Cardiovascular Research最新文献

{"title":"Sirt1 inhibits the recruitment of RNA polymerase II to metabolic gene promoter during pressure overload through competition with the preinitiation complex on Sub1","authors":"Shin-ichi Oka, Youssef Mourad, Samta Veera, Peiyong Zhai, Ralph Alcendor, Yunping Guo, Jamie Ades, Sanchita Kashyap, Xiaoyong Xu, Chengchen Hu, Toshihide Kashihara, Takanobu Yamamoto, Yoshiyuki Ikeda, Akihiro Shirakabe, Shohei Ikeda, Wataru Mizushima, Yasuki Nakada, Danish Sayed, Zhi Yang, Maha Abdellatif, Junichi Sadoshima","doi":"10.1093/cvr/cvag178","DOIUrl":"https://doi.org/10.1093/cvr/cvag178","url":null,"abstract":"Aims Heart failure is marked by suppression of fatty acid oxidation (FAO) and mitochondrial ATP production gene expression. While transcriptional downregulation via PGC-1 and PPARα/ERRα has been well documented, the involvement of the general transcriptional machinery remains insufficiently understood. Distinct from its salutary role in many cardiac conditions, endogenous Sirt1 negatively affects cardiac function during pressure overload (PO). This study investigates how Sirt1 modulates preinitiation complex (PIC) assembly and RNA polymerase II (Pol II) recruitment during pathological PO. Methods and Results Cardiac-specific Sirt1 knock-out (Sirt1 cKO) mice were subjected to PO. Interaction between Sirt1 and Sub1, a protein recruiting GTFs to the gene promoter, was assessed with co-immunoprecipitation, protein pull-down and molecular docking. Pol II recruitment was evaluated with ChIP-sequencing and -qPCR analyses. The binding affinity of Sirt1 and GTF to the Sub1 GTF binding domain was assessed by immunoprecipitation and protein pull-down assays. Unbiased ChIP-sequencing and -qPCR analyses showed that Pol II binding to metabolic gene promoters was downregulated during PO, which was reversed in Sirt1 cKO mice. PO upregulated Sirt1 in the heart and increased its binding to Sub1, which interacts PPARα and ERRα, but not NF-kB. The Sirt1 binding to Sub1 competitively displaced the interaction between Sub1 and GTFs, thereby inhibiting the PIC formation at the Sub1-PPARα/ERRα complex. Conclusions Sirt1 impairs metabolic gene transcription during PO by competitively inhibiting Sub1-mediated recruitment of GTFs and PIC formation. This repression of general transcriptional machinery contributes to the metabolic disturbance and may represent a maladaptive component of the heart failure phenotype.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"159 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148768021","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":"Free fatty acid receptor 4 in cardiac myocytes ameliorates ischemic cardiomyopathy.","authors":"Michael J Zhang, Sara J Puccini, Sergey Karachenets, Dylan J Gyberg, Shanmugasundaram Pakkiriswami, Megan K Sumera, Ryan Gemilere, Natalie L Weir, Sebastian L Torres, Chastity L Healy, Brian A Harsch, Steven C Wu, Julia C Liu, Gregory C Shearer, Timothy D O'Connell","doi":"10.1093/cvr/cvag175","DOIUrl":"10.1093/cvr/cvag175","url":null,"abstract":"<p><strong>Aims: </strong>Free fatty acid receptor 4 (Ffar4) is a receptor for long-chain fatty acids that attenuates heart failure driven by increased afterload. Recent findings suggest that Ffar4 prevents ischemic injury in brain, liver, and kidney, and therefore, we hypothesized that Ffar4 would attenuate cardiac ischemic injury.</p><p><strong>Methods and results: </strong>Using a mouse model of ischemia-reperfusion (I/R), we found in mice with systemic deletion of Ffar4 (Ffar4KO), loss of Ffar4 impaired the recovery of left ventricular systolic function post-I/R with no effect on initial infarct size. To identify potential mechanistic explanations for the cardioprotective effects of Ffar4, we performed bulk RNAseq to compare the transcriptomes from wild-type (WT) and Ffar4KO infarcted myocardium 3-days post-I/R. The transcriptome analysis identified the downregulation of several metabolic pathways suggesting impaired mitochondrial function in the infarcted Ffar4KO myocardium. Mechanistically, basal mitochondrial function and morphology were impaired in cardiac myocytes from Ffar4KO mice corroborating the results of the transcriptome analysis. Interestingly, phosphodiesterase 6c (Pde6c), which degrades cGMP, was the most upregulated gene in the Ffar4KO heart. Further, the soluble guanylyl cyclase stimulator, vericiguat, failed to increase cGMP in Ffar4KO cardiac myocytes, suggesting increased phosphodiesterase activity. Finally, cardiac myocyte-specific overexpression of Ffar4 in vivo and activation of Ffar4 in cardiac myocytes in vitro attenuated ischemic/hypoxic injury respectively.