Atherosclerosis最新文献

{"title":"Corrigendum to EAS Abstracts 2024 [Atherosclerosis (2024) Article number; 117943, 118076, 118078]","authors":"","doi":"10.1016/j.atherosclerosis.2025.119182","DOIUrl":"10.1016/j.atherosclerosis.2025.119182","url":null,"abstract":"","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"404 ","pages":"Article 119182"},"PeriodicalIF":4.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of ADAMTS5 promotes vascular calcification via versican/integrin β1/FAK signal","authors":"Zhenyu Zhu ,&nbsp;Hao Liu ,&nbsp;Liyun Feng ,&nbsp;Lihe Lu ,&nbsp;Jiahui Zhu ,&nbsp;Qingchun Liang ,&nbsp;Zirong Lan ,&nbsp;Yuanzhi Ye ,&nbsp;Siyi Wang ,&nbsp;An Chen ,&nbsp;Jianyun Yan","doi":"10.1016/j.atherosclerosis.2025.119190","DOIUrl":"10.1016/j.atherosclerosis.2025.119190","url":null,"abstract":"<div><h3>Introduction</h3><div>Extracellular matrix (ECM) proteases have been closely linked to the pathogenesis of vascular calcification. A disintegrin and metalloprotease with thrombospondin motifs-5 (ADAMTS5) is an ECM-degrading enzyme involved in ECM remodeling. Versican, a critical ECM component in the arteries, can be proteolytically cleaved by ADAMTS5 and activates integrin β1. However, whether ADAMTS5 is involved in the regulation of the pathogenesis of vascular calcification remains unclear. This study investigates the regulatory role of ADAMTS5 in vascular calcification and its mechanistic link to versican-integrin β1/FAK signaling.</div></div><div><h3>Methods and results</h3><div>Western blot, immunofluorescence, and immunohistochemistry analysis revealed that <em>ADAMTS5</em> expression was significantly downregulated in rat and human vascular smooth muscle cells (VSMCs), as well as in rat and human arteries during vascular calcification. In addition, both pharmacological inhibition of ADAMTS5 and knockdown of <em>ADAMTS5</em> by siRNA significantly aggravated mineral deposition in rat and human VSMCs under osteogenic conditions. Moreover, adenovirus-mediated <em>ADAMTS5</em> overexpression markedly attenuated calcification of VSMCs and aortic calcification in rats with chronic kidney disease. Furthermore, inhibition of ADAMTS5 promoted aortic calcification in VitD₃-overloaded mice. Mechanistically, overexpression of <em>ADAMTS5</em> significantly reduced versican protein levels, and inhibited integrin β1 and FAK phosphorylation in rat VSMCs, but increased versikine protein levels. Moreover, either knockdown of versican or pharmacological inhibition of FAK phosphorylation repressed VSMC calcification mediated by loss of ADAMTS5.</div></div><div><h3>Conclusions</h3><div>We have demonstrated for the first time that ADAMTS5 deficiency promotes versican accumulation and activates integrin β1/FAK signaling. These findings suggest ADAMTS5 as a potential therapeutic target for vascular calcification.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"404 ","pages":"Article 119190"},"PeriodicalIF":4.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143817243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Why has the “Lp(a) receptor” proven so elusive?","authors":"Gilles C. Lambert ,&nbsp;Michael B. Boffa","doi":"10.1016/j.atherosclerosis.2025.119189","DOIUrl":"10.1016/j.atherosclerosis.2025.119189","url":null,"abstract":"","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"404 ","pages":"Article 119189"},"PeriodicalIF":4.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143817242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetically determined increase in apolipoprotein C-III (APOC3 gain-of-function) delays very low-density lipoprotein clearance in humans","authors":"C.J. Packard ,&nbsp;M.R. Taskinen ,&nbsp;E. Björnson ,&nbsp;N. Matikainen ,&nbsp;S. Söderlund ,&nbsp;L. Andersson ,&nbsp;M. Adiels ,&nbsp;J. Borén","doi":"10.1016/j.atherosclerosis.2025.119166","DOIUrl":"10.1016/j.atherosclerosis.2025.119166","url":null,"abstract":"<div><h3>Aim</h3><div>Apolipoprotein C-III (apoC-III) is an important regulator of triglyceride (TG) metabolism and a target for intervention. The present study examined the effects of gain-of-function (GOF) variants in <em>APOC3</em> on apolipoprotein B kinetics to understand further how changes in the synthesis of this apolipoprotein impact triglyceride-rich lipoprotein (TRL) metabolism.