Circulation research最新文献

{"title":"Targeting Endothelial Cell Mitochondrial Quality Control in PAH.","authors":"Mahin Gadkari,Karthik Suresh","doi":"10.1161/circresaha.124.325940","DOIUrl":"https://doi.org/10.1161/circresaha.124.325940","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"37 1","pages":"209-210"},"PeriodicalIF":20.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988666","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":"Heart to Heal: Unveiling Follistatin's Potential for Myocardial Regeneration.","authors":"Alessia Costa,Christian Bär","doi":"10.1161/circresaha.124.325939","DOIUrl":"https://doi.org/10.1161/circresaha.124.325939","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"4 1","pages":"177-179"},"PeriodicalIF":20.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988664","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":"Epigenetic Regulation of Innate and Adaptive Immune Cells in Salt-Sensitive Hypertension.","authors":"Ashley L Mutchler,Alexandria Porcia Haynes,Mohammad Saleem,Sydney Jamison,Mohd Mabood Khan,Lale Ertuglu,Annet Kirabo","doi":"10.1161/circresaha.124.325439","DOIUrl":"https://doi.org/10.1161/circresaha.124.325439","url":null,"abstract":"Access to excess dietary sodium has heightened the risk of cardiovascular diseases, particularly affecting individuals with salt sensitivity of blood pressure. Our research indicates that innate antigen-presenting immune cells contribute to rapid blood pressure increases in response to excess sodium intake. Emerging evidence suggests that epigenetic reprogramming, with subsequent transcriptional and metabolic changes, of innate immune cells allows these cells to have a sustained response to repetitive stimuli. Epigenetic mechanisms also steer T-cell differentiation in response to innate immune signaling. Immune cells respond to environmental and nutritional cues, such as salt, promoting epigenetic regulation changes. This article aims to identify and discuss the role of epigenetic mechanisms in the immune system contributing to salt-sensitive hypertension.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"1 1","pages":"232-254"},"PeriodicalIF":20.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988720","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 Vaccine Against Fibroblast Activation Protein Improves Murine Cardiac Fibrosis by Preventing the Accumulation of Myofibroblasts.","authors":"Shota Yoshida, Hiroki Hayashi, Takuro Kawahara, Shunsuke Katsuki, Mitsukuni Kimura, Rissei Hino, Jiao Sun, Ryo Nakamaru, Akiko Tenma, Masayoshi Toyoura, Satoshi Baba, Munehisa Shimamura, Tomohiro Katsuya, Ryuichi Morishita, Hiromi Rakugi, Tetsuya Matoba, Hironori Nakagami","doi":"10.1161/CIRCRESAHA.124.325017","DOIUrl":"10.1161/CIRCRESAHA.124.325017","url":null,"abstract":"<p><strong>Background: </strong>Myofibroblasts are primary cells involved in chronic response-induced cardiac fibrosis. Fibroblast activation protein (FAP) is a relatively specific marker of activated myofibroblasts and a potential target molecule. This study aimed to clarify whether a vaccine targeting FAP could eliminate myofibroblasts in chronic cardiac stress model mice and reduce cardiac fibrosis.</p><p><strong>Methods: </strong>We coadministered a FAP peptide vaccine with a cytosine-phosphate-guanine (CpG) K3 oligonucleotide adjuvant to male C57/BL6J mice and confirmed an elevation in the anti-FAP antibody titer. After continuous angiotensin II and phenylephrine administration for 28 days, we evaluated the degree of cardiac fibrosis and the number of myofibroblasts in cardiac tissues.</p><p><strong>Results: </strong>We found that cardiac fibrosis was significantly decreased in the FAP-vaccinated mice compared with the angiotensin II and phenylephrine control mice (3.45±1.11% versus 8.62±4.79%; <i>P</i>=4.59×10^-3) and that the accumulation of FAP-positive cells was also significantly decreased, as indicated by FAP immunohistochemical staining (4077±1746 versus 7327±1741 cells/mm²; FAP vaccine versus angiotensin II and phenylephrine control; <i>P</i>=6.67×10^-3). No systemic or organ-specific inflammation due to antibody-dependent cell cytotoxicity induced by the FAP vaccine was observed. Although the transient activation of myofibroblasts has an important role in maintaining the structural robustness in the process of tissue repair, the FAP vaccine showed no adverse effects in myocardial infarction and skin injury models.