Cardiovascular Research最新文献

{"title":"Fetuin-A increases thrombosis risk in non-alcoholic fatty liver disease by binding to TLR-4 on platelets","authors":"Peng Zhang, Zhiyong Qi, Huajie Xu, Luning Zhou, Xin Zhao, Haoxuan Zhong, Wenxuan Zhou, Bing Fan, Hongyi Wu, Junbo Ge","doi":"10.1093/cvr/cvaf096","DOIUrl":"https://doi.org/10.1093/cvr/cvaf096","url":null,"abstract":"Aims Fetuin-A, a liver-derived heterodimeric plasma glycoprotein, exhibits abnormal elevation in non-alcoholic fatty liver disease (NAFLD). Plasma fetuin-A levels correlate closely with both morbidity and mortality associated with cardiovascular diseases. However, the precise influence of fetuin-A on NAFLD-related platelet activation and thrombosis remains to be elucidated. Methods and results Fetuin-A directly amplified agonist-induced platelet aggregation, dense granule adenosine triphosphate release, P-selectin exposure, integrin αIIbβ3 activation, spreading, and clot retraction. Mechanistically, fetuin-A bound to platelet Toll-like receptor-4 (TLR-4), activating TLR-4/MyD88, SFK/PI3 K/AKT, cGMP/PKG, and mitogen-activated protein kinase signalling pathways to enhance platelet activation. TLR-4 specific antagonist TAK-242 and TLR-4-deficient mice confirmed the TLR-4 dependence of these effects. Oral administration of firsocostat, rosuvastatin, or pioglitazone demonstrated efficacy in alleviating thrombosis formation in NAFLD mice by reducing fetuin-A levels and attenuating platelet hyperreactivity. Notably, the fetuin-A-inhibiting antibody potently suppressed platelet activation and inhibited thrombosis formation in NAFLD mice. Administration of this antibody attenuated thromboembolism and microvascular thrombosis in NAFLD mice, thereby safeguarding the lung, heart, and brain from exacerbated tissue infarcts. Finally, a positive correlation between plasma fetuin-A concentration and platelet aggregation was observed in NAFLD patients. Conclusion Fetuin-A emerges as a positive regulator of platelet hyperreactivity in NAFLD. Acting via TLR-4-dependent signalling pathways, plasma fetuin-A directly amplifies platelet activation and promotes in vivo thrombosis. Firsocostat, rosuvastatin, and pioglitazone abrogate these enhancing effects by reducing fetuin-A levels. The fetuin-A-inhibiting antibody presents potential therapeutic advantages to prevent thrombotic complications in NAFLD.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"22 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144503539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Local arterial administration of acidified malonate as an adjunct therapy to mechanical thrombectomy in ischaemic stroke","authors":"Jordan J Lee, Hiran A Prag, Karthik Chary, Jiro Abe, Shinpei Uno, Annabel Sorby-Adams, Chak Shun Yu, Olga Sauchanka, Amin Mottahedin, Joshua D Kaggie, Ferdia A Gallagher, Michael P Murphy, Thomas Krieg","doi":"10.1093/cvr/cvaf118","DOIUrl":"https://doi.org/10.1093/cvr/cvaf118","url":null,"abstract":"Aims Ischaemic stroke is increasingly treated by mechanical thrombectomy (MT) with the more rapid and complete reperfusion of the ischaemic tissue enhancing patient outcome, compared to recombinant tissue plasminogen activator (rtPA) alone. Even so, there is still extensive brain infarction and disability following MT, that is exacerbated by ischaemia-reperfusion injury (IRI) and other pathological processes during reperfusion. Hence, an adjunct therapy to MT that decreases IRI should enhance patient outcomes. Methods and Results To test this possibility, we adapted the transient middle cerebral artery occlusion (tMCAO) mouse model to allow local intra-arterial administration of acidified disodium malonate (aDSM) to decrease IRI as the ischaemic tissue was reperfused. Administration of aDSM (160 mg/kg; pH 6) during reperfusion decreased brain infarct volume by ∼60 % when assessed by magnetic resonance imaging (MRI) 24 h after reperfusion and improved neurological function. Conclusion These findings suggest aDSM as a potential adjunct therapy to further improve outcomes for stroke patients treated by MT.