</div></div><div><h3>Methods</h3><div>Two groups of subjects were recruited by population screening, 9 carriers of known <em>APOC3</em> GOF variants and 9 age-, sex- and BMI-matched non-carriers. The kinetics of TRL were determined using stable isotope tracers of apoprotein and triglyceride metabolism in a non-steady-state protocol involving administration of a fat-rich meal.</div></div><div><h3>Results</h3><div><em>APOC3</em> GOF carriers had 47 % higher plasma apoC-III levels compared to non-carriers (P = 0.022) and higher production rates for the apolipoprotein. Post-prandial response (total area-under-curve) for plasma TG was 108 % greater in GOF carriers compared to non-carriers (P = 0.002) due specifically to higher levels of VLDL₁. In contrast, no difference was seen in the chylomicron apoB48 response. Comparison of TRL kinetics between groups showed that <em>APOC3</em> GOF carriers had lower fractional clearance rates for VLDL₁-apoB100 and VLDL₁-apoB48-containing particles (P &lt; 0.02), but no difference in VLDL₁-apoB100 or chylomicron apoB48 production rates. Both the rate of VLDL lipolysis and the rate of clearance of VLDL particles from the circulation were lower in <em>APOC3</em> GOF carriers than in non-carriers. In contrast, chylomicron apoB clearance rates did not differ between <em>APOC3</em> GOF carriers and non-carriers.</div></div><div><h3>Conclusion</h3><div><em>APOC3</em> GOF carriers showed specific alterations in TRL metabolism (compared to matched non-carriers), namely slower lipolysis and delayed clearance of VLDL₁-sized particles, but no difference in chylomicron metabolism. Our findings suggest that intervention to reduce apoC-III production can be modelled as a reduction in TRL, particularly VLDL particle levels, without deleterious effects on fat absorption or hepatic VLDL production.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"404 ","pages":"Article 119166"},"PeriodicalIF":4.9,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143799716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the role of GATA4 in endothelial cell senescence and atherosclerosis development","authors":"Chun-Min Kang ,&nbsp;Jing-Jing Zhao ,&nbsp;Xi-Xi Xie ,&nbsp;Ke-Wei Yu ,&nbsp;Bai-Cong Lai ,&nbsp;Yun-Xiu Wang ,&nbsp;Ting Ting Li ,&nbsp;Pei-Feng Ke ,&nbsp;Xian-Zhang Huang","doi":"10.1016/j.atherosclerosis.2025.119183","DOIUrl":"10.1016/j.atherosclerosis.2025.119183","url":null,"abstract":"<div><h3>Background and aims</h3><div>Cellular senescence is intimately linked to atherosclerosis development and progression. However, the mechanism is not well known. GATA4 is a classical regulator in human fibroblast senescence. This study aimed to determine the role of GATA4 in endothelial cell (EC) senescence and atherosclerosis development and the mechanisms by which it acts.</div></div><div><h3>Methods</h3><div>Senescence ECs were induced using H₂O₂ by isolating human primary umbilical vein ECs from umbilical veins. The level of GATA4 was examined in endothelial progenitor cells (EPCs), ECs of arterial tissue from older individuals (&gt;65 years), and aged mice (&gt;24 months). Adeno-associated virus with EC-selective Tie1 promoter, an EC-specific gene transduction system, was used to explore the role of GATA4 in EC senescence and atherosclerosis development in <em>ApoE</em>^{<em>−/−</em>} mice. RT-qPCR, Western blot, ChIP-PCR, and ELISA were conducted to further explore the mechanism of GATA4 in EC senescence and atherosclerosis development.