</p><p><strong>Conclusions: </strong>Our study demonstrates the FAP vaccine can be a therapeutic tool for cardiac fibrosis.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"26-40"},"PeriodicalIF":16.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11692786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766658","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":"Editors and Editorial Board.","authors":"","doi":"10.1161/RES.0000000000000706","DOIUrl":"https://doi.org/10.1161/RES.0000000000000706","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 1","pages":"1"},"PeriodicalIF":16.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920956","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":"Targeting Cardiac Fibrosis With a Vaccine Against Fibroblast Activation Protein.","authors":"William M Oldham","doi":"10.1161/CIRCRESAHA.124.325804","DOIUrl":"10.1161/CIRCRESAHA.124.325804","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 1","pages":"41-43"},"PeriodicalIF":16.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11698487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920959","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":"Transcription Factor 21 Regulates Cardiac Myofibroblast Formation and Fibrosis.","authors":"Anne Katrine Z Johansen, Rajesh K Kasam, Ronald J Vagnozzi, Suh-Chin J Lin, Jose Gomez-Arroyo, Adenike Shittu, Stephanie L K Bowers, Yasuhide Kuwabara, Kelly M Grimes, Kathrynne Warrick, Michelle A Sargent, Tanya A Baldwin, Susan E Quaggin, Artem Barski, Jeffery D Molkentin","doi":"10.1161/CIRCRESAHA.124.325527","DOIUrl":"10.1161/CIRCRESAHA.124.325527","url":null,"abstract":"<p><strong>Background: </strong>TCF21 (transcription factor 21) is a bHLH (basic helix-loop-helix) protein required for the developmental specification of cardiac fibroblasts (CFs) from epicardial progenitor cells that surround the embryonic heart. In the adult heart, TCF21 is expressed in tissue-resident fibroblasts and is downregulated in response to injury or stimuli leading to myofibroblast differentiation. These findings led to the hypothesis that TCF21 regulates fibroblast differentiation in the adult mammalian heart to affect fibrosis.</p><p><strong>Methods: </strong>Tamoxifen-inducible Cre genetic mouse models were used to permit either <i>Tcf21</i> gene deletion or its enforced expression in adult CFs. Histological and echocardiographic analyses were used, as well as transcriptomic analysis to determine the consequences of TCF21 gain-of-function and loss-of-function in vivo. Genomic <i>Tcf21</i> occupancy was identified by chromatin immunoprecipitation and sequencing in CFs. Myocardial infarction and AngII (angiotensin II)/phenylephrine served as models of cardiac fibrosis.</p><p><strong>Results: </strong>Acute and long-term deletion of <i>Tcf21</i> in CFs of the adult mouse heart does not alter fibroblast numbers, myofibroblast differentiation, or fibrosis. Fibroblast-specific <i>Tcf21</i> gene-deleted mice demonstrate no significant alterations in cardiac function or scar formation in response to cardiac injury compared with control mice. In contrast, enforced expression of TCF21 in CFs inhibits myofibroblast differentiation and significantly reduces cardiac fibrosis and hypertrophy in response to 1 week of Ang II/phenylephrine infusion. Mechanistically, sustained TCF21 expression prevents the induction of genes associated with fibrosis and ECM (extracellular matrix) organization.</p><p><strong>Conclusions: </strong>TCF21 expression is not required to maintain the cell state of CFs in the adult heart. However, preventing the normal downregulation of TCF21 expression with injury reduces myofibroblast formation, cardiac fibrosis, and the acute cardiac hypertrophic response following 1 week of Ang II/phenylephrine stimulation.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"44-58"},"PeriodicalIF":16.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766663","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":"Loss of the Endothelial Glycocalyx Component EMCN Leads to Glomerular Impairment.","authors":"Zhengping Hu, Issahy Cano, Fengyang Lei, Jie Liu, Ramon Bossardi Ramos, Harper Gordon, Eleftherios I Paschalis, Magali Saint-Geniez, Yin Shan Eric Ng, Patricia A D'Amore","doi":"10.1161/CIRCRESAHA.124.325218","DOIUrl":"10.1161/CIRCRESAHA.124.325218","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;EMCN (endomucin), an endothelial-specific glycocalyx component, was found to be highly expressed by the endothelium of the renal glomerulus. We reported an anti-inflammatory role of EMCN and its involvement in the regulation of VEGF (vascular endothelial growth factor) activity through modulating VEGFR2 (VEGF receptor 2) endocytosis. The goal of this study is to investigate the phenotypic and functional effects of EMCN deficiency using the first global EMCN knockout mouse model.