Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Cardiovascular Disease and Cancer: A Dangerous Liaison.","authors":"Alexandra A C Newman, Jessie M Dalman, Kathryn J Moore","doi":"10.1161/ATVBAHA.124.319863","DOIUrl":"10.1161/ATVBAHA.124.319863","url":null,"abstract":"<p><p>The field of cardio-oncology has traditionally focused on the impact of cancer and its therapies on cardiovascular health. Mounting clinical and preclinical evidence, however, indicates that the reverse may also be true: cardiovascular disease can itself influence tumor growth and metastasis. Numerous epidemiological studies have reported that individuals with prevalent cardiovascular disease have an increased incidence of cancer. In parallel, studies using preclinical mouse models of myocardial infarction, heart failure, and cardiac remodeling support the notion that cardiovascular disorders accelerate the growth of solid tumors and metastases. These findings have ushered in a new and burgeoning field termed reverse cardio-oncology that investigates the impact of cardiovascular disease pathophysiology on cancer emergence and progression. Recent studies have begun to illuminate the mechanisms driving this relationship, including shared risk factors, reprogramming of immune responses, changes in gene expression, and the release of cardiac factors that result in selective advantages for tumor cells or their local milieu, thus exacerbating cancer pathology. Here, we review the evidence supporting the relationship between cardiovascular disease and cancer, the mechanistic pathways enabling this connection, and the implications of these findings for patient care.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"359-371"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11864891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142943409","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":"Endothelium Modulates the Prothrombotic Phenotype of Factor V Leiden: Evidence From an Ex Vivo Model.","authors":"Nadine Schwarz, Jens Müller, Hannah L McRae, Sara Reda, Behnaz Pezeshkpoor, Johannes Oldenburg, Bernd Pötzsch, Heiko Rühl","doi":"10.1161/ATVBAHA.124.322116","DOIUrl":"10.1161/ATVBAHA.124.322116","url":null,"abstract":"<p><strong>Background: </strong>Clinical expressivity of the thrombophilic factor V Leiden (FVL) mutation is highly variable. Recently, we demonstrated an increased APC (activated protein C) response in asymptomatic FVL carriers compared with FVL carriers with a history of venous thromboembolism (VTE) after in vivo coagulation activation. Here, we further explored this association using a recently developed ex vivo model based on patient-specific endothelial colony-forming cells (ECFCs).</p><p><strong>Methods: </strong>ECFCs and citrated plasma were obtained from FVL carriers with previous VTE (VTE+, n=9), FVL carriers without previous VTE (VTE-, n=8), and 7 healthy controls. Coagulation was activated by TF (tissue factor) in defibrinated recalcified plasma added to confluent cell cultures. Thrombin and APC concentration were measured over time, and the respective areas under the curve (AUCs) were calculated. Additionally, inhibition kinetics of exogenously added APC, APC inhibitor levels, and APC sensitivity ratios were measured in plasma. Expression of TM (thrombomodulin) and EPCR (endothelial protein C receptor) on ECFCs was assessed using cell-based ELISAs.</p><p><strong>Results: </strong>In autologous plasma on ECFCs, the APC response (AUC APC/AUC thrombin) was higher in FVL VTE- than in FVL VTE+ patients (0.138 versus 0.028; <i>P</i>=0.026). APC inhibitor levels, APC inactivation kinetics, and APC sensitivity ratios did not differ between cohorts. Crossover experiments, which combined pooled plasma from FVL VTE- patients with FVL VTE+ ECFCs in the ex vivo model, and vice versa, showed increased APC response rates when FVL VTE- ECFCs were used, regardless of the plasma component. In cell-based ELISAs, TM and EPCR expression showed no significant difference.