</div></div><div><h3>Results</h3><div>GATA4 protein levels are elevated in EC senescence induced by H₂O₂ and EPCs in older individuals. Additionally, GATA4 protein levels are increased in the ECs of arterial tissue from older individuals and aged mice and are strongly correlated with the progression of atherosclerosis plaques. Knockdown of GATA4 decreased EC senescence, dysfunction, and monocyte adhesion. Mechanistically, we found that GATA4 activates NFκB2 transcription and induces senescence-associated secretory phenotype (SASP) expression (IL-6, IL-8, CXCL1, CXCL3, ICAM-1). In vivo experiments on <em>ApoE</em>^{<em>−/−</em>} mice demonstrated that GATA4 overexpression in ECs contributes to higher SASP expression, vascular senescence, atherosclerotic plaque formation, and impaired cardiac function.</div></div><div><h3>Conclusions</h3><div>Taken together, our findings indicate that elevated EC GATA4 levels contribute to the progression of atherosclerosis through the GATA4-NFκB2-SASP pathway, suggesting potential therapeutic targets for atherosclerosis-related diseases.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"404 ","pages":"Article 119183"},"PeriodicalIF":4.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143799715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NAD+ boosting increases atherosclerotic plaques and inflammation in Apoe knockout mice","authors":"Yu-Jen Wang ,&nbsp;Daniel S. Gaul ,&nbsp;Era Gorica ,&nbsp;Jürgen Pahla ,&nbsp;Zeneng Wang ,&nbsp;Shafeeq A. Mohammed ,&nbsp;Tina Dahlby ,&nbsp;Elisa Dietrich ,&nbsp;Elena Osto ,&nbsp;Karim Gariani ,&nbsp;Sarah Costantino ,&nbsp;Stephan Winnik ,&nbsp;Sokrates Stein ,&nbsp;Stanley L. Hazen ,&nbsp;Frank Ruschitzka ,&nbsp;Johan Auwerx ,&nbsp;Christian M. Matter","doi":"10.1016/j.atherosclerosis.2025.119188","DOIUrl":"10.1016/j.atherosclerosis.2025.119188","url":null,"abstract":"<div><h3>Background and aims</h3><div>NAD⁺ (nicotinamide adenine dinucleotide) is a cosubstrate of the sirtuins (SIRT) that are activated upon caloric restriction. Supplementing NAD⁺ precursors such as nicotinamide riboside (NR) has been reported to extend life span and combat metabolic syndrome through <em>pan</em>-sirtuin activation in mice. Notably, sirtuins compete with poly (ADP-ribose) polymerase (PARP)1 and CD38 for NAD⁺. Supplementing NAD⁺ precursors did not improve cardiovascular outcome in the AIM-HIGH trial. Recently, the terminal NAD⁺ metabolite 4PY (<em>N</em>¹-methyl-4-pyridone-3-carboxamide) was reported to increase inflammation and to be associated with cardiovascular risk. We aimed to investigate whether NR provides atheroprotection.</div></div><div><h3>Methods</h3><div>8-week-old male apolipoprotein E (<em>Apoe</em>) knockout mice were fed for 12 weeks a high-cholesterol diet supplemented with three NR doses: NR-, NR+, and NR++. RAW264.7 mouse macrophages and bone marrow macrophages were stimulated with oxLDL and NR.</div></div><div><h3>Results</h3><div>NR++ enhanced plaque lesions in aortic sinus sections and increased plasma levels of TNFα, IL-6, and LDL-cholesterol. Liver and plasma NAD⁺ concentrations remained unchanged, but the downstream metabolite 4PY increased. In liver lysates, SIRT1 and lipoprotein receptors were decreased and CD38 increased in NR++; cleaved PARP1 and total PARylation decreased upon NR supplementation. In oxLDL-treated macrophages, high NR levels increased CD38 and CD86 expression.</div></div><div><h3>Conclusions</h3><div>High-dose NR supplementation in mice did not decrease but increase both aortic plaque lesions and systemic inflammation. These effects may be mediated by increased CD38 expression in macrophages, with NAD⁺ metabolism shifted from sirtuins towards CD38 and PARP1 pathways. Caution should be applied with presumed NAD⁺ boosters in patients with atherosclerosis.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"404 ","pages":"Article 119188"},"PeriodicalIF":4.