</p><p><strong>Conclusions: </strong>Our results define a novel protective role for Ffar4 in cardiac myocytes to attenuate systolic dysfunction and prevent ischemic cardiomyopathy post I/R by preserving mitochondrial function and activating cGMP signaling.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757863","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":"Obicetrapib-ezetimibe combination therapy: a novel oral strategy for enhanced lipid lowering.","authors":"Mitra Chitsazan, Mandana Chitsazan, Christopher P Cannon","doi":"10.1093/cvr/cvag138","DOIUrl":"https://doi.org/10.1093/cvr/cvag138","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"122 11","pages":"1409-1411"},"PeriodicalIF":12.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148758325","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":"PKC-PKD-NFκB signalling induces cardiomyocyte t-tubule loss via a conserved macropinocytic mechanism.","authors":"Aiora Martinez-Vilchez, Ann-Katrin M Pfeuffer, Jonas Weßolowski, Dominik J Fiegle, Philipp Andrä, Prapassorn Potue, Linda K Küpfer, Thirupura S Shankar, Craig H Selzman, Stavros G Drakos, Christian Heim, Tilmann Volk, Thomas Seidel","doi":"10.1093/cvr/cvag121","DOIUrl":"10.1093/cvr/cvag121","url":null,"abstract":"<p><strong>Aims: </strong>Deterioration of transverse-axial tubules (t-tubules) contributes to insufficient excitation-contraction coupling in heart failure, yet the key signals and mechanisms remain unclear. Here, we aimed to identify the signalling pathways that trigger cardiomyocyte t-tubule loss and its underlying cellular process.</p><p><strong>Methods and results: </strong>Adult rat, rabbit, and human ventricular cardiomyocytes and living myocardial slices were exposed to pharmacological activators of protein kinase C (PKC). PKC activation caused rapid t-tubule loss and impaired Ca2+ transients, which were prevented by inhibition of protein kinase D (PKD) or NFκB. RNA sequencing and phosphoprotein analysis showed activation and crosstalk between PKD-, ERK-, and NFκB-dependent pathways, with up-regulation of genes involved in membrane trafficking and endocytosis. Fluorescent dextran uptake assays revealed a clathrin-independent, PI3K- and myosin-I-dependent macropinocytic process whose rate matched the internalization of t-tubule membranes and which was blocked by NFκB inhibition. Constitutive activation of IKK2 in cardiomyocytes of transgenic mice reduced t-tubule density in vivo, confirming that prolonged NFκB activation is sufficient to induce t-tubule remodelling in intact hearts. NFκB inhibition suppressed PKC-induced macropinocytosis also in non-cardiac human cell lines, suggesting that this process represents a conserved cellular response to inflammatory signalling.</p><p><strong>Conclusion: </strong>PKC-PKD-NFκB signalling triggers a macropinocytic form of membrane remodelling that degrades the t-tubule network and impairs excitation-contraction coupling. This identifies a previously unrecognized mechanism linking inflammatory kinase activation to structural and functional decline of cardiomyocytes and suggests that targeting the PKD-NFκB axis could preserve t-tubule integrity and cardiac performance in heart failure.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1470-1486"},"PeriodicalIF":12.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148148607","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":"Different responses of coronary endothelial populations to hypoxia during heart development.","authors":"Agnieszka Łoboda, Józef Dulak","doi":"10.1093/cvr/cvag144","DOIUrl":"https://doi.org/10.1093/cvr/cvag144","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"122 11","pages":"1417-1419"},"PeriodicalIF":12.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural resilience improves survival in cardiovascular patients.","authors":"Nidaa Mikail, Isabelle Glarner, Pimrapat Gebert, Noemi Sablonier, Adriana Vinzens, Achi Haider, Atanas Todorov, Susan Bengs, Angela Portmann, Valerie Treyer, Susanne Wegener, Christoph Gräni, Aju P Pazhenkottil, Caroline E Gebhard, Vera Regitz-Zagrosek, Felix C Tanner, Philipp A Kaufmann, Ronny R Buechel, Alexia Rossi, Catherine Gebhard","doi":"10.1093/cvr/cvag113","DOIUrl":"10.1093/cvr/cvag113","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1420-1423"},"PeriodicalIF":12.