Circulation research最新文献

{"title":"Taxing Hearts: <i>TAX1BP3</i> Loss Stirs Up TRPV4 Channels in Arrhythmogenic Cardiomyopathy.","authors":"Sandra Ratnavadivel, Afaf Jreije, Farah Sheikh","doi":"10.1161/CIRCRESAHA.124.325502","DOIUrl":"10.1161/CIRCRESAHA.124.325502","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 7","pages":"685-687"},"PeriodicalIF":16.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-Hydroxybutyrate Facilitates Postinfarction Cardiac Repair via Targeting PHD2.","authors":"Cheng Wang, Wenjing Xu, Shushu Jiang, Yichen Wu, Jiangcheng Shu, Xinyuan Gao, Kai Huang","doi":"10.1161/CIRCRESAHA.124.325179","DOIUrl":"10.1161/CIRCRESAHA.124.325179","url":null,"abstract":"<p><strong>Background: </strong>Acute myocardial infarction (MI) remains one of the major causes of death worldwide, and innovative treatment strategies for MI represent a major challenge in cardiovascular medicine. Caloric restriction (CR) is the most potent nonpharmacological intervention known to prevent age-related disorders and extend lifespan. CR reduces glycolysis and elevates ketone body metabolism. However, whether and how CR or ketone body prevents the progression of MI remains poorly defined.</p><p><strong>Methods: </strong>Mice treated with CR and β-hydroxybutyrate (β-OHB) underwent MI induced by ligation of the left anterior descending coronary artery. Cardiac function was assessed by echocardiographic measurements. Histological analysis, fluorescence-activated cell sorting, and immunofluorescence were used to assess myocardial neovascularization and macrophage filtration. The interaction and modification of β-OHB on PHD2 were analyzed by molecular docking, cellular thermal shift assay, liquid chromatography with tandem mass spectrometry, and coimmunoprecipitation. Macrophage-specific PHD2 K239R and K385R knock-in mice were used to determine the functional significance of β-OHB/PHD2 axis in vivo.</p><p><strong>Results: </strong>Twelve weeks of CR markedly rescued postinfarction cardiac function by enhancing neovascularization. CR significantly increased circulating and cardiac ketone bodies, including β-OHB and acetoacetate. We identified β-OHB but not acetoacetate selectively targeted macrophages to stimulate VEGF (vascular endothelial growth factor) production in the peri-infarct area to promote neovascularization and cardiac repair. Mechanistically, β-OHB binds to and induces lysine β-hydroxybutyrylation of PHD2 at lysines 239 and 385, thus blocking its function in the hydroxylation of HIF-1α (hypoxia-inducible factor 1α) and resulting in enhanced HIF1α-dependent VEGF transcription and secretion. More importantly, specific PHD2 lys239 and lys385 mutations in macrophages abolished the preventive effects of exogenous β-OHB on MI in mice.</p><p><strong>Conclusions: </strong>These data reveal a novel regulation of lysine β-hydroxybutyrylation on PHD2 and demonstrate a promising and therapeutic role for β-OHB/PHD2 in effectively accelerating neovascularization and preserving heart function after cardiac ischemia.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"704-718"},"PeriodicalIF":16.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial PPARδ Ablation Exacerbates Vascular Hyperpermeability via STAT1/CXCL10 Signaling in Acute Lung Injury.","authors":"Huiling Hong, Yalan Wu, Yangxian Li, Yumeng Han, Xiaoyun Cao, Vivian Wei Yan Wu, Thomas Ting Hei Chan, Jingying Zhou, Qin Cao, Kathy O Lui, Chun-Kwok Wong, Zhiyu Dai, Xiao Yu Tian","doi":"10.1161/CIRCRESAHA.124.325855","DOIUrl":"10.1161/CIRCRESAHA.124.325855","url":null,"abstract":"<p><strong>Background: </strong>Vascular hyperpermeability is one of the hallmarks of acute lung injury, contributing to excessive inflammation and respiratory failure. The PPARδ (peroxisome proliferator-activated receptor delta) is an anti-inflammatory transcription factor, although its role in endothelial barrier function remains unclear. Here, we studied the essential role of PPARδ in maintaining vascular endothelial barrier integrity during lung inflammation and investigated the underlying mechanisms.