Cardiovascular Research最新文献

{"title":"Lysosomal signaling pathways influence heart rhythm, and regulate atrial function.","authors":"Emily Akerman, Rebecca A Capel, Eva A Rog-Zielinska, Annika Winbo, Daniel Aston, Florian Falter, Razik Bin Abdul Mu-U-Min, Matthew J Read, Samuel J Bose, Pawel Swietach, Jingyu Wang, Alexander D Corbett, Andreas Koschinski, Serena Calamaio, Dario Melgari, Rachele Prevostini, Ilaria Rivolta, Thamali Ayagama, Ifan Jenkin, Jillian N Simon, Funsho E Fakuade, Julius R Pronto, Parveen Sharma, Charlotte Melia, Qianqian Song, Martin J Booth, Frances M Platt, Ming Lei, Svenja Hester, Roman Fischer, Niels Voigt, Ulrich Schotten, Sander Verheule, Aiswarya Dev, Marie Held, Thomas Waring, Antony Galione, Marco Keller, Franz Bracher, Manuela Zaccolo, Derek A Terrar, Rebecca A B Burton","doi":"10.1093/cvr/cvag207","DOIUrl":"https://doi.org/10.1093/cvr/cvag207","url":null,"abstract":"<p><strong>Aims: </strong>In the heart, endogenous nicotinic acid adenine dinucleotide phosphate (NAADP) triggers lysosomal calcium (Ca2+) release to augment sarcoplasmic reticulum (SR) Ca2+ sequestration, producing larger Ca2+ transients. However, the role of lysosomal Ca2+ signals in pacemaker activity, a distinct Ca2+-operated function of the sinoatrial node (SAN), or in the atrial myocardium has not been investigated.</p><p><strong>Methods and results: </strong>Pharmacological or genetic ablation of the NAADP pathway inhibits the spontaneous beating rate response to β-adrenergic stimulation in intact SAN. We found intracellular signaling microdomains between lysosomes and neighboring SR or mitochondria in mouse, and goat tissue. The spatial relationship between lysosomes and other Ca2+-handling organelles are altered in goat atrial fibrillation. Furthermore, we demonstrate atrial myocytes produce 3'-5'-cyclic adenosine monophosphate (cAMP) in response to lysosomal signaling, adding a novel trigger for cyclic nucleotide signaling.</p><p><strong>Conclusions: </strong>Our findings support the hypothesis that lysosomal Ca2+ signaling contributes to regulation of cardiomyocyte cAMP levels and pacemaker activity.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001319","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":"Artificial intelligence-derived splenic response in cardiac positron emission tomography is associated with major adverse cardiovascular events: a multi-site study.","authors":"Giselle Ramirez, Naga L Dharmavaram, Aakash Shanbhag, Robert J H Miller, Paul B Kavanagh, Jirong Yi, Mark Lemley, Valerie Builoff, Anna Marcinkiewicz, Damini Dey, Jon Hainer, Samuel Wopperer, Stacey Knight, Viet T Le, Steve Mason, Erick Alexanderson, Isabel Carvajal-Juarez, René R S Packard, Thomas L Rosamond, Mouaz H Al-Mallah, Leandro Slipczuk, Mark I Travin, Wanda Acampa, Andrew J Einstein, Panithaya Chareonthaitawee, Daniel S Berman, Marcelo F Di Carli, Piotr J Slomka","doi":"10.1093/cvr/cvag184","DOIUrl":"10.1093/cvr/cvag184","url":null,"abstract":"<p><strong>Aims: </strong>Inadequate pharmacologic stress may limit the diagnostic and prognostic accuracy of myocardial perfusion imaging (MPI). The splenic ratio (SR), a measure of stress adequacy, has emerged as a potential imaging biomarker. We developed an artificial intelligence (AI) method to derive SR and evaluated the prognostic value in a large multicentre 82Rb-PET cohort undergoing regadenoson stress testing.