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13473968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147939610","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":"Hypoxia differentially affects coronary vessel formation during heart development.","authors":"Sophie Payne, Susann Bruche, Dorota Szumska, Lucija Fleisinger, Alice Neal, Mark D Preston, Sarah De Val","doi":"10.1093/cvr/cvag124","DOIUrl":"10.1093/cvr/cvag124","url":null,"abstract":"<p><strong>Aims: </strong>The coronary vessel system is a dense and diverse network of arteries, veins, and capillaries formed by endothelial cells from a variety of sources. While hypoxia is a known stimulus for angiogenic sprouting generally, the exact mechanisms by which hypoxia, and resultant increased VEGFA, influences vessel growth in the heart are not clearly delineated.</p><p><strong>Methods and results: </strong>We used a genetic model to mimic hypoxia through ectopic stabilization of myocardial HIFα. This enabled us to study the consequences of hypoxia without vascular depletion. Changes in coronary endothelial cells (ECs) in these hearts relative to littermate controls were assessed by single-cell RNA sequencing, and by examining the activity of enhancer:reporter transgenes active in different coronary vessel beds downstream of distinct vascular regulatory pathways. Analysis of hypoxia-mimic hearts found increased angiogenic gene expression alongside expanded activity of the VEGFA-MEF2-driven angiogenic regulatory pathway in a pattern that indicated increased endocardial-derived angiogenic sprouting. Conversely, regulatory pathways specifically active in the sinus venosus (SV)-derived plexus showed little variance, and sprouting from the SV was not expanded. Although hypoxia and increased VEGFA levels have been previously linked to increased arterial differentiation, we saw little change in initial arterial EC differentiation in the experimental hypoxia-mimic hearts. However, mature coronary arterial formation was delayed.</p><p><strong>Conclusion: </strong>These observations further emphasize a direct and specific link between the hypoxia pathway and endocardial coronary vessel sprouting and suggest a role of hypoxia/VEGFA in guiding coronary arterial coalescence.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1487-1505"},"PeriodicalIF":12.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13473972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148197331","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":"Long-term outcomes of obstructive hypertrophic cardiomyopathy undergoing surgical myectomy: impact of symptom severity at presentation.","authors":"Shada Jadam, Mohammed Abusafia, Sana Sultana, Susan Keen, Andrew Gaballa, Susan Ospina, Katy Rutkowski, Bo Xu, Zoran Popovic, Per Wierup, Maran Thamilarasan, Nicholas Smedira, Milind Y Desai","doi":"10.1093/cvr/cvag115","DOIUrl":"10.1093/cvr/cvag115","url":null,"abstract":"<p><p>Surgical myectomy (SM), performed to relieve dynamic left ventricular outflow tract obstruction in symptomatic obstructive hypertrophic cardiomyopathy (oHCM) patients, provides improved quality of life and symptoms and excellent long-term survival. Guidelines recommend SM in symptomatic oHCM patients refractory to optimal medical therapy. We sought to assess whether SM in patients with fewer symptoms at initial referral is associated with improved long-term outcomes in oHCM. Baseline symptom burden at the time of referral emerged as a powerful prognostic discriminator among 3546 HCM patients undergoing SM. Our findings suggest that earlier surgical referral before advanced decompensation may be associated with more favourable long-term outcomes. Women were more likely to present with advanced symptoms and had higher adjusted risk. These results underscore the need to determine whether a proactive therapeutic strategy, including an earlier intervention, can modify long-term survival in oHCM.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1424-1426"},"PeriodicalIF":12.