</p><p><strong>Conclusions: </strong>Although the FVL gene product induces an almost identical APC resistance phenotype in plasma, the endothelial cell-dependent APC response rates differ significantly, with a higher APC response in asymptomatic FVL carriers. Further studies are warranted to elucidate the disease-modulating role of the endothelium in FVL carriers at the molecular level.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"412-423"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021649","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 HIF2 Signaling Prevents Cardiomegaly, Alveolar Congestion, and Capillary Remodeling During Chronic Hypoxia.","authors":"Teresa Albendea-Gomez, Susana Mendoza-Tamajon, Rosana Castro-Mecinas, Beatriz Escobar, Susana Ferreira Rocha, Sonia Urra-Balduz, Jose Angel Nicolas-Avila, Eduardo Oliver, Maria Villalba-Orero, Silvia Martin-Puig","doi":"10.1161/ATVBAHA.124.321780","DOIUrl":"10.1161/ATVBAHA.124.321780","url":null,"abstract":"<p><strong>Background: </strong>Hypoxia is associated with the onset of cardiovascular diseases including cardiac hypertrophy and pulmonary hypertension. HIF2 (hypoxia inducible factor 2) signaling in the endothelium mediates pulmonary arterial remodeling and subsequent elevation of the right ventricular systolic pressure during chronic hypoxia. Thus, novel therapeutic opportunities for pulmonary hypertension based on specific HIF2 inhibitors have been proposed. Nevertheless, HIF2 relevance beyond the pulmonary endothelium or in the cardiac adaptation to hypoxia remains elusive. Wt1 (Wilms tumor 1) lineage contributes to the heart and lung vascular compartments, including pericytes, endothelial cells, and smooth muscle cells.</p><p><strong>Methods: </strong>Here, we describe the response to chronic hypoxia of a novel HIF2 mutant mouse model in the Wt1 lineage (<i>Hif2/Wt1</i> cKO [conditional knockout]), characterizing structural and functional aspects of the heart and lungs by means of classical histology, immunohistochemistry, flow cytometry, echocardiography, and lung ultrasound analysis.</p><p><strong>Results: </strong><i>Hif2/Wt1</i> cKO is protected against pulmonary remodeling and increased right ventricular systolic pressure induced by hypoxia, but displays alveolar congestion, inflammation, and hemorrhages associated with microvascular instability. Furthermore, lack of HIF2 in the Wt1 lineage leads to cardiomegaly, capillary remodeling, right and left ventricular hypertrophy, systolic dysfunction, and left ventricular dilation, suggesting pulmonary-independent cardiac direct roles of HIF2 in hypoxia. These structural defects are partially restored upon reoxygenation, while cardiac functional parameters remain altered.</p><p><strong>Conclusions: </strong>Our results indicate that cardiopulmonary HIF2 signaling prevents excessive vascular proliferation during chronic hypoxia and define novel protective roles of HIF2 to warrant stable microvasculature and organ function.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e78-e98"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021579","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":"Circulating ANGPTL3/8 Concentrations Are Associated With an Atherogenic Lipoprotein Profile and Increased CHD Risk in Swedish Population-Based Studies.","authors":"Karin Leander, Yan Q Chen, Max Vikström, Angela Silveira, Rachel M Fisher, Robert J Konrad, Ferdinand M van 't Hooft","doi":"10.1161/ATVBAHA.124.321308","DOIUrl":"10.1161/ATVBAHA.124.321308","url":null,"abstract":"<p><strong>Background: </strong>Binding of ANGPTL (angiopoietin-like protein)-3 to ANGPTL8 generates a protein complex (ANGPTL3/8) that strongly inhibits LPL (lipoprotein lipase) activity, as compared with ANGPTL3 alone, suggesting that ANGPTL3/8 concentrations are critical for the regulation of circulation lipoprotein concentrations and subsequent increased coronary heart disease (CHD) risk. To test this hypothesis in humans, we evaluated the associations of circulating free ANGPTL3 and ANGPTL3/8 complex concentrations with lipoprotein concentrations and CHD risk in 2 prospective cohort studies.