</p><p><strong>Methods and results: </strong>We retrospectively analysed 16 650 patients from six sites in the REFINE PET registry with clinically indicated MPI and linked clinical outcomes. SR was calculated using fully automated algorithms as the ratio of splenic uptake at stress vs. rest. Patients were stratified by SR into decile groups. The primary outcome was major adverse cardiovascular events (MACE). Survival analysis was conducted using Kaplan-Meier and Cox proportional hazards models adjusted for clinical and imaging covariates, including myocardial flow reserve (MFR ≥2 vs. <2) and presence of ischaemia. The cohort had a median age of 69 years, with 59% male patients. Common risk factors included hypertension (81%), dyslipidaemia (77%), diabetes (35%), and prior coronary artery disease (31%). Median follow-up was 3.4 years. Patients with high SR in the testing cohort (n = 950) had an increased risk of MACE [hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.06-1.34, P = 0.005]. Among testing patients with preserved MFR (≥2; n = 8067), high SR remained independently associated with MACE (HR 1.43, 95% CI 1.20-1.70, P < 0.001). Even among patients with preserved MFR and no ischaemia in the testing cohort(MFR≥2, SDS<2; n = 6508), high SR remained independently associated with MACE (HR 1.54 95% CI 1.26-1.88, P < 0.001).</p><p><strong>Conclusion: </strong>Elevated AI-derived SR was independently associated with adverse cardiovascular outcomes, including among patients with preserved MFR. These findings support SR as a novel, automated imaging biomarker for risk stratification in 82Rb PET MPI.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149007761","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":"Reintroducing FABP5 in adulthood activates cell cycle in cardiomyocytes.","authors":"Abou Bakr M Salama, Qinghui Ou, Marc Dwenger, Collin K Wells, Ahmad Gebreil, Jessica Miller, Kamal Abou Farraj, Yibing Nong, Reham M Wahid, Hania Abdelhafez, Momo Arai, Muzammil Dastagir, Mohammad Salman Khan, Pretty R Mathew, Mohamed Hamouda, Nourhan M Baraka, Waleed M Elhelaly, Jordan Rhamfield, Om Kulkarni, Joern Huelsmann, Sara Taha, Rebecca Liu, Sarah Bench, Sung Wook Kang, Victoria Rodriguez, Daniel Kraushaar, Hyun-Sung Lee, Livia S Eberlin, Bradford G Hill, Todd K Rosengart, Riham R E Abouleisa, Tamer M A Mohamed","doi":"10.1093/cvr/cvag206","DOIUrl":"https://doi.org/10.1093/cvr/cvag206","url":null,"abstract":"<p><strong>Background and aims: </strong>Adult cardiomyocytes (CMs) have minimal proliferative capacity, limiting the heart's ability to regenerate after injury. While neonatal CMs can proliferate, the signaling pathways governing this process are poorly understood. This study aims to identify and reintroduce the neonatal-specific CM proliferation sensitizing signal to restore cell-cycle in adult CMs.</p><p><strong>Methods and results: </strong>We identified CD36 as a marker for the neonatal spontaneously proliferating CMs. Bulk and Single cell RNAseq, and spatial transcriptomics analyses of the P1 WT, CD36KO and CD36CKO hearts revealed that a CD36/FABP5/PPARδ signaling axis was uniquely expressed in spontaneously proliferating CMs. Using unbiased metabolomics and spatial metabolomics, we discovered that CD36KO and CD36cKO hearts had a 50% reduction in retinoic acid (RA) levels, implicating CD36 in regulating RA intracellular levels. Moreover, the pro-proliferative effect of RA treatment was lost in CD36KO or FABP5 knockdown CMs. To confirm the causality of this proposed mechanism, in vivo, crossing CD36KO with CM-specific PPARδ overexpression (PPARδCTG) only in CMs rescued the proliferation deficiency phenotype in CD36KO in the P1 hearts. Finally, reintroduction of FABP5, the rate limiting step of this signaling pathway, in adult hearts, using an inducible CM-specific FABP5 knock-in mouse (FABP5KI) was sufficient to drive CM cell cycle entry and led to significantly improved cardiac function following myocardial infarction in adult mice.</p><p><strong>Conclusion: </strong>RA/CD36/FABP5/PPARδ signaling pathway is essential for spontaneous neonatal CM proliferation. Re-activating this pathway in adult hearts through FABP5 overexpression is sufficient to induce functional recovery after ischemic injury, identifying FABP5 as a potential therapeutic target for cardiac regeneration.