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147947777","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":"Gene expression profiles of carotid plaques differ between patients with amaurosis fugax and those with cerebral transient ischaemic attack or stroke.","authors":"Tian Lan, Floor B H van der Zalm, Kaylin C A Palm, Yayuan Zhu, Ernest Diez Benavente, Sander W van der Laan, Dominique P V de Kleijn, Ynte M Ruigrok, Joost A van Herwaarden, Gert J de Borst, Hendrik Bart van der Worp, Martin Dichgans, Hester M den Ruijter, Gerard Pasterkamp, Michal Mokry","doi":"10.1093/cvr/cvag116","DOIUrl":"10.1093/cvr/cvag116","url":null,"abstract":"<p><strong>Aims: </strong>In patients with atherosclerotic internal carotid artery stenosis, the risk of subsequent ischaemic stroke is higher in those presenting with a cerebral transient ischaemic attack (TIA) than in those with amaurosis fugax (AFX; transient monocular blindness). While AFX is associated with more stable histological characteristics, the underlying molecular mechanisms remain unclear. We hypothesized that biological processes and gene expression profiles in carotid plaques of patients with AFX differ from those with cerebral TIA and stroke.</p><p><strong>Methods and results: </strong>We analysed carotid plaques from 2508 patients undergoing endarterectomy between 2002 and 2022. Bulk RNA sequencing (RNA-seq) was performed on 1088 plaques (136 asymptomatic, 179 AFX, 481 TIA, 292 stroke). Single-cell RNA-seq from 46 previously profiled plaques was used to identify cell-specific transcriptomic signatures. Mass spectrometry-based proteomics (n = 189) and targeted plasma proteomics (n = 1291) were used to validate the molecular differences. AFX plaques showed fewer lipid-rich cores than those from cerebral TIA [odds ratio (95% CI): 1.41 (1.03-1.94)] or stroke [1.42 (1.01-1.99)]. RNA-seq identified 408 differentially expressed genes (DEGs) between AFX and TIA and 463 between AFX and stroke (FDR < 0.1), while AFX and asymptomatic plaques showed only 10 DEGs. AFX plaques were enriched for vascular smooth muscle cell signatures and extracellular matrix remodelling, while cerebral TIA and stroke plaques exhibited macrophage-driven inflammatory molecular signatures. These transcriptomic differences were confirmed by plaque proteomic analyses. In parallel, circulating proteomic profiling revealed higher levels of inflammatory and thrombo-inflammatory markers in cerebral TIA and stroke compared with AFX.</p><p><strong>Conclusion: </strong>AFX plaques exhibit stable, SMC-dominant molecular signatures that differ markedly from the macrophage-driven inflammatory profiles of cerebral TIA and stroke plaques. These findings support AFX as a biologically distinct entity with potential implications for risk stratification and personalized treatment.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1443-1454"},"PeriodicalIF":12.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13473970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148148578","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":"The aorta in Marfan syndrome: from molecular mechanisms to mechanobiological dysfunction.","authors":"Jay D Humphrey, Dianna M Milewicz","doi":"10.1093/cvr/cvag114","DOIUrl":"10.1093/cvr/cvag114","url":null,"abstract":"<p><p>Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that affects cardiovascular, musculoskeletal, and ocular tissues, with premature death often resulting from dissection of the thoracic aorta. MFS results from pathogenic variants in FBN1, which encodes fibrillin-1, a glycoprotein that promotes elastic fibre organization and stability and contributes to smooth muscle cell mechano-sensing of extracellular matrix. It has been 35 years since the discovery that FBN1 variants cause MFS, yet understanding links between a variant and thoracic aortic disease remains incomplete, and definitive treatments remain wanting. We review advances in understanding disease progression in the aorta in MFS from perspectives of genetics, histology, mechanobiology, and biomechanics, with a focus on mouse models that include further genetic modifications to assess factors contributing to disease progression as well as effects of pharmacological treatments. This monogenic disease results in hundreds of differentially expressed genes in the aorta, many cell specific, that should be delineated as protective compensations, pathologic consequences, or neutral changes, and therapies should promote beneficial compensations and prevent detrimental consequences. Given the complexity of aortic disease in MFS, data-informed and data-driven computational models promise to help integrate multimodal data and increase understanding of molecular and cellular changes that drive disease progression, with a goal of improved therapies that prevent disease progression.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1427-1442"},"PeriodicalIF":12.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147947775","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}