</p><p><strong>Methods: </strong>Fasting blood samples were obtained in conjunction with the baseline evaluation of 9479 subjects from 2 population-based Swedish cohorts of middle-aged men and women. Standard biochemical blood analyses, including all lipid/lipoprotein measurements, were performed in these samples at baseline. Additional serum samples were stored at -80 °C and used at a later stage for ANGPTL3 and ANGPTL3/8 concentration measurements. Information about incident CHD was obtained for both cohorts by matching to the Swedish National Patient Register and the Cause of Death Register.</p><p><strong>Results: </strong>ANGPTL3 concentrations showed modest, positive associations with all lipoprotein concentrations but were not associated with CHD risk. In contrast, ANGPTL3/8 concentrations were associated in both cohorts with an atherogenic lipoprotein profile (characterized by increased triglyceride and LDL [low-density lipoprotein] concentrations and reduced HDL [high-density lipoprotein] concentrations). In the combined cohort, ANGPTL3/8 was associated with increased CHD risk. Hazard ratio per 1 SD increase was 1.10 (95% CI, 1.03-1.17) after adjustment for age, sex, cohort, smoking, and hypertension.</p><p><strong>Conclusions: </strong>Elevated concentrations of ANGPTL3/8, but not ANGPTL3, are associated with an atherogenic lipoprotein profile and increased CHD risk in humans.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"443-451"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063428","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":"Reevaluating Anti-Inflammatory Therapy: Targeting Senescence to Balance Anti-Cancer Efficacy and Vascular Disease.","authors":"Bernardo Casso-Chapa, Norma Alicia Vazquez González, Nhat-Tu Le, Nicolas L Palaskas, Kevin T Nead, Lydia P Eutsey, Venkata S K Samanthapudi, Abigail M Osborn, Jonghae Lee, Gilbert Mejia, Oanh Hoang, Steven H Lin, Anita Deswal, Joerg Herrmann, Guangyu Wang, James L Kirkland, Sunil Krishnan, Xander H T Wehrens, Eduardo N Chini, Syed Wamique Yusuf, Cezar A Iliescu, Abhishek Jain, Jared K Burks, Erin Seeley, Philip L Lorenzi, Khanh M Chau, Keila C Ostos-Mendoza, Isabella M Grumbach, Paul S Brookes, Nordin M J Hanssen, Menno P J de Winther, Laurent Yvan-Charvet, Sivareddy Kotla, Keri Schadler, Jun-Ichi Abe","doi":"10.1161/ATVBAHA.124.319870","DOIUrl":"10.1161/ATVBAHA.124.319870","url":null,"abstract":"<p><p>Modulating immune function is a critical strategy in cancer and atherosclerosis treatments. For cancer, boosting or maintaining the immune system is crucial to prevent tumor growth. However, in vascular disease, mitigating immune responses can decrease inflammation and slow atherosclerosis progression. Anti-inflammatory therapy, therefore, presents a unique dilemma for cancer survivors: while it may decrease cardiovascular risk, it might also promote cancer growth and metastasis by suppressing the immune response. Senescence presents a potentially targetable solution to this challenge; senescence increases the risk of both cancer therapy resistance and vascular disease. Exercise, notably, shows promise in delaying this premature senescence, potentially improving cancer outcomes and lowering vascular disease risk post-treatment. This review focuses on the long-term impact of cancer therapies on vascular health. We underscore the importance of modulating senescence to balance cancer treatment's effectiveness and its vascular impact, and we emphasize investigating the role of exercise-mediated suppression of senescence in improving cancer survivorship.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"372-385"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11864897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999216","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":"Sex-Divergent Blood Pressure Associations With Multiorgan System Metabolic Stress.","authors":"Alan C Kwan, Minhao Wang, Hongwei Ji, Brian Claggett, David Ouyang, Hirsh Trivedi, Sonia Sharma, John Shyy, Amanda Velazquez, Joseph E Ebinger, Susan Cheng","doi":"10.1161/ATVBAHA.124.322169","DOIUrl":"10.1161/ATVBAHA.124.322169","url":null,"abstract":"<p><strong>Background: </strong>Women experience excess cardiovascular risk compared with men in the setting of similar metabolic disease burden. We aimed to examine sex differences in the vascular response to various forms of metabolic stress.