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988202","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":"Differential control of cardiac pacemaker activity by PDE4 subfamily members.","authors":"Walma Pereira De Vasconcelos, Pietro Mesirca, Anne Breidenstein, Audrey Varin, Eleonora Torre, Eliane Morais-Pinto, Laetitia Bouchard, Kaouter Bouadjel, Jérôme Leroy, Patrick Lechène, Florence Lefebvre, Natalie Fournier, Vincent Algalarrondo, Marco Conti, Francesca Rochais, Jean-Pierre Benitah, Guillaume Pidoux, Rodolphe Fischmeister, Ana-Maria Gomez, Matteo E Mangoni, Grégoire Vandecasteele, Delphine Mika","doi":"10.1093/cvr/cvag201","DOIUrl":"https://doi.org/10.1093/cvr/cvag201","url":null,"abstract":"<p><strong>Aims: </strong>The cAMP-specific phosphodiesterases 4B and 4D (PDE4B and PDE4D) are critical regulators of cardiac excitation-contraction coupling, but their role in controlling heart rate (HR) remains poorly defined. This study aimed to evaluate their respective contributions to cardiac automaticity.</p><p><strong>Methods and results: </strong>PDE4 activity, measured by a radioenzymatic assay, accounted for ∼60% of the total cAMP-hydrolytic activity in the mouse sinoatrial node (SAN). Western blot and in situ RNA fluorescence hybridization (RNAscope) showed that both PDE4B and PDE4D are expressed in the SAN and in isolated pacemaker cardiomyocytes. HR, measured by ECG telemetry, was increased in Pde4b knockout (Pde4b-/-) and Pde4d knockout (Pde4d-/-) mice compared with wild-type (WT) littermates, during both day and night. Upon autonomic nervous system (ANS) blockade, elevated HR persisted in Pde4b-/- but not in Pde4d-/- mice. Consistently, isolated perfused hearts from Pde4b-/- mice beat faster than wild-type littermates, whereas Pde4d-/- did not. Increased automaticity in Pde4b-/- hearts was not accompanied by modified Ca2+ homeostasis in Fluo-4-loaded isolated SAN tissue, either at baseline or during β-adrenergic (β-AR) stimulation with 10 nM isoprenaline (ISO). In contrast, Pde4d-/- SAN challenged with ISO exhibited an increased total sarcoplasmic reticulum (SR) Ca2+ leak and prolonged Ca2+ transients. Patch-clamp recordings revealed an increased action potential firing rate in Pde4b-/- but not in Pde4d-/- pacemaker cardiomyocytes. In Pde4b-/- cells, basal and ISO-stimulated L-type calcium current (ICa,L) densities were not significantly altered, whereas funny current (If) density was increased. Conversely, Pde4d ablation did not alter basal ICa,L nor If.</p><p><strong>Conclusion: </strong>These results show that PDE4B controls intrinsic SAN automaticity by regulating the voltage clock through the pacemaker current If, whereas PDE4D regulates the calcium clock via β-AR-induced calcium release through RyR2.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982100","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":"Reassessing safety signals in low-dose thrombolysis for intermediate-high-risk pulmonary embolism.","authors":"Jaskaran Ghotraa, Belinda Rivera-Lebron, Parth Rali, Charles B Ross, Steven Pugliese, Mina A Bushra","doi":"10.1093/cvr/cvag203","DOIUrl":"https://doi.org/10.1093/cvr/cvag203","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975820","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":"Oscillatory shear stress-induced endothelial extracellular vesicles exacerbate aortic valve calcification.","authors":"Shiqi Chen, Xiaoke Shang, Jianjun Xu, Zhengfeng Fan, Shaoshao Zhang, Rui Li, Ming Liu, Zhou Liu, Leilei Fan, Junwei Liu, Xin Jin, Tingwen Zhou","doi":"10.1093/cvr/cvag205","DOIUrl":"https://doi.org/10.1093/cvr/cvag205","url":null,"abstract":"<p><strong>Aims: </strong>Calcific aortic valve disease (CAVD) lacks effective pharmacotherapies. Although small extracellular vesicles (sEVs) are established mediators of cellular communication, how they translate oscillatory shear stress (OSS) into pro-calcific signals through endothelial-interstitial crosstalk remains unknown. This study aimed to delineate a complete mechanosensitive pathway by which sEVs drive aortic valve calcification (AVC).