Circulation research最新文献

{"title":"Calprotectin Accelerates Pathogenic Calciprotein Particle Maturation to Promote Vascular Calcification in Chronic Kidney Disease.","authors":"Jingxuan Zhang, Tomoko Kanki, Masayuki Tsushida, Hirotaka Komaba, Ryosuke Date, Daisuke Fujimoto, Yutaka Kakizoe, Yuichiro Izumi, Masataka Adachi, Masashi Mukoyama, Hideki Yokoi, Takashige Kuwabara","doi":"10.1161/CIRCRESAHA.126.328252","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.126.328252","url":null,"abstract":"<p><strong>Background: </strong>Vascular calcification is a hallmark of chronic kidney disease (CKD)-mineral and bone disorder and a major determinant of cardiovascular mortality. Secondary calciprotein particles (CPP2) are key mediators of vascular calcification; however, the mechanisms regulating their maturation and pathogenic properties remain incompletely understood. CPT (Calprotectin, S100A8/A9), a myeloid-derived inflammatory mediator, is elevated in CKD and predicts cardiovascular events and mortality, particularly under high-phosphate conditions, but the underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>We investigated the role of CPT in vascular calcification using CKD-mineral and bone disorder mice with myeloid-specific CPT deletion. Aortic calcification was assessed by ex vivo imaging, histology, and calcium quantification. Serum calciprotein particle (CPP) fractions were determined by flow cytometry. Mechanistic studies were performed in vascular smooth muscle cells exposed to CPP2 in the presence or absence of macrophage-derived CPT. Calcification propensity was evaluated using the T50 assay, and CPP2 elemental composition was analyzed by high-angle annular dark-field scanning transmission electron microscopy-energy-dispersive X-ray spectroscopy.</p><p><strong>Results: </strong>Myeloid-specific CPT deletion significantly attenuated aortic calcification and osteogenic gene expression in CKD-mineral and bone disorder mice without altering renal function or systemic mineral parameters. These changes were accompanied by an increased circulating immature CPP fraction. Macrophage-derived CPT markedly enhanced CPP2-induced vascular smooth muscle cell calcification by accelerating CPP maturation, reflected by a shortened T50, and by altering CPP2 composition to be enriched in calcium and phosphate. Although no direct interaction between CPT and CPPs was detected, CPT modified the physicochemical milieu, including ionized calcium and pH. Consistently, CPP2 from CPT-deficient serum exhibited substantially reduced calcification potency, indicating that CPT shapes CPP pathogenicity by modulating particle quality rather than quantity. Importantly, CPT-mediated CPP maturation occurred in a cell-free milieu, indicating a TLR4-independent mechanism distinct from its known receptor-mediated actions.</p><p><strong>Conclusions: </strong>CPT is a previously unrecognized regulator of pathogenic CPP maturation and composition, thereby promoting vascular calcification in CKD-mineral and bone disorder. Targeting CPT may represent a novel therapeutic strategy to attenuate vascular calcification in CKD.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164739","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":"Splicing the Hypertrophic Heart: MBNL2, Tropomyosin, and Mitochondrial Stress.","authors":"Edoardo Bertero, Vasco Sequeira","doi":"10.1161/CIRCRESAHA.126.329604","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.126.329604","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"139 9","pages":"e329604"},"PeriodicalIF":18.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135058","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":"Inducing CD8⁺ Tregs Limits Atherosclerosis via Notch-Mediated VSMC Quiescence.","authors":"Wentao Gao, Yangfeng Hou, Jiaxing Liu, Cheng Kiu Ho, Alfred Sze-Lok Cheng, Herman Waldmann, Bin Zhou, James Y W Lau, Kathy O Lui","doi":"10.1161/CIRCRESAHA.126.328918","DOIUrl":"10.1161/CIRCRESAHA.126.328918","url":null,"abstract":"<p><strong>Background: </strong>CD8⁺ (cluster of differentiation 8) T cells contribute to atherosclerosis, but how they affect VSMCs (vascular smooth muscle cells) is unclear. The protective role of CD8⁺ regulatory T cells (Tregs) and in vivo induction strategies also remain undefined.</p><p><strong>Methods: </strong>We analyzed human atherosclerosis single-cell RNA sequencing to map immune-VSMC communication. Atherosclerosis was modeled in adeno-associated virus-<i>Pcsk9</i> or <i>Apoe</i>^<i>-/-</i> mice. CD8⁺ T-cell activity was modulated by adoptive transfer of CD45.1⁺CD8⁺ T cells into syngeneic CD45.2⁺ <i>Apoe</i>^<i>-/-</i> recipients (gain-of-function) or nonlytic anti-CD8α antibodies (loss-of-function). VSMC-specific Notch loss was tested in <i>Myh11</i>^<i>CreER</i><i>;Rbpj</i>^<i>fl/fl</i><i>;Apoe</i>^<i>-/-</i> mice. Ligand-receptor interactions were perturbed with neutralizing antibodies. Lineage tracing was performed using <i>Myh11</i>^<i>CreER</i><i>;Rosa26</i>^<i>YFP</i><i>;Apoe</i>^<i>-/-</i> mice. CD8⁺CD44⁺CD122⁺ Tregs were adoptively transferred to assess therapeutic potential. Transcription factor chromatin immunoprecipitation sequencing (ChIP-seq) was used to define VSMC gene regulation.