</p><p><strong>Methods: </strong>We conducted an observational study of 4299 adult participants (52% women, aged 59±13 years) of the National Health and Nutrition Examination Survey 2017 to 2018 cohort and 110 225 adult outpatients (55% women, aged 64±16 years) from the Cedars-Sinai Medical Center in 2019. We used natural splines to examine the association of systemic and organ-specific measures of metabolic stress including body mass index, hemoglobin A1c, hepatic FIB-4 score, and CKD-EPI estimated glomerular filtration rate with systolic blood pressure (SBP). Piecewise linear models were generated using normal value thresholds (body mass index <25 kg/m², hemoglobin A1c <5.7%, FIB-4 <1.3, and estimated glomerular filtration rate ≥90 mL/min), which approximated observed spline break points. The primary outcome was an increase in SBP in association with increase in each metabolic measure.</p><p><strong>Results: </strong>Women compared with men demonstrated larger magnitudes and an earlier onset of increase in SBP per increment increase across all metabolic stress measures. The slope of SBP increase per increment of each metabolic measure was greater for women than men particularly for metabolic measures within the normal range, with slope differences of 1.86 mm Hg per kg/m² of body mass index, 12.48 mm Hg per %hemoglobin A1c, 6.87 mm Hg per FIB-4 unit, and 0.44 mm Hg per mL/min decrement of estimated glomerular filtration rate in the National Health and Nutrition Examination Survey cohort (<i>P</i> difference <0.05 for all). Overall results were consistent in the Cedars-Sinai Medical Center cohort.</p><p><strong>Conclusions: </strong>Women exhibited greater SBP alteration in the setting of multiple types of metabolic stress, particularly in periods representing the transition from metabolic health to disease. These findings suggest potential benefit of early metabolic health interventions as part of efforts to mitigate vascular risks in both women and men.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514492","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":"Transcytosis of LDL Across Arterial Endothelium: Mechanisms and Therapeutic Targets.","authors":"Israel O Bolanle, Gaetan C de Liedekerke Beaufort, Peter D Weinberg","doi":"10.1161/ATVBAHA.124.321549","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321549","url":null,"abstract":"<p><p>Transport of LDL (low-density lipoprotein) from plasma to arterial intima is thought to be rate limiting in the development of atherosclerosis. Its variation likely determines where lesions develop within arteries and might account for some of the currently unexplained difference in disease susceptibility between individuals. It may also be critical in the development of lipid-rich, unstable plaques. Mechanisms have been controversial but recent evidence suggests that caveolar transcytosis across endothelial cells is the dominant pathway. Receptors involved are LDLR (LDL receptor), SR-B1 (scavenger receptor class B type 1), and ALK1 (activin receptor-like kinase 1). The role of LDLR is influenced by IL-1β (interleukin-1β); the role of SR-B1 by HDL (high-density lipoprotein), DOCK4 (dedicator of cytokinesis 4), GPER (G-protein-coupled estrogen receptor), and HMGB1 (high mobility group box 1); and the role of ALK1 by BMP (bone morphogenetic protein) 9. Additionally, BMP4 stimulates transcytosis, and FSTL1 (follistatin-like 1 protein) inhibits it. Fundamental transcytotic mechanisms include caveola formation, undocking, trafficking, and docking; they are influenced by cholesterol-lowering agents, MYDGF (myeloid-derived growth factor), MFSD2a (major facilitator superfamily domain containing 2a; in the blood-brain barrier), and inhibitors of dynamin-2 and tubulin polymerization. The relative merits of different therapeutic approaches are discussed, with statins, colchicine, benzimidazoles, and metformin being existing drugs that might be repurposed and salidroside and glycyrrhizic acid being nutraceuticals worth investigating. Finally, we discuss evidence against the ferry-boat model of transcytosis, the contributions of receptor-mediated, fluid-phase, and active transcytosis, and where inhibition of transcytosis might be most beneficial.