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Global EMCN knockout mice were generated by crossing EMCN-floxed mice with ROSA26-Cre mice. Flow cytometry was used to analyze infiltrating myeloid cells in the kidneys. The ultrastructure of the glomerular filtration barrier was examined by transmission electron microscopy, whereas urinary albumin, creatinine, and total protein levels were analyzed from freshly collected urine samples. Expression and localization of EMCN, EGFP (enhanced green fluorescent protein), CD45 (cluster of differentiation 45), CD31, CD34, podocin, and albumin were examined by immunohistochemistry. Mice were weighed regularly, and their systemic blood pressure was measured using a noninvasive tail-cuff system. Glomerular endothelial cells and podocytes were isolated by fluorescence-activated cell sorting for RNA sequencing. Transcriptional profiles were analyzed to identify differentially expressed genes in both endothelium and podocytes, followed by gene ontology analysis. Protein levels of EMCN, albumin, and podocin were quantified by Western blot.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The EMCN&lt;sup&gt;-/-&lt;/sup&gt; mice exhibited increased infiltration of CD45&lt;sup&gt;+&lt;/sup&gt; cells, with an increased proportion of Ly6G&lt;sup&gt;high&lt;/sup&gt;Ly6C&lt;sup&gt;high&lt;/sup&gt; myeloid cells and higher VCAM-1 (vascular cell adhesion molecule 1) expression. EMCN&lt;sup&gt;-/-&lt;/sup&gt; mice displayed albuminuria with increased albumin in the Bowman's space compared with the EMCN&lt;sup&gt;+/+&lt;/sup&gt; littermates. Glomeruli in EMCN&lt;sup&gt;-/-&lt;/sup&gt; mice revealed fused and effaced podocyte foot processes and disorganized endothelial fenestrations. We found no significant difference in blood pressure between EMCN knockout mice and their wild-type littermates. RNA sequencing of glomerular endothelial cells revealed downregulation of cell-cell adhesion and MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) pathways, along with glycocalyx and extracellular matrix remodeling. In podocytes, we observed reduced VEGF signaling and alterations in cytoskeletal organization. Notably, there was a significant decrease in both mRNA and protein levels of podocin, a key component of the slit diaphragm.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Our study demonstrates a critical role of the endothelial marker EMCN in supporting normal glomerular filtration barrier structure and function by maintaining glomerular endothelial tight junction and homeostasis and podocyte function through endoth","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"59-74"},"PeriodicalIF":16.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11692785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709441","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":"Autoimmune-Like Mechanism in Heart Failure Enables Preventive Vaccine Therapy.","authors":"Elisa Martini, Marco Cremonesi, Arianna Felicetta, Simone Serio, Simone Puccio, Erica Pelamatti, Jasper J P van Beek, Vasiliki Papadopoulou, Chiara Catalano, Francesca Fanuele, Desirée Giuliano, Gianluca Basso, Cecilia Assunta Bonfiglio, Cristina Panico, Marco Vacchiano, Pierluigi Carullo, Laura Papa, Carla D'Andrea, Naz Tuzger, Sergio Marchini, Paola Magistroni, Silvia Deaglio, Antonio Amoroso, Enrico Lugli, Gianluigi Condorelli, Marinos Kallikourdis","doi":"10.1161/CIRCRESAHA.124.324999","DOIUrl":"10.1161/CIRCRESAHA.124.324999","url":null,"abstract":"<p><strong>Background: </strong>Heart failure (HF) is strongly associated with inflammation. In pressure overload (PO)-induced HF, cardiac stress triggers adaptive immunity, ablation or inhibition of which blocks disease progression. We hypothesized that PO-HF might fulfill the often-used criteria of autoimmunity: if so, the associated adaptive immune response would be not only necessary but also sufficient to induce HF; it should also be possible to identify self-antigens driving the autoimmune response. Finally, we hypothesized that such an antigen-specific response can be manipulated to preventively reduce the severity of PO-HF in a tolerizing vaccine.