</p><p><strong>Results: </strong>CD8⁺ T cells are the dominant immune partners communicating with VSMCs via CD8α in human plaques. Transferred CD8⁺ T cells localize to the media and inhibit VSMC Notch signaling. VSMC Notch ablation accelerates atherosclerosis, enhancing VSMC proliferation, inflammation, and phenotypic switching. CD8α blockade induces CD8⁺CD44⁺CD122⁺ Tregs, which, partly via IL-10 (interleukin-10), activate VSMC Notch, suppress proliferation, and limit VSMC-to-macrophage transdifferentiation. These Tregs express higher Notch ligands than conventional CD8⁺ T cells and decline with a high-cholesterol diet. Their adoptive transfer slows atherosclerosis progression. Blocking Notch1-Jag2 (Jagged 2), or synergistically blocking DLL1/4 (delta-like ligand 1/4) and Jag1/2, negates Treg protection. Mechanistically, Notch-RBPJ (recombination signal binding protein for immunoglobulin kappa J region) activates <i>Hes1</i> (<i>hairy and enhancer of split 1</i>), which suppresses <i>Klf4</i> (<i>Krüppel-like factor 4</i>) and <i>Rel</i> via Hes1/EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit)-mediated trimethylation of histone H3 at lysine 27 (H3K27me3).</p><p><strong>Conclusions: </strong>CD8⁺ T cells promote atherosclerosis by inhibiting VSMC Notch; CD8⁺CD44⁺CD122⁺ Tregs restore Notch, preserve VSMC quiescence, and stabilize plaques. The CD8⁺ Treg-Notch axis is a novel and promising therapeutic target against atherosclerosis.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e328918"},"PeriodicalIF":18.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910833","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":"Big Job for the Small Titin: Don't Underestimate the \"Little\" Guy.","authors":"Michaela M Door, Jonathan A Kirk","doi":"10.1161/CIRCRESAHA.126.329603","DOIUrl":"10.1161/CIRCRESAHA.126.329603","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"139 9","pages":"e329603"},"PeriodicalIF":18.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134956","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":"Nx3 Is a Z-Disk Structural and Signaling Hub That Is Reduced in Heart Failure.","authors":"Wolfgang A Linke, Lisa Kümper, Andrey Fomin, Isabel Martin, Nadezda Ignatyeva, Ken Hashimoto, Clemens G Mohr, Josefine Bässler, Anna Gärtner, Momoko Ohira, Akira Hanashima, Annika J Klotz, Kai Schiffer, Tobias Voelkel, Johanna K Freundt, Anna Hucke, Franziska Koser, Tao Zhang, Anastasia J Hobbach, Ian A Glass, Jan F Gummert, Cristobal G Dos Remedios, Sebastiaan van Heesch, Jorge Ruiz-Orera, Satoshi Mohri, Norbert Hubner, Michael Regnier, Hendrik Milting, Olga Mayans, Andreas Unger, Antje Ebert","doi":"10.1161/CIRCRESAHA.125.327786","DOIUrl":"10.1161/CIRCRESAHA.125.327786","url":null,"abstract":"<p><strong>Background: </strong>Nx3 (novex-3) is an exceptionally small isoform of the giant protein titin, whose structural and functional roles within the sarcomere remain poorly understood.</p><p><strong>Methods: </strong>We used a comprehensive, multimodal approach to define the key properties of Nx3 in healthy and failing hearts, including its abundance relative to FLT (full-length titin), sarcomeric localization, protein interactions, and functional relevance in mouse and human cardiomyocytes under physiological and pathological conditions. Using Western blotting, quantitative polymerase chain reaction, total RNA sequencing, and ribosome profiling, we show that Nx3 is constitutively expressed from fetal development through adulthood.</p><p><strong>Results: </strong>In adult mouse and human myocardium, Nx3 accounts for ≈20% to 25% of total titin protein, despite representing only ≈8% to 14% at the transcript level. Immunoelectron microscopy and binding studies reveal that Nx3 adopts a nonlinear configuration within the sarcomere: its N terminus is anchored at the Z-disk, although the proximal portion of its unique region encoded by <i>Ttn</i> exon 48, enriched in coiled-coil motifs, engages laterally with adjacent titin or Nx3 molecules at the Z-disk/I-band interface. Its monomeric C terminus extends toward the A-band but remains confined to the Z-/I-band region. This architecture confers enhanced stability and flexibility to the Z-disk under mechanical load. Protein interaction studies, including yeast 2-hybrid screening and coimmunoprecipitation, identified Pin1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) and TBC1D4 (TBC1 domain family member 4) as binding partners of the Nx3 C terminal region, suggesting participation in signaling networks regulating cardiomyocyte metabolism. Genetic ablation of Nx3 in mouse hearts and human induced pluripotent stem cell-derived cardiomyocytes indicates that, although dispensable for sarcomere assembly, Nx3 is required for optimal Z-disk organization and mechanical performance. In end-stage dilated cardiomyopathy, human hearts exhibit dysregulated Nx3 expression, with reduced protein abundance relative to nonfailing controls and focal Z-disk disruption, likely contributing to impaired contractile function.