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"17 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144503528","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":"Delineation of a thrombin receptor-stimulated vascular smooth muscle cell transition generating cells in the plaque-stabilising fibrous cap","authors":"James C K Taylor, Matthew D Worssam, Sebnem Oc, Jordi Lambert, Krishnaa T Mahbubani, Kirsty Foote, Allie Finigan, Yee-Hung Chan, Nichola Figg, Murray C H Clarke, Martin R Bennett, Helle F Jørgensen","doi":"10.1093/cvr/cvaf112","DOIUrl":"https://doi.org/10.1093/cvr/cvaf112","url":null,"abstract":"Aims Vascular smooth muscle cells (VSMCs) accumulate in atherosclerotic plaques and exhibit remarkable phenotypic plasticity, contributing to both plaque growth and stability. The plaque-stabilising fibrous cap is rich in VSMC-derived cells, yet the cellular transitions and regulatory mechanisms governing fibrous cap formation remain unclear. Here, we aimed to identify the VSMC phenotypic transitions associated with this critical process. Methods and Results Mapping of lineage-traced VSMCs during plaque development revealed investment of VSMCs prior to fibrous cap formation. Using single-cell RNA-sequencing (scRNA-seq) profiles of lineage-traced VSMCs from atherosclerotic and acutely injured mouse arteries, we identified a disease-specific VSMC state co-expressing contractile genes with extracellular matrix (ECM) components (including fibrillar collagens and elastin) and NOTCH3, which are associated with fibrous cap formation. Computational trajectory analysis predicted that this proposed fibrous cap-related VSMC (fcVSMC) state arises from a previously described plastic, intermediate VSMC population expressing SCA1 and VCAM1. Clonal analysis further showed that NOTCH3+ fcVSMCs derive from intermediate VSMCs in both atherosclerosis and an acute vascular injury model, suggesting a conserved disease-relevant mechanism. The fcVSMCs were enriched in plaque fibrous caps compared to lesion cores, consistent with a role in fibrous cap formation. By combining scRNA-seq trajectory analysis and spatial transcriptomics of human atherosclerotic plaques, we identified protease-activated receptor-1 (PAR1) as a candidate regulator of fcVSMC generation. PAR1 was expressed by VSMCs in human plaque fibrous caps and PAR1 activation by thrombin induced expression of contractile genes and ECM components associated with the fcVSMC state in human VSMCs. Conclusions Our findings identify a VSMC transition linked to fibrous cap formation in atherosclerosis and show this is modelled by vascular injury. We identify VSMC-expressed PAR1 as a potential therapeutic target for promoting plaque stability by driving the transition to the matrix-producing, fibrous cap-associated VSMC state.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"70 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144503529","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":"Systematic review and meta-analysis of respiratory viral triggers for acute myocardial infarction and stroke","authors":"Tu Q Nguyen, Diana Vlasenko, Aishwarya N Shetty, Eric Zhao, Christopher M Reid, Hazel J Clothier, Jim P Buttery","doi":"10.1093/cvr/cvaf092","DOIUrl":"https://doi.org/10.1093/cvr/cvaf092","url":null,"abstract":"Respiratory viral infections may trigger acute cardiovascular events. However, relative pathogen-specific associations are poorly understood, limiting optimal preventive recommendations. The aim of this study was to systematically review the association between respiratory viruses with two primary outcomes, acute myocardial infarction (AMI) and stroke. We searched MEDLINE, PubMed, Embase, Cochrane, and Web of Science, from database inception to 26 August 2024. Analytical epidemiological studies of respiratory viruses identified by laboratory-confirmatory testing, involving human participants of any age in any country, were eligible for inclusion. Risk of bias was assessed using the Cochrane Collaboration approach. Data from studies of sufficient quality and homogeneity were pooled using a random-effects model. Certainty of the evidence was assessed for each identified viral trigger. Of 11 017 articles identified, we included a total of 48 studies published between 1978 and 2024. All were observational studies, of which 28 were suitable for quantitative synthesis. There was moderate-certainty evidence that influenza triggers AMI (incidence rate ratio, 5.37; 95% CI, 3.48–8.28; I2 = 69.4%). We found high-certainty evidence that influenza triggers stroke—influenza was associated with a 4.7-fold increased risk of stroke within the first 28 days following infection (incidence rate ratio, 4.72; 95% CI, 3.78–5.90; I2 = 0%). SARS-CoV-2 and cytomegalovirus may trigger stroke, while SARS-CoV-2, respiratory syncytial virus, and Coxsackie B were also identified as potential triggers for AMI. In this systematic review and meta-analysis, the findings suggest that common, often vaccine-preventable, respiratory viral infections are associated with an increased risk of acute cardiovascular events.