</p><p><strong>Methods: </strong>Endothelial cell (EC)-selective PPARδ knockout mice (Ppard^EC-KO) and littermate control mice (Ppard^EC-WT) received lipopolysaccharide injection to induce acute lung injury. Lung inflammation, pulmonary vascular leakage, and mouse mortality were monitored. Single-cell RNA sequencing was performed on sorted mouse lung ECs.</p><p><strong>Results: </strong>Ppard^EC-KO mice exhibited aggravated lung inflammation, characterized by increased leukocyte infiltration, elevated production of proinflammatory cytokines, and higher mortality rates. The enhanced inflammatory responses were associated with increased protein leakage, interstitial edema, and impaired endothelial barrier structure, leading to vascular hyperpermeability in Ppard^EC-KO mice. Mechanistically, with single-cell RNA sequencing, we identified the emergence of an interferon-activated capillary EC population marked by CXCL10 (C-X-C motif chemokine 10) expression following lipopolysaccharide challenge. PPARδ silencing significantly increased CXCL10 expression in ECs through activating STAT1 (Signal transducer and activator of transcription 1). Notably, CXCL10 treatment induced degradation of tight junction proteins ZO-1 (zonula occludens protein 1) and claudin-5 through the ubiquitin-proteasome system, disrupting membrane junction continuity in ECs. Administration of anti-CXCL10 antibody or CXCL10 receptor antagonist AMG487 suppressed both lipopolysaccharide-induced lung inflammation and vascular leakage in Ppard^EC-KO mice.</p><p><strong>Conclusions: </strong>These results highlighted a novel anti-inflammatory role of PPARδ in ECs by suppressing CXCL10-mediating vascular hyperpermeability. Targeting the CXCL10 signaling shows therapeutic potential against vascular injury in acute lung injury.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"735-751"},"PeriodicalIF":16.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>TAX1BP3</i> Causes TRPV4-Mediated Autosomal Recessive Arrhythmogenic Cardiomyopathy.","authors":"Robin M Perelli, Enya R Dewars, Heidi Cope, Alexander S Behura, Anna Q Ponek, Angelina M Sala, Zhushan Zhang, Padmapriya Muralidharan, Mary E Moya-Mendez, Amy Berkman, Gabrielle G Monaco, Molly C Sullivan, Jordan E Ezekian, Qixin Yang, Bo Sun, Leonie M Kurzlechner, Tulsi Asokan, Andrew M Breglio, M Jay Campbell, Zebulon Z Spector, Catherine W Rehder, Paul C Tang, Cynthia A James, Hugh Calkins, Vandana Shashi, Andrew P Landstrom","doi":"10.1161/CIRCRESAHA.124.325180","DOIUrl":"10.1161/CIRCRESAHA.124.325180","url":null,"abstract":"<p><strong>Background: </strong>Arrhythmogenic cardiomyopathy (ACM) is one of the leading causes of sudden cardiac death in children, young adults, and athletes and is characterized by the fibro-fatty replacement of the myocardium, predominantly of the right ventricle. Sixty percent of patients with ACM have a known genetic cause, but for the remainder, the pathogenesis is unknown. This lack of mechanistic understanding has slowed the development of disease-modifying therapies, and children with ACM have a high degree of morbidity and mortality.</p><p><strong>Methods: </strong>Induced pluripotent stem cells (iPSCs) from 3 family members were differentiated into cardiac myocytes (CMs). Calcium imaging was conducted by labeling calcium with CAL-520 and confocal imaging to capture calcium sparks after iPSC-CMs were electrically paced. A cardiac-specific, inducible knockout mouse (<i>Tax1bp3^-/-</i>) was made and intracardiac electrophysiology studies conducted to observe arrhythmia inducibility following pacing.