</p><p><strong>Conclusions: </strong>Nx3 regulates Z-disk stability and modulates signaling pathways that optimize cardiac performance, and its dysregulation contributes to heart failure pathogenesis.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e327786"},"PeriodicalIF":18.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918607","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":"Metabolic Insights Into Dynamic Glucose Trajectories: Importance of Perturbation.","authors":"Frank Qian, Matthew Nayor, Ravi V Shah","doi":"10.1161/CIRCRESAHA.126.329600","DOIUrl":"10.1161/CIRCRESAHA.126.329600","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"139 9","pages":"e329600"},"PeriodicalIF":18.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135099","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":"Novel Calcium Channel Modulator Ameliorates Hypertrophic Cardiomyopathy.","authors":"Teagan S Er, Daniel Reinke, Henrietta Cserne Szappanos, Alice J Francis, Caitlyn M Richworth, Padmapriya Ponnuswamy, Juan E Camacho Londoño, Livia C Hool","doi":"10.1161/CIRCRESAHA.126.329377","DOIUrl":"10.1161/CIRCRESAHA.126.329377","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e329377"},"PeriodicalIF":18.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988077","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":"Mechanosensitive Stanniocalcin-1 Suppresses Smooth Muscle Cell Proliferation and Attenuates Experimental Pulmonary Hypertension.","authors":"Mariko Kogami, Yuko Kato, Satoko Ito, Keiko Uchida, Hana Inoue, Yuko Hidaka, Shota Tanifuji, Mayumi Yokotsuka, Yoshinari Yamamoto, Toshitaka Nagao, Shinji Abe, Roger R Reddel, Kazufumi Nakamura, Utako Yokoyama","doi":"10.1161/CIRCRESAHA.125.327869","DOIUrl":"10.1161/CIRCRESAHA.125.327869","url":null,"abstract":"<p><strong>Background: </strong>Idiopathic pulmonary arterial hypertension (IPAH) is driven by progressive vascular remodeling, particularly smooth muscle cell (SMC) proliferation. Current combination vasodilator therapies have markedly improved outcomes; however, prognosis remains poor in subgroups such as patients with respiratory comorbidities. Elevation of intravascular hydrostatic pressure is a hallmark of IPAH, yet its direct role in pulmonary artery SMCs remains unclear. We aimed to identify pressure-responsive mediators using a newly developed hydrostatic pressurization system to model hypertensive hemodynamics.</p><p><strong>Methods: </strong>Pulmonary artery SMCs from 4 patients with IPAH were exposed to high hydrostatic pressure (70/40 mm Hg, 60 bpm). Transcriptomic profiling identified differentially expressed genes, which were validated by quantitative polymerase chain reaction. Functional studies included PIEZO1 (piezo type mechanosensitive ion channel component 1) modulation, rhSTC1 (recombinant human stanniocalcin-1) treatment, bromodeoxyuridine incorporation, and Western blotting for cell-cycle regulators. Chronic hypoxia-induced pulmonary hypertension was assessed in wild-type and <i>Stc1</i>^-/- mice by hemodynamic and histological analyses, with or without intratracheal rhSTC1 administration.</p><p><strong>Results: </strong>RNA sequencing revealed <i>STC1</i> to be a pressure-induced gene in IPAH SMCs. PIEZO1 activation upregulated <i>STC1</i>, whereas knockdown blunted this response. <i>STC1</i> was upregulated in IPAH lungs, while rhSTC1 reduced pulmonary arterial SMC proliferation and increased p-p53, p21, and p27 expression. <i>Stc1</i>^-/- mice under hypoxia exhibited significantly higher right ventricular systolic pressure and greater pulmonary arterial medial thickness than wild-type mice. CD68-positive macrophages were increased in <i>Stc1</i>^-/- mice under normoxia and further elevated with hypoxia. Intratracheal administration of rhSTC1 attenuated PAH in wild-type and <i>Stc1</i>^-/- mice.</p><p><strong>Conclusions: </strong>Elevated hydrostatic pressure drives <i>STC1</i> expression via PIEZO1, suggesting an adaptive but insufficient protective response in IPAH. Modulation of STC1 (stanniocalcin-1) may represent a potential therapeutic approach.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e327869"},"PeriodicalIF":18.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910862","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":"Cardio-Immunologic Dissection of Myocardial Infarction After CMV Infection.","authors":"Marco Cremonesi, Marinos Kallikourdis","doi":"10.1161/CIRCRESAHA.126.329684","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.126.329684","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"139 9","pages":"e329684"},"PeriodicalIF":18.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135065","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":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000771","DOIUrl":"https://doi.org/10.1161/RES.0000000000000771","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"139 9","pages":"e000771"},"PeriodicalIF":18.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135091","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}