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"630 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500618","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":"The role of uremic toxin indoxyl sulfate in the pathophysiology of aortic valve stenosis","authors":"Philip Düsing, Isabel Göbel, Ansgar Ackerschott, Laurine Reese, Patrick Giavalisco, Frederik Dethloff, Sven Thomas Niepmann, Marta Stei, Thomas Beiert, Sebastian Zimmer, Christian Kurts, Georg Nickenig, Felix Jansen, Andreas Zietzer","doi":"10.1093/cvr/cvaf106","DOIUrl":"https://doi.org/10.1093/cvr/cvaf106","url":null,"abstract":"Aims Chronic kidney disease (CKD) is closely associated with cardiovascular disease (CVD). This includes aortic valve stenosis (AS), one of the most common valve diseases among adults. CKD leads to the retention of uremic toxins such as indoxyl sulfate (IS), which is known to induce inflammatory and pro-calcific processes. We hypothesise that IS specifically induces AS formation. Methods and Results Stimulation of human valvular interstitial cells (VICs) with IS in addition to phosphate led to increased calcification. RNA sequencing identified naked cuticle homolog 2 (NKD2) as an upregulated gene in VICs under uremic conditions. Knockdown of NKD2 reduced calcification of VICs and upregulation of IL-6. The organic anion transporting polypeptide 3A1 (OAT3A1) was identified to mediate IS uptake as well as upregulation of NKD2 and IL-6. We identified NF-κB signalling to be involved in IS-induced IL-6 upregulation. In vivo, we investigated combined models of adenine-induced kidney injury or oral IS supplementation with wire injury-induced AS in C57BL/6J mice. Echocardiography showed aggravated AS in uremic mice compared to control mice after wire injury. Explanted valves from uremic mice with AS exhibited a significant increase in macrophage infiltration, fibrotic areas and valvular NKD2 expression compared to controls. IS-treated mice showed aggravated AS compared to control mice. This was accompanied by more prominent valve fibrosis, macrophage infiltration, and NKD2 expression in explanted valves of IS-treated mice. In the blood and bone marrow, IS treatment led to the differentiation of monocytes into intermediate and non-classical monocytes. This was paralleled by IS-induced monocyte adhesion to valvular endothelial cells in vitro. Conclusion Uremic conditions aggravate AS development in mice by inducing valvular fibrosis and macrophage infiltration. Indoxyl sulfate is involved in this process and stimulates monocyte differentiation and adhesion to the valvular endothelium. On a cellular level, we hypothesize that IS-mediated NKD2 induction leads to a calcifying and inflammatory response in VICs.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"46 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500627","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":"Low-fibre diet is associated with high-risk coronary plaque features.","authors":"Ingrid Larsson,Jiangming Sun,Shafqat Ahmad,Göran Bergström,Carl-Johan Carlhäll,Kerstin Cederlund,Isabel Drake,Jan E Engvall,Mats Eriksson,Henrik Hagström,Tomas Jernberg,Tanja Kero,Krister Lindmark,Maria Mannila,Marju Orho-Melander,Araz Rawshani,Ulf Risérus,Annika Rosengren,Mats Ryberg,Caroline Schmidt,Emily Sonestedt,Maria Wennberg,Carl Johan Östgren,Isabel Goncalves","doi":"10.1093/cvr/cvaf088","DOIUrl":"https://doi.org/10.1093/cvr/cvaf088","url":null,"abstract":"AIMSDiet is a determinant of cardiovascular diseases (CVD) with coronary disease as predominant cause of pre-mature death. To analyse how diet was associated with coronary atherosclerosis, including plaque features.METHODS AND RESULTSThe cross-sectional population-based study using data from the Swedish CArdioPulmonary BioImage Study (SCAPIS) included 24 079 adults aged 50-64 years, recruited in 2013 to 2018 who were free of clinical cardiovascular disease. The recruitment and comprehensive examinations were conducted at six locations in Sweden. A dietary index (DI) based on a previously published anti-inflammatory DI including high proportion of plant-based foods, and low in red or processed meat and sugar-sweetened beverages was constructed. The reference group was within lowest DI tertile. Coronary atherosclerosis assessed by coronary computed tomography angiography, including any-, significant-, and adverse or high-risk coronary plaque, which is non-calcified with a significant stenosis ≥50%. Lowest, compared to highest DI tertile was associated with younger age, more often men (62.2% vs. 32.9%), higher high-sensitive C-reactive protein, more cardiometabolic risk and smokers, higher alcohol-, and higher energy-intake. In the highest and lowest tertile, coronary plaques were present in 36.3% and 44.3%, respectively, stenosis ≥ 50% in 3.7% and 6.0%. Non-calcified coronary plaques with stenosis ≥50% were present in 0.9% and 1.5% in highest and lowest tertiles. In multivariable analyses, the lowest tertile of DI was associated with high-risk plaque features after adjusting for age, sex, smoking, with waist circumference, triglycerides (TGs), and hypertension as possible mediators.CONCLUSIONA low-fibre diet with high red meat content was associated with high-risk plaques features, increased coronary calcification and significant stenosis. Waist circumference, TGs, and hypertension emerged as potential mediators of these associations, underscoring the role of metabolic and hemodynamic factors in the dietary impact on coronary atherosclerosis. Our findings strengthen the importance of cardioprotective dietary recommendations.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"38 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295662","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":"An activator of PI3Kα restores cardioprotection from ischaemia/reperfusion injury in mice with coronary atherosclerosis or insulin resistance","authors":"Pelin Golforoush, Elias Sulaiman, David He, Derek M Yellon, Sean M Davidson","doi":"10.1093/cvr/cvaf111","DOIUrl":"https://doi.org/10.1093/cvr/cvaf111","url":null,"abstract":"Background In patients with coronary artery disease (CAD), morbidity and mortality from myocardial infarction remain high. Cardioprotective strategies such as Remote Ischaemic Conditioning (RIC) are highly effective in animal models but have disappointed in large clinical trials. One explanation may be that ischaemia and reperfusion (I/R) experiments are typically conducted in mice that lack CAD. Unlike most mouse models, double-knockout Scarb1;Ldlr (DKO) mice do develop CAD when fed a high-fat diet (HFD). The aim of this study was therefore to use these mice to investigate cardioprotection in the setting of CAD. We hypothesized that RIC, which requires cell-surface receptor signalling, would be ineffective in these mice; but that UCL-TRO-1938, a PI3Kalpha activator that bypasses cell-surface receptors, would be cardioprotective. Methods and results After 6-weeks HFD, DKO mice, but not WT or Ldlr KO mice, developed CAD as determined by histology. Anaesthetized mice were subject to 30-min coronary ischaemia and 2-h reperfusion. In line with our hypothesis, RIC did reduce infarct size in WT and Ldlr KO mice, but did not reduce infarct size in DKO mice subject to I/R. We sought to understand the effects of CAD in DKO hearts that might impair RIC, using RNAseq, immunostaining and Western blot analysis. RNAseq revealed significantly altered gene expression in DKO hearts compared to WT and Ldlr KO hearts, primarily in inflammatory pathways; in particular the IL-17 pathway. Coronary endothelial cells were activated, as shown by ICAM-1 expression in DKO but not Ldlr KO or WT. In contrast to RIC, treatment with UCL-TRO-1938 was cardioprotective in DKO mice. Conclusions The DKO mouse may be a more clinically translatable mouse model of I/R and cardioprotection. Furthermore, UCL-TRO-1938 is a promising cardioprotective drug as it remains effective in a mouse model with CAD.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"37 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288409","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":"Upfront lipid-lowering combination therapy in high cardiovascular risk patients: a route to effective atherosclerotic cardiovascular disease prevention.","authors":"Maciej Banach, Stanisław Surma, Tomasz J Guzik, Peter E Penson, Michael J Blaha, Fausto J Pinto, Laurence S Sperling","doi":"10.1093/cvr/cvaf045","DOIUrl":"10.1093/cvr/cvaf045","url":null,"abstract":"<p><p>Despite three decades of using statin therapy, 20 years of experience with ezetimbe, and availability of innovative non-statin lipid lowering therapies (LLT), there are still about 70% patients over the low-density lipoprotein cholesterol (LDL-C) goal, with every 5th to 6th being over the target from the group of very high and extremely high cardiovascular disease (CVD) risk patients. Adding another even every 5th patient at very high CVD risk without any LLT makes this situation highly frustrating, especially lipid disorders are the most common CVD risk factor with the prevalence of over 60%, with the worst awareness within all cardiovascular risk factors (only about 15% people knows their LDL-C level). To answer this since 2021, there is an approach to apply upfront (immediate) lipid-lowering combination therapy of statin and ezetimibe in very high and extremely high-risk patients to be on the LDL-C target as low as possible, but especially as early as possible, enabling to introduce the third line therapy (i.e. bempedoic acid and/or PCSK9 targeted therapy) already after 4-6 weeks. This review discusses the current stage of knowledge and recent data on the group of patients that might benefit the most from the upfront combination LLT, when it should be optimally implemented, and the recent data on its role on LDL-C reduction, cardiovascular and mortality outcomes as well as safety issues.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"851-859"},"PeriodicalIF":10.2,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647477","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":"The Mediterranean diet displays an immunomodulatory effect that correlates with beneficial changes in carotid atherosclerosis.","authors":"Ana Maria Ruiz-Leon, Miguel Camafort, Aleix Sala-Vila, Rosa Gilabert, Isabel Núñez, Sara Castro-Barquero, Montserrat Fitó, Rosa María Lamuela-Raventós, Xavier Pintó, Ana García-Arellano, Emilio Ros, Ramon Estruch, Rosa Casas","doi":"10.1093/cvr/cvaf027","DOIUrl":"10.1093/cvr/cvaf027","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"847-850"},"PeriodicalIF":10.2,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482389","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":"CTRP7 as a molecular biomarker associating with responsiveness to pulmonary vasodilators: insights from human and animal studies in pulmonary arterial hypertension.","authors":"Kaito Yamada, Taijyu Satoh, Nobuhiro Yaoita, Naoki Chiba, Yusuke Yamada, Kohei Komaru, Sho Onuma, Shigeo Godo, Saori Yamamoto, Haruka Sato, Takashi Nakata, Kotaro Nochioka, Hisashi Oishi, Satoshi Miyata, Yoshinori Okada, Satoshi Yasuda","doi":"10.1093/cvr/cvaf064","DOIUrl":"10.1093/cvr/cvaf064","url":null,"abstract":"<p><strong>Aims: </strong>Pulmonary arterial hypertension (PAH) is a life-threatening condition. Although pulmonary vasodilators have shown promise in managing PAH, the improvement in prognosis is modest, partly because of a lack of biomarkers to guide their selection. Herein, we aimed to identify molecular-based predictors of responsiveness to pulmonary vasodilators using clinical and preclinical investigations.</p><p><strong>Methods and results: </strong>RNA sequencing was conducted on cultured pulmonary artery smooth muscle cells (PASMCs) from patients with and without pulmonary hypertension (PH), identifying variations in 3017 genes. Next, we performed a case-control study (PAH, n = 114; non-PH, n = 70) and examined plasma samples to identify potential clinical biomarkers. PASMCs exhibited elevated expression of C1q/TNF-related protein 7 (CTRP7; log2 fold change 5.37, P < 0.01). Patients with PAH had higher plasma CTRP7 levels [19.7 (9.8-90.5)] than those without PH [11.8 (0.6-61.6) ng/mL; P < 0.01]. Plasma and single-cell assessments revealed a significant correlation between CTRP7 and interleukin (IL)-6 levels (P < 0.001). Chromatin immunoprecipitation demonstrated that IL-6 up-regulated CTRP7 in PASMCs. CTRP7 reduced the expression of prostacyclin analogue receptor (PTGIR) through Rab5a-mediated internalization, resulting in diminished responsiveness to selexipag (prostacyclin analogue). Consistent with human study results, PTGIR expression was reduced in the pulmonary arteries of hypoxic PH mice, correlating with limited responses to selexipag treatment (low cardiac output and persistent pulmonary artery resistance); this effect was mitigated by the IL-6-R neutralizing antibody or adeno-associated virus-mediated silencing of CTRP7 expression in the pulmonary arteries.</p><p><strong>Conclusion: </strong>In patients with PAH, RNA sequencing of PASMCs revealed elevated expression of CTRP7 among candidate biomarkers. Patients with PAH had higher plasma CTRP7 levels than those without PH. Mechanistically, CTRP7 regulated PTGIR internalization via the IL-6-Rab5a axis, influencing responsiveness to selexipag. Herein, CTRP7 emerged as a crucial biomarker associating with responsiveness to prostacyclin analogues, advancing the development of PAH treatment strategies.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"121 6","pages":"929-942"},"PeriodicalIF":10.2,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274268","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}