</p><p><strong>Methods and results: </strong>Using circRNA microarray sequencing, we identified circILRUN as the most markedly upregulated circRNA in sEVs from OSS-stimulated human valvular endothelial cells (hVECs). Endothelial-derived sEVs delivered circILRUN to human valvular interstitial cells (hVICs) and promoted osteogenic reprogramming of hVICs. Genetic ablation of circILRUN attenuated AVC in two independent mouse models, improving echocardiographic parameters and reducing calcium deposition. Mechanistically, circILRUN acted as a protein scaffold that recruited USP11 to NAT10, thereby stabilizing NAT10 via suppression of K48-linked ubiquitination. Integrated N4-acetylcytidine (ac4C) acetylome and transcriptome analyses identified CD36 as a key downstream target, with NAT10 catalyzing ac4C modification within its coding sequence to enhance CD36 mRNA stability and translation. Therapeutically, pharmacological inhibition of NAT10 reversed the pro-calcific effects of circILRUN in vitro and ameliorated AVC in vivo.</p><p><strong>Conclusions: </strong>Our study delineates a novel OSS induced sEV-circILRUN-NAT10-CD36 axis that integrates mechanical stress, epitranscriptomic regulation to drive AVC. These findings not only elucidate a fundamental mechanotransduction pathway in CAVD but also identify NAT10 as a candidate therapeutic target for clinical intervention.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975810","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":"Fatty acid synthase in cardiovascular disease: from molecular mechanisms to therapeutic targeting","authors":"Dina Ibrahim, Mohamed S Zaghloul, Bera Koklu, Abdullah Elahi, James L Januzzi, Marc P Bonaca, Mohamed A Zayed","doi":"10.1093/cvr/cvag200","DOIUrl":"https://doi.org/10.1093/cvr/cvag200","url":null,"abstract":"Fatty acid synthase (FAS), the rate-limiting enzyme of de novo lipogenesis, is now recognized as a multifunctional regulator of cardiovascular homeostasis; its roles extend beyond simple FA biosynthesis to encompass calcium signaling, cholesterol trafficking, and inflammatory modulation. This review synthesizes current understanding of FAS molecular biology, tissue-specific expression, and pathophysiological contributions to cardiovascular disease. Circulating FAS (cFAS) associates with lipoproteins and promotes macrophage foam cell formation independently of low-density lipoprotein cholesterol concentration, establishing a novel atherogenic mechanism. cFAS is primarily hepatic in origin and is released under conditions of enhanced de novo lipogenesis and insulin resistance. Adipose tissue may also contribute through extrusion of FAS. In macrophages, Fasn deletion enhances cholesterol efflux through liver X receptor alpha induction and ATP-binding cassette transporter A1 upregulation, reducing atherosclerosis by 20-40% in preclinical models without affecting serum lipids. Vascular smooth muscle cells upregulate FAS during phenotypic switching, facilitating transformation into foam cells within plaques. Clinical studies have established cFAS as a diagnostic biomarker for peripheral arterial disease, with higher concentrations present in affected individuals; elevated cFAS may also discriminate more severe disease. Despite its pathogenic roles in atherosclerosis, cardiac FAS serves essential stress-adaptive functions through calcium/calmodulin-dependent