</p><p><strong>Methods: </strong>We used the transfer of lymphocytes or serum from PO-HF mice into healthy recipients to assess whether the adaptive response is sufficient to induce disease. We devised a novel pipeline to identify self-antigens driving the response. We immunized healthy mice with novel antigens to assess whether they induce disease. To determine whether these antigens could be present in human patients, we sought to detect existing responses against these antigens in patients with HF. Finally, we used the antigens in an oral tolerance protocol to preventively protect mice from subsequently induced PO-HF, analyzing the results with next-generation sequencing.</p><p><strong>Results: </strong>We found that PO-HF fulfills the criteria of an autoimmune disease, albeit partially, and identified novel cardiac self-antigens, capable of inducing cardiac dysfunction. The novel antigens in a tolerizing vaccine formulation preemptively reduced the severity of disease triggered by subsequent application of PO, via induction of effector regulatory T cells, enabling a potent reduction of PO-driven loss of systolic function, cardiac inflammation, and proinflammatory CD4⁺ T-cell clonal expansion.</p><p><strong>Conclusions: </strong>We demonstrate that PO-HF is triggered by hemodynamic stress and then sets off an autoimmune-like response against cardiac self-antigens. The antigens can be used to reduce the severity of future-onset disease, via oral tolerization, effectively acting as a protective vaccine.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"4-25"},"PeriodicalIF":16.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11692788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766661","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":"Discovery of Titin and Its Role in Heart Function and Disease.","authors":"Henk L Granzier, Siegfried Labeit","doi":"10.1161/CIRCRESAHA.124.323051","DOIUrl":"10.1161/CIRCRESAHA.124.323051","url":null,"abstract":"<p><p>This review examines the giant elastic protein titin and its critical roles in heart function, both in health and disease, as discovered since its identification nearly 50 years ago. Encoded by the TTN (titin gene), titin has emerged as a major disease locus for cardiac disorders. Functionally, titin acts as a third myofilament type, connecting sarcomeric Z-disks and M-bands, and regulating myocardial passive stiffness and stretch sensing. Its I-band segment, which includes the N2B element and the PEVK (proline, glutamate, valine, and lysine-rich regions), serves as a viscoelastic spring, adjusting sarcomere length and force in response to cardiac stretch. The review details how alternative splicing of titin pre-mRNA produces different isoforms that greatly impact passive tension and cardiac function, under physiological and pathological conditions. Key posttranslational modifications, especially phosphorylation, play crucial roles in adjusting titin's stiffness, allowing for rapid adaptation to changing hemodynamic demands. Abnormal titin modifications and dysregulation of isoforms are linked to cardiac diseases such as heart failure with preserved ejection fraction, where increased stiffness impairs diastolic function. In addition, the review discusses the importance of the A-band region of titin in setting thick filament length and enhancing Ca²⁺ sensitivity, contributing to the Frank-Starling Mechanism of the heart. TTN truncating variants are frequently associated with dilated cardiomyopathy, and the review outlines potential disease mechanisms, including haploinsufficiency, sarcomere disarray, and altered thick filament regulation. Variants in TTN have also been linked to conditions such as peripartum cardiomyopathy and chemotherapy-induced cardiomyopathy. Therapeutic avenues are explored, including targeting splicing factors such as RBM20 (RNA binding motif protein 20) to adjust isoform ratios or using engineered heart tissues to study disease mechanisms. Advances in genetic engineering, including CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), offer promise for modifying TTN to treat titin-related cardiomyopathies. This comprehensive review highlights titin's structural, mechanical, and signaling roles in heart function and the impact of TTN mutations on cardiac diseases.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 1","pages":"135-157"},"PeriodicalIF":16.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920955","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}