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex related coronary plaque progression patterns among patients with family history as the sole cardiovascular risk factor: A PARADIGM sub-study","authors":"Edoardo Conte ,&nbsp;Sang-Eun Lee ,&nbsp;Hyuk-Jae Chang ,&nbsp;Martin Hadamitzky ,&nbsp;Yong-Jin Kim ,&nbsp;Gianluca Pontone ,&nbsp;Matthew J. Budoff ,&nbsp;Ilan Gottlieb ,&nbsp;Byoung Kwon Lee ,&nbsp;Eun Ju Chun ,&nbsp;Filippo Cademartiri ,&nbsp;Erica Maffei ,&nbsp;Hugo Marques ,&nbsp;Francesca Di Lenarda ,&nbsp;Gianluca Guarnieri ,&nbsp;Jonathon A. Leipsic ,&nbsp;Sanghoon Shin ,&nbsp;Jung Hyun Choi ,&nbsp;Al-Mallah Mouaz ,&nbsp;Kavitha Chinnaiyan ,&nbsp;Daniele Andreini","doi":"10.1016/j.atherosclerosis.2025.119184","DOIUrl":"10.1016/j.atherosclerosis.2025.119184","url":null,"abstract":"<div><h3>Background and aims</h3><div>How sex may influence the prevalence and progression of coronary atherosclerosis in patients with positive family history for CAD is still unclear. Aim of the present study was to explore the role of family history of CAD in coronary atherosclerosis expression and progression in male and female subjects.</div></div><div><h3>Methods</h3><div>A total of 2252 patients who underwent clinically indicated serial CCTAs at an interscan interval of more than 2 years were enrolled in the PARADIGM Study. For the present sub-analysis, a selected population was identified after applying the following exclusion criteria:1)uncomplete plaque analysis data; 2)occurrence of any MACE between CT scans; 3) positive history for coronary artery disease before the first CT scan; 4) the presence of any traditional risk factors a part from positive family history of CAD. Subjects enrolled were classified according to family history of CAD status and separate analysis for male and female were performed.</div></div><div><h3>Results</h3><div>Among 210 subjects finally enrolled, no differences in annual total plaque progression according to family history of CAD were detected even when plaque subtypes were evaluated. On the contrary, an higher annual fibrous-fatty plaque progression was evident only among male subjects with family history of CAD [0.3 mm³(IQR 0–3.7) vs 0 mm³(IQR -0.5–0.9), p = 0.0302 for patients with vs without family history respectively] but not among female. At multivariate analysis significative annual fibrous-fatty plaque progression was recorded only among male with family history [OR 3.29(95 % CI 1.05–10.35),p = 0.0412].</div></div><div><h3>Conclusions</h3><div>Family history of CAD resulted to be associated with rapid high risk plaque volume progression among males but not among females.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"404 ","pages":"Article 119184"},"PeriodicalIF":4.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of the clinical diagnostic strata of familial hypercholesterolemia on risk stratification among patients with hypercholesterolemia","authors":"Hayato Tada ,&nbsp;Atsushi Nohara ,&nbsp;Soichiro Usui ,&nbsp;Kenji Sakata ,&nbsp;Masa-aki Kawashiri ,&nbsp;Masayuki Takamura","doi":"10.1016/j.atherosclerosis.2025.119185","DOIUrl":"10.1016/j.atherosclerosis.2025.119185","url":null,"abstract":"<div><h3>Background and aims</h3><div>In 2022, the Japan Atherosclerosis Society (JAS) revised clinical diagnostic criteria of familial hypercholesterolemia (FH), adopting the use of definite, probable, possible, and unlikely FH categories following the Dutch Lipid Clinic Network (DLCN) FH criteria. However, whether these strata would be useful for the risk stratification of coronary artery disease (CAD) events among patients with hypercholesterolemia is unclear.</div></div><div><h3>Methods</h3><div>We retrospectively reviewed the data of patients with hypercholesterolemia (LDL cholesterol ≥180 mg/dL) aged ≥15 years (N = 1,273, male = 631) admitted to Kanazawa University Hospital between 2000 and 2022. Using the Cox proportional hazard model, we assessed whether factors, including the diagnostic strata of FH, were associated with CAD events.</div></div><div><h3>Results</h3><div>We identified 572, 174, 196, and 331 patients with definite, probable, possible, and unlikely FH, respectively. The prevalence of the pathogenic variant of FH was 71.0 %, 25.9 %, 11.7 %, and 1.5 %, respectively, among patients with definite, probable, possible, and unlikely FH (<em>p</em> &lt; 0.001). We identified 144 CAD events during the 12.4 year median follow-up. Compared with the reference group of unlikely FH, subjects with definite, probable, and possible FH had significantly higