatment.TRIAL REGISTRATIONNCT04152291.FUNDINGJenny and Antti Wihuri Foundation, Research Council of Finland, Sigrid Jusélius Foundation, Finnish Foundation for Cardiovascular Research, Emil Aaltonen Foundation, Ida Montin Foundation, Novo Nordisk Foundation, Finnish Cultural Foundation, and Jane and Aatos Erkko Foundation.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 19","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12513490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251048","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":"Faithful modeling of terminal CD8+T cell dysfunction and epigenetic stabilization in vitro.","authors":"Amir Yousif, Abbey A Saadey, Ava Lowin, Asmaa M Yousif, Ankita Saini, Madeline R Allison, Kelley Ptak, Eugene M Oltz, Hazem E Ghoneim","doi":"10.1172/jci.insight.191220","DOIUrl":"10.1172/jci.insight.191220","url":null,"abstract":"<p><p>Epigenetic scarring of terminally dysfunctional (TDysf) CD8+ T cells hinders long-term protection and response to immune checkpoint blockade during chronic infections and cancer. We developed a faithful in vitro model for CD8+ T cell terminal dysfunction as a platform to advance T cell immunotherapy. Using TCR-transgenic CD8+ T cells, we found that 1-week peptide stimulation, mimicking conditions in previous models, failed to induce a stable exhaustion program. In contrast, prolonged stimulation for 2-3 weeks induced T cell dysfunction but triggered activation-induced cell death, precluding long-term investigation of exhaustion programs. To better mimic in vivo exhaustion, we provided post-effector, chronic TGF-β1 signals, enabling survival of chronically stimulated CD8+ T cells for over 3 weeks. These conditions induced a state of terminal dysfunction, marked by a stable loss of effector, cytotoxicity, and memory programs, along with mitochondrial stress and impaired protein translation. Importantly, transcriptomic and epigenetic analyses verified the development of terminal exhaustion-specific signatures in TDysf cells. Adoptive transfer of TDysf cells revealed their inability to recall effector functions or proliferate after acute lymphocytic choriomeningitis virus rechallenge. This tractable model system enables investigation of molecular pathways driving T cell terminal dysfunction and discovery of therapeutic targets for cancer or chronic infections.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 19","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12513483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250999","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":"AI662270/GRP94 axis couples the unfolded protein response to mitochondrial dynamics during acute myocardial infarction.","authors":"Suling Ding, Wen Liu, Zhiwei Zhang, Xiyang Yang, Dili Sun, Jianfu Zhu, Xiaowei Zhu, Shijun Wang, Mengshi Xie, Hongyu Shi, Junbo Ge, Xiangdong Yang","doi":"10.1172/jci.insight.188904","DOIUrl":"10.1172/jci.insight.188904","url":null,"abstract":"<p><p>The unfolded protein response (UPR), triggered by endoplasmic reticulum (ER) stress, comprises distinct pathways orchestrated by conserved molecular sensors. Although several of these components have been suggested to protect cardiomyocytes from ischemic injury, their precise functions and mechanisms remain elusive. In this study, we observed a marked increase in glucose-regulated protein 94 (GRP94) expression at the border zone of cardiac infarct in a mouse model. GRP94 overexpression ameliorated post-infarction myocardial damage and reduced infarct size. Conversely, GRP94 deficiency exacerbated myocardial dysfunction and infarct size. Mechanistically, GRP94 alleviated hypoxia-induced mitochondrial fragmentation, whereas its depletion exacerbated this fragmentation. Molecular investigations revealed that GRP94 specifically facilitated the cleavage of Opa1 into L-Opa1, but not S-Opa1. The study further elucidated that under hypoxic conditions, the binding shift of Yy1 from lncRNA Oip5os1 to AI662270 promoted Yy1's binding on the GRP94 promoter, thereby enhancing GRP94 expression. AI662270 attenuated mitochondrial over-fragmentation and ischemic injury after myocardial infarction similarly to GRP94. Moreover, coimmunoprecipitation coupled with LC-MS/MS identified the interaction of GRP94 with Anxa2, which regulates Akt1 signaling to maintain L-Opa1 levels. Overall, these findings unveiled what we believe is a novel role for the AI662270/GRP94 axis in linking ER stress to mitochondrial dynamics regulation, proposing new therapeutic avenues for managing cardiovascular conditions through ER stress modulation.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 19","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12513489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251053","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":"Atrial fibrillation induced neurocognitive and vascular dysfunction is averted by mitochondrial oxidative stress reduction.","authors":"Pavithran Guttipatti, Ruiping Ji, Najla Saadallah, Uma Mahesh R Avula, Deniz Z Sonmez, Albert Fang, Eric Li, Amar D Desai, Samantha Parsons, Parmanand Dasrat, Christine Sison, Yanping Sun, Chris N Goulbourne, Steven R Reiken, Elaine Y Wan","doi":"10.1172/jci.insight.189850","DOIUrl":"https://doi.org/10.1172/jci.insight.189850","url":null,"abstract":"<p><p>Atrial fibrillation (AF) is a prevalent arrhythmia with known detriments such as heart failure, stroke, and cognitive decline even in patients without prior stroke. The mechanisms by which AF leads to cognitive dysfunction are yet unknown and there is a lack of animal models to study this disease process. We previously developed a murine model of spontaneous and prolonged episodes of AF, a double transgenic mouse model with cardiac specific expression of a gain-of-function mutant voltage-gated sodium channel (DTG-AF mice). Herein, we show for the first time a murine model of AF without any cerebral infarcts exhibiting cognitive dysfunction, including impaired visual learning and cognitive flexibility on touchscreen testing. Mesenteric resistance arterial function of DTG-AF mice showed significant loss of myogenic tone, increased wall thickness and distensibility, and mitochondrial dysfunction. Brain pial arteries also showed increased wall thickness and mitochondrial enlargement. Furthermore, DTG-AF mice have decreased brain perfusion on laser speckle contrast imaging compared to controls. Cumulatively, these findings demonstrate AF leads to vascular structural and functional alterations necessary for dynamic cerebral autoregulation resulting in increased cerebral stress and cognitive dysfunction. Expression of mitochondrial catalase (mCAT) to reduce mitochondrial reactive oxygen species (ROS) was sufficient to prevent vascular dysfunction due to AF, restore perfusion, and improve cognitive flexibility.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244565","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}