protein kinase II regulation, as cardiac-specific Fasn knockout mice exhibit profound stress intolerance and accelerated aging-related cardiac dysfunction, demonstrating that FAS-mediated de novo lipogenesis is indispensable for myocardial stress responses. This observation necessitates tissue-specific therapeutic approaches. Pharmacological FAS inhibitors, including TVB-2640 (denifanstat), demonstrate acceptable safety profiles in clinical trials and reduce hepatic de novo lipogenesis by 50-70%, while platensimycin reduces atherosclerotic burden in preclinical models. These findings position FAS as both a mechanistic driver and promising therapeutic target for cardiovascular disease. However, the divergent consequences of FAS modulation across tissues underscore the need for targeted delivery strategies that suppress pathological lipogenesis while preserving essential cardiac functions.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"78 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148946721","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":"Atherosclerotic plaque fibroblasts derive from adventitial and medial Pdgfra-lineage-positive cells and predominantly maintain fibroblast identity.","authors":"Guanliang Li, Sebastiaan E J Asselberghs, Baixue Yu, Cong Feng, Paul-Lennard Mendez, Dimitri Kasakovski, Pieter Goossens, Tia M Ackermans, Renée J H A Tillie, Marion J Gijbels, Lieve Temmerman, He Xu, Marjo M P C Donners, Dlzar A Kheder, Sidrah Maryam, Han Jin, Chenyi Xue, Sikander Hayat, Austin C Conklin, Casey E Romanoski, Mauro Giacca, Clint L Miller, Muredach P Reilly, Ming Chen, Rafael Kramann, Barend Mees, Andrew H Baker, Judith C Sluimer","doi":"10.1093/cvr/cvag183","DOIUrl":"https://doi.org/10.1093/cvr/cvag183","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Aims: &lt;/strong&gt;Fibroblasts are mesenchymal cells in the healthy vascular adventitia. In atherosclerosis, single-cell sequencing datasets suggest fibroblasts are abundant in plaques. However, their identity, origin, and fate during plaque progression remain unclear, which we aim to unravel here.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Approach and results: &lt;/strong&gt;To robustly define fibroblast identity, origin, and fate, we employed meta-analyses of 54 single-cell RNA sequencing libraries, including murine smooth muscle cell (Myh11) and endothelial cell (EC) (Cdh5) lineage reporter mice with and without atherosclerosis; human control and atherosclerotic arteries; and murine adventitia and atherosclerotic plaques processed separately from low-density lipoprotein (LDL) receptor knockout (Ldlr-/-) mice. These meta-analyses showed that murine and human plaque fibroblast identity was robustly defined by Pdgfra, Pi16, Cygb, and Serpinf1 mRNA. Ninety-five percent of plaque fibroblasts do not derive from the Myh11 lineage, while no Cdh5-lineage-positive cells were present in the fibroblast cluster. We identified five murine arterial fibroblast subsets in atherosclerotic murine aorta: progenitor fibroblasts, matrix fibroblasts, inflammatory fibroblasts, an EC-like fibroblast subset, detected in both adventitia and plaques, and Col5a3+ fibroblasts, unique to the adventitia. We next studied fibroblast identity, origin, and fate using pseudotime analysis and Pdgfra-CreERT2/tdTomato lineage reporter mice (Pdgfra Lin+). Healthy Pdgfra Lin+ reporter mice showed predominant adventitial tdTomato expression, and infrequent medial and intimal Pdgfra Lin+ cells co-expressing MYH11 and PECAM1, respectively. The Pdgfra Lin+ plaque area increased with diet duration. Pdgfra Lin+ cells largely maintain fibroblast identity in the plaque, while &lt;10% co-express SMC markers (MYH11, SM22α), or contribute to ACTA2+ cap cells. ECs gaining mesenchymal markers are