</p><p><strong>Results: </strong>We identified a kindred with multiple members affected by ACM cosegregating with biallelic variants in the gene <i>TAX1BP3</i>, which encodes the protein TAX1BP3 (Tax1-binding protein 3). iPSC-CMs derived from this kindred demonstrated increased intracellular lipid droplets, induction of TRPV4 (transient receptor potential vanilloid type 4) expression, and inducible TRPV4 current. This was associated with depletion of the intracellular sarcoplasmic reticulum Ca²⁺ store and increased RyR2 (ryanodine receptor 2)-mediated store Ca²⁺ leak and delayed afterdepolarizations, a known mechanism of Ca²⁺-mediated arrhythmogenesis. Similarly, <i>Tax1bp3</i> cardiac-specific knockout mice had increased Ca²⁺ leak and were predisposed to ventricular arrhythmias compared with wild-type mice. Ca²⁺ leak in both the iPSC-CMs and mouse ventricular myocytes was rescued by small molecule TRPV4 inhibition. This strategy also effectively reduced Ca²⁺ leak in a PKP2 (plakophilin 2) p.His773AlafsX8 iPSC-CM model of ACM.</p><p><strong>Conclusions: </strong>We conclude that <i>TAX1BP3</i> is associated with rare autosomal recessive ACM through TRPV4-mediated Ca²⁺ leak from RyR2. Further, TRPV4 current inhibition has the potential to be a new therapeutic target for ACM.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"667-684"},"PeriodicalIF":16.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiomic Analysis of Calf Muscle in Peripheral Artery Disease and Chronic Kidney Disease.","authors":"Kyoungrae Kim, Trace Thome, Caroline Pass, Lauren Stone, Nicholas Vugman, Victoria Palzkill, Qingping Yang, Kerri A O'Malley, Erik M Anderson, Brian Fazzone, Feng Yue, Scott A Berceli, Salvatore T Scali, Terence E Ryan","doi":"10.1161/CIRCRESAHA.124.325642","DOIUrl":"10.1161/CIRCRESAHA.124.325642","url":null,"abstract":"<p><strong>Background: </strong>Chronic kidney disease (CKD) has emerged as a significant risk factor that accelerates atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the modulators underlying this exacerbated pathobiology are ill-defined. Recent work has demonstrated that uremic toxins are associated with limb amputation in PAD and have pathological effects in both the limb muscle and vasculature. Herein, we use multiomics to identify novel modulators of disease pathobiology in patients with PAD and CKD.</p><p><strong>Methods: </strong>A cross-sectional study enrolled 4 groups of participants: controls without PAD or CKD (n=28), patients with PAD only (n=46), patients with CKD only (n=31), and patients with both PAD and CKD (n=18). Both targeted (uremic toxins) and nontargeted metabolomics in plasma were performed using mass spectrometry. Calf muscle biopsies were used to measure histopathology, perform bulk and single-nucleus RNA sequencing, and assess mitochondrial function. Differential gene and metabolite analyses, as well as pathway and gene set enrichment analyses, were performed.</p><p><strong>Results: </strong>Patients with both PAD and CKD exhibited significantly lower calf muscle strength and smaller muscle fiber areas compared with controls and those with only PAD. Compared with controls, mitochondrial function was impaired in patients with CKD, with or without PAD, but not in PAD patients without CKD. Plasma metabolomics revealed substantial alterations in the metabolome of patients with CKD, with significant correlations observed between uremic toxins (eg, kynurenine and indoxyl sulfate) and both muscle strength and mitochondrial function. RNA sequencing analyses identified downregulation of mitochondrial genes and pathways associated with protein translation in patients with both PAD and CKD. Single-nucleus RNA sequencing further highlighted a mitochondrial deficiency in muscle fibers along with unique remodeling of fibro-adipogenic progenitor cells in patients with both PAD and CKD, with an increase in adipogenic cell populations.</p><p><strong>Conclusions: </strong>CKD significantly exacerbates ischemic muscle pathology in PAD, as evidenced by diminished muscle strength, reduced mitochondrial function, and altered transcriptome profiles. The correlation between uremic toxins and muscle dysfunction suggests that targeting these metabolites may offer therapeutic potential for improving muscle health in PAD patients with CKD.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"688-703"},"PeriodicalIF":16.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440054","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":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000712","DOIUrl":"https://doi.org/10.1161/RES.0000000000000712","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 7","pages":"643-644"},"PeriodicalIF":16.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728983","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":"Correction to: LncRNA PSR Regulates Vascular Remodeling Through Encoding a Novel Protein Arteridin.","authors":"Junyi Yu, Wei Wang, Jining Yang, Ye Zhang, Xue Gong, Hao Luo, Nian Cao, Zaicheng Xu, Miao Tian, Peili Yang, Qiao Mei, Zhi Chen, Zhuxin Li, Chuanwei Li, Xudong Duan, Qing Rex Lyu, Chen Gao, Bing Zhang, Yibin Wang, Gengze Wu, Chunyu Zeng","doi":"10.1161/RES.0000000000000711","DOIUrl":"https://doi.org/10.1161/RES.0000000000000711","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 7","pages":"e52"},"PeriodicalIF":16.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728981","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":"Stop Me at Your Own PeRiL: PRL2 Constrains AMPK in the Pressure-Overloaded Heart.","authors":"Edoardo Bertero, Alessandra Ghigo, Pietro Ameri","doi":"10.1161/CIRCRESAHA.124.325806","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.325806","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 7","pages":"664-666"},"PeriodicalIF":16.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728984","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":"MAIT Cells Promote Cholesterol Excretion Pathways Mitigating Atherosclerosis.","authors":"Hua Wang, Pukar K C, Kaidi Zhang, Clément Materne, Marie Lhomme, Sophie Galier, Farid Ichou, Carolina Neves, Agnes Lehuen, Joel T Haas, Joe-Elie Salem, Maryse Guerin, Philippe Lesnik","doi":"10.1161/CIRCRESAHA.124.325841","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.325841","url":null,"abstract":"<p><strong>Background: </strong>Previous clinical studies have indicated reduced circulating mucosal-associated invariant T (MAIT) cells in individuals with coronary artery disease. However, the precise role and underlying mechanisms of MAIT cells in this context remain unclear. Immune homeostasis plays a pivotal role in the development of atherosclerosis. This study explores the impact of MAIT cells on atherosclerosis.</p><p><strong>Methods: </strong>Vα19^+/- Ldlr^-/- mice, characterized by a high MAIT cell frequency, and MAIT cell deficient MR1^-/- (major histocompatibility complex-related molecule 1) Ldlr^-/- mice and their respective controls were used. Starting at 6 weeks of age, mice were subjected to a 1% cholesterol diet for 16 weeks. Additionally, the study analyzed circulating MAIT cell frequency and cholesterol levels in 68 patients with hypercholesterolemia.</p><p><strong>Results: </strong>In Vα19^+/- Ldlr^-/- mice, increased MAIT cells demonstrated a protective effect against atherosclerosis by reducing VLDL-C (very-low-density lipoprotein cholesterol) levels through heightened cholesterol excretion. This effect was accompanied by elevated jejunal ABCB1a, ABCG5, and ABCG8 expression, mediated by augmented levels of LXR transcription and activation, likely through intestinal IL-22 (interleukin-22) signaling. Conversely, cholesterol reduction mediated by intestinal cholesterol excretion was blocked by inhibition of MAIT cells. Moreover, MAIT cell-deficient MR1^-/- Ldlr^-/- mice exhibited elevated total cholesterol levels and increased atherosclerotic lesions. In patients with hypercholesterolemia, circulating MAIT cell frequency displayed negative correlations with VLDL-C levels and positive correlations with HDL-C (high-density lipoprotein cholesterol) levels.