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514254","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":"Discovery of the Low-Hemorrhagic Antithrombotic Effect of Montelukast by Targeting FXIa in Mice.","authors":"Yang Zhou, Dong Wang, Juhong Wu, Yingying Qi, Meiru Song, Huiqiao Yao, Christopher Kai Liao, Haili Lin, Meijuan Huang, Dexiang Zhuo, Longguang Jiang, Cai Yuan, Yuanzhong Chen, Mingdong Huang, Jinyu Li, Peng Xu","doi":"10.1161/ATVBAHA.124.322145","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.322145","url":null,"abstract":"<p><strong>Background: </strong>FXIa (coagulation factor XIa) is considered as a promising antithrombotic target with reduced hemorrhagic liabilities. The objective of this study was to identify a small-molecule inhibitor of FXIa as a potential low-hemorrhagic anticoagulant.</p><p><strong>Methods: </strong>A high-throughput virtual screening was conducted using a drug repurposing library with the catalytic domain of FXIa as the bait. The identified inhibitor's anticoagulant activity was evaluated in vitro and in both arterial and venous murine thrombotic models. The dependency of the inhibitor on FXIa was further examined using FXI^-/- mice. Hemorrhagic risks were subsequently evaluated in models of both localized and major bleeding.</p><p><strong>Results: </strong>Virtual screening led to the identification of montelukast, a commonly used antiasthmatic drug, as a potent and specific FXIa inhibitor (IC₅₀, 0.17 μmol/L). MK exhibited anticoagulant effects comparable to those of 2 mostly prescribed anticoagulants (warfarin and apixaban) in both arterial and venous thrombotic models. Notably, in stark contrast to the pronounced hemorrhagic risks of warfarin and apixaban, MK did not measurably increase the tendency of localized or major bleeding. Furthermore, MK did not prolong the time to arterial thrombotic occlusion in FXI^-/- mice, while effectively inhibited arterial occlusion induced by the reinfusion of recombinant FXIa, confirming that MK's anticoagulant activity is mediated by plasma FXIa. Additionally, MK ameliorated inflammation levels and mitigated pulmonary microthrombus formation in a septic mouse model. Moreover, combination therapy with MK enhanced the antithrombotic effects of antiplatelets without an obvious increase of hemorrhage.</p><p><strong>Conclusions: </strong>This proof-of-concept study suggests the potent low-hemorrhage antithrombotic effect of MK by targeting FXIa and unveiling a new therapeutic application of MK.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514545","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":"Development of Zafirlukast Analogues for Improved Antithrombotic Activity Through Thiol Isomerase Inhibition.","authors":"Justine A Keovilay, Kaitlind C Howard, Kirk A Taylor, Sabeeya Khan, Sienna E Wurl, Melanie K Szahaj, Tanya Sage, Nishad Thamban Chandrika, Caixia Hou, Oleg V Tsodikov, Jonathan M Gibbins, Sylvie Garneau-Tsodikova, Daniel R Kennedy","doi":"10.1161/ATVBAHA.124.321579","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321579","url":null,"abstract":"<p><strong>Background: </strong>Thiol isomerases play essential and nonredundant roles in platelet activation, aggregation, and thrombus formation. Thiol isomerase inhibitors have the potential to overcome the 2 major drawbacks of current antithrombotic therapies, as they target both arterial and venous thrombosis without enhancing bleeding risks. Recently, a Food and Drug Administration-approved drug, zafirlukast (ZAF), was shown to be a promising pan-thiol isomerase inhibitor. The objective of this study is to develop analogues of ZAF with optimized thiol isomerase inhibition and antithrombotic activity.</p><p><strong>Methods: </strong>Thirty-five ZAF analogues were tested in an insulin turbidometric assay for thiol isomerase inhibition. Analogues were tested for platelet activation, aggregation, P-selectin expression, and laser-induced thrombosis in mice and compared with the parent compound.</p><p><strong>Results: </strong>Of the 35 analogues, 12 retained activity, with 1, compound 21, that demonstrated a greater potency than that of ZAF, 5 had a similar potency to that of ZAF, and 6 had a weaker potency. Analogues demonstrated inhibition of platelet aggregation and P-selectin expression as compared with ZAF, consistent with their potencies. ZAF and compound 21 were shown to be reversible inhibitors of thiol isomerases, and not cytotoxic to cultured, lung, liver, and kidney cells. Finally, in an in vivo assessment of thrombus formation, compound 21 was able to significantly inhibit thrombus formation without affecting bleeding times.</p><p><strong>Conclusions: </strong>A ZAF analogue, compound 21, with properties superior to those of ZAF was synthesized, demonstrating improved inhibition of platelet activation, aggregation, and thrombus formation as compared with the parent ZAF. This approach could yield a promising clinical candidate for treatment and prophylaxis of arterial and venous thrombosis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456717","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":"SRSF4-Associated ca-circFOXP1 Regulates Hypoxia-Induced PASMC Proliferation by the Formation of R Loop With Host Gene.","authors":"Xinyue Song, Ya Xu, Mengnan Li, Xiaoyu Guan, Huiyu Liu, Jingya Zhang, Hanliang Sun, Cui Ma, Lixin Zhang, Xijuan Zhao, Xiaodong Zheng, Daling Zhu","doi":"10.1161/ATVBAHA.124.322026","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.322026","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary hypertension (PH) is a rare and fatal disease, the pathological changes of which include pulmonary arterial smooth muscle cell (PASMC) proliferation, which is the pathological basis of pulmonary vascular remodeling. Studies have demonstrated that chromatin-associated circRNA can regulate a variety of biological processes, including PASMC proliferation in patients with hypoxic PH. However, the role of chromatin-associated circRNA in the proliferation of PH remains largely unexplored. In this study, we aimed to identify the function and mechanism of chromatin-associated circRNA in PASMC proliferation in PH.</p><p><strong>Methods: </strong>The role of ca-circFOXP1 was investigated in hypoxic mouse PASMCs and SuHX (Sugen5416+hypoxia) model mice through the use of antisense oligonucleotide knockdown and adeno-associated virus-mediated knockdown. Through bioinformatic sequence alignment, chromatin isolation by RNA purification, Cell Counting Kit 8, 5-ethynyl-2-deoxyuridine, Western blot, and other experiments, the function and mechanism of ca-circFOXP1 were verified.</p><p><strong>Results: </strong>The expression of ca-circFOXP1 was found to be significantly increased in SuHX model mice and hypoxic mouse PASMCs. Moreover, ca-circFOXP1 was found to regulate the level of the host protein FOXP1 (forkhead box protein 1) through the R loop, thereby influencing the phosphorylation activity of SMAD2 (SMAD family member 2) and, consequently, the proliferation of mouse PASMCs. It is noteworthy that the m6A modification was found to promote the formation of the R loop between ca-circFOXP1 and the host gene <i>FOXP1</i>, thereby regulating the expression of the host protein. Furthermore, we have identified that the splicing factor SRSF4 (serine/arginine rich splicing factor 4) can upregulate the expression of ca-circFOXP1 by splicing exons 6 and 9 of FOXP1 pre-mRNA.</p><p><strong>Conclusions: </strong>The results demonstrated that the splicing factor SRSF4 upregulated the expression of ca-circFOXP1, and m6A methylation promoted R-loop formation between ca-circFOXP1 and host genes, regulated the level of host protein FOXP1, and then affected the phosphorylation activity of SMAD2, mediating PASMC proliferation, leading to pulmonary vascular remodeling. These results provide a theoretical basis for further study of the pathological mechanisms of hypoxic PH and may provide certain insights.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456720","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}