transcriptionally distinct from Cdh5-lineage-negative fibroblasts gaining EC markers. Plaque-resident EC-like fibroblasts displayed a mesenchymal-to-endothelial transition transcriptome, which was induced in human primary fibroblasts in vitro by starvation, and dampened or reversed by IL1B, TGFB1, TGFB3, and oxidized LDL. Cross-species integration showed that all murine plaque fibroblasts were conserved in human atherosclerosis, with one additional subset partially resembling murine subsets, and three human-specific subsets. Importantly, human fibroblast subsets differentially correlated to human plaque traits, with EC-like fibroblasts correlating to plaque instability.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Our results indicate that 95% of plaque-residing fibroblasts are Myh11 Lin- Plaque fibroblasts have a dual origin, predominantly adventitial Pdgfra Lin+ progenitor fibroblasts, with a minor contribution from medial Pdgfra Lin+  Myh11+ SMCs. Most plaque fibroblasts maintain fibroblast identity. Murine plaque fibroblast subsets were con","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910704","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":"Sirtuin 1 modulation unlocks the therapeutic potential of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in calcific aortic valve stenosis.","authors":"Vincenza Valerio, Ilaria Massaiu, Matteo Franchi, Antoine Rimbert, Zoé Begué-Racapé, Mattia Chiesa, Veronika A Myasoedova, Valentina Rusconi, Francesca Bertolini, Donato De Giorgi, Alice Bonomi, Sergio Pirola, Marco Zanobini, Paola Di Pietro, Albino Carrizzo, Michele Ciccarelli, Romain Capoulade, Stefano Genovese, Paolo Poggio","doi":"10.1093/cvr/cvag199","DOIUrl":"https://doi.org/10.1093/cvr/cvag199","url":null,"abstract":"<p><strong>Background: </strong>Calcific aortic valve stenosis (AS) affects 3% of older adults and lacks medical treatment. The deacetylase Sirtuin 1 (SIRT1) could be involved in many pathways linked to AS progression. Sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucose-lowering agents, have been shown to reduce cardiovascular events (likely via SIRT1), but their possible benefits in AS are unknown. Our study aims to uncover the role of SIRT1 in AS progression and assess the benefit of SGLT2i to slow down the aortic valve fibro-calcification processes.</p><p><strong>Methods: </strong>RNA-seq data of human aortic valve specimens were collected from the ARChS4 database. SIRT1 knockdown (SIRT1 KD) and overexpressing (SIRT1 Over) valve interstitial cells (VIC) were generated by CRISPR/Cas9. Real-time PCR, immunofluorescence, and calcification assays were used to characterise mutant VICs. Conditioned medium experiments were implemented to evaluate SGLT2i effect on cellular cross-talk and calcification. Diabetic patients' data from the Lombardy regional healthcare database, treated with sulphonylureas (SU; no effect on SIRT1) and SGLT2i (acting on SIRT1), were selected and matched 1:1 by age, sex, and multisource comorbidity score. Cumulative incidence of hospitalisation for non-rheumatic aortic valve disease was assessed by Kaplan-Meier and Fine and Gray models were used to estimate subdistribution hazard ratios.</p><p><strong>Results: </strong>RNA-seq showed that SIRT1 could be an upstream regulator of multiple AS-related pathways. Functional studies on mutant VICs revealed that SIRT1 directly regulates antioxidant processes, extracellular-matrix remodelling, and calcification by modulating key transcription factors. Moreover, calcification assays further support this role, revealing an increased calcification in SIRT1 KD VICs and a concomitant decrease in VIC SIRT1 Over when compared to wild type. Then, exploring SGLT2i impact on calcification, we showed that VICs cultured in SGLT2i-treated-endothelial medium exhibited reduced calcification associated with endothelial-increased nitric oxide levels, while SIRT1 inhibition enhanced VIC calcification. The real-world data analysis revealed that SGLT2i-treated group had a lower incidence of hospitalised patients for non-rheumatic aortic valve disease compared to SU-treated group.</p><p><strong>Conclusions: </strong>Our data identify SIRT1 as an upstream regulator of fibro-calcific processes in AS and suggest that SGLT2i may slow the aortic valve degeneration through SIRT1 modulation. These findings support SGLT2i as a potential therapeutic strategy for AS prevention and care.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905244","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":"Vascular smooth muscle cell-derived osteoprotegerin drives pulmonary arterial hypertension via AKT activation and is attenuated by monoclonal antibody therapy.","authors":"Merve Keles, Laura E West, Nadine D Arnold, Astrid Weiss, Nadiya V Mykytyuk, Julia Baldauf, Josephine A Pickworth, Amira A Zawia, Helena A Turton, Megan F Allen, Clemens Ruppert, A A Roger Thompson, Sheila E Francis, Ralph T Schermuly, Allan Lawrie","doi":"10.1093/cvr/cvag197","DOIUrl":"https://doi.org/10.1093/cvr/cvag197","url":null,"abstract":"<p><strong>Aim: </strong>Pulmonary arterial hypertension (PAH) is driven by sustained vasoconstriction and structural remodelling of distal pulmonary arteries. We have previously demonstrated that osteoprotegerin (OPG, tnfrsf11b) is upregulated in PAH animal models and patient tissues, with circulating levels being prognostic. OPG knockout mice exhibit an attenuated PAH phenotype, and therapeutic inhibition using a human monoclonal anti-OPG antibody reduces disease severity in multiple rodent models. However, the key cellular source of pathogenic OPG and the mechanism underlying therapeutic blockade remain unknown.</p><p><strong>Methods and results: </strong>To define the main cellular source of OPG, conditional Tnfrsf11b deletion was generated by crossing OPGfl/fl mice with PGKcretg/+ (global), LysMcretg/+ (myeloid), Myl2cretg/+ (cardiac myocytes), Cdh5cretg/+ (endothelial cells, ECs), smMHCcretg/+ (VSMCs), Col1a2cretg/+ (fibroblasts, FBs). Knockouts were induced by tamoxifen injection, and PAH established using Sugen5416/hypoxia (SuHx) model. Cardiopulmonary phenotyping included echocardiography, cardiac catheterisation, and histological analysis. Mechanistic studies were performed in VSMCs using peptide-based kinase activity profiling (PamStation).PGKcretg/+/OPGfl/fl mice phenocopied the previous results obtained with global OPG knockout (OPG-/-). Only VSMC-specific deletion (smMHCcretg/0/OPGfl/fl) resulted in significantly improved haemodynamic parameters, evidenced by reduced RVSP and pulmonary vascular resistance (PVR), and reduced pulmonary vascular remodelling demonstrating that VSMC-derived OPG is the primary driver of PAH pathogenesis.Kinome profiling of control and IPAH-PASMCs treated with OPG +/- anti-OPG antibody revealed IPAH specific regulation of PI3K-Akt and enrichment of pathways involving autophagy, and longevity regulation linked to cellular stress resistance and growth. Anti-OPG antibody treatment reduced AKT phosphorylation in IPAH PASMCs. Knock-down of AKT1 by siRNA reduced OPG-induced proliferation and migration of human PASMC. These results align with emerging data implicating OPG in cellular senescence and vascular aging.</p><p><strong>Conclusion: </strong>Together, these findings highlight VSMC-derived OPG as a critical mediator of pulmonary vascular remodelling in PAH pathogenesis and suggest that targeting OPG via a therapeutic antibody is mediated through PI3K-Akt signalling.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148900232","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}