</p><p><strong>Conclusions: </strong>Our findings demonstrate a new mechanism for plasma VLDL-C clearance by MAIT cell-mediated cholesterol excretion. The results provide further evidence that immunity is involved in cholesterol homeostasis. Targeting intestinal immunity to regulate cholesterol homeostasis holds promise as a new cholesterol-lowering modality to prevent atherosclerotic cardiovascular disease.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":16.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708823","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":"Local DIO2 Elevation Is an Adaption in Malformed Cerebrovasculature.","authors":"Ruofei Li, Yushan Tang, Haiyue Wang, Pengyan Hu, Liang Yu, Cheng Lv, Yu Zhang, A Martin Gerdes, Yibo Wang","doi":"10.1161/CIRCRESAHA.124.325857","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.325857","url":null,"abstract":"<p><strong>Background: </strong>Cerebrovascular malformations are a pivotal cause of hemorrhage and neurological disability alongside lacking effective medication. Thyroid hormones (THs), including thyroxine and triiodothyronine, are essential for vascular development, yet whether they participate in malformed cerebrovascular pathology remains elusive.</p><p><strong>Methods: </strong>Single-cell transcriptome analysis characterized human cerebral cavernous malformations and brain arteriovenous malformations, 2 typical cerebrovascular malformation diseases. Adeno-associated virus-mediated DIO2 (iodothyronine deiodinase 2; an enzyme that converts thyroxine to active triiodothyronine) overexpression/knockdown or triiodothyronine/methimazole (an antithyroid drug) treatment was applied to mouse models of cerebral cavernous malformations (endothelial-specific <i>Pdcd10</i> knockout mice, <i>Pdcd10</i> KO) and brain arteriovenous malformations (endothelial-specific <i>Kras</i>^<i>G12D</i> mutant mice, <i>Kras</i>^<i>G12D</i>) to evaluate the involvement of DIO2 and TH signaling in cerebrovascular malformations.</p><p><strong>Results: </strong>TH signaling was markedly activated in fibroblasts of human cerebral cavernous malformation and arteriovenous malformation single-cell samples, accompanied by elevated DIO2 expression. Similar DIO2 upregulation was observed in cerebrovascular fibroblasts of <i>Pdcd10</i> KO/<i>Kras</i>^<i>G12D</i> mice and patient brain sections. Exogenous DIO2 or triiodothyronine replenishment effectively reduced brain hemorrhage, excessive ECM (extracellular matrix) remodeling, and vascular leakage in juvenile and adult male and female <i>Pdcd10</i> KO/<i>Kras</i>^<i>G12D</i> mice. In contrast, DIO2 silencing or TH inhibition deteriorated vascular anomalies. Mechanistically, transcription factor Foxk1 (forkhead box K1) was determined to interact with the <i>DIO2</i> promoter region. The activation of fibroblast PI3K-Akt-mTOR signaling in <i>Pdcd10</i> KO/<i>Kras</i>^<i>G12D</i> mice triggered Foxk1 nuclear translocation to promote <i>DIO2</i> transcription. Triiodothyronine treatment mitigated inflammatory infiltration, normalized mitochondrial morphology, and restored mitochondrial biogenesis in malformed brain vessels by activating the Pgc1a (peroxisome proliferator-activated receptor gamma coactivator 1-alpha)-Sod2 (superoxide dismutase 2)/Prdx3 (peroxiredoxin 3)/Gpx1 (glutathione peroxidase 1) axis to reduce reactive oxygen species accumulation. We also determined that the vascular repair effects of triiodothyronine were Pgc1a-dependent.</p><p><strong>Conclusions: </strong>We delineate a novel DIO2-mediated adaption in malformed cerebrovasculature and conclude that targeting TH signaling may represent a potential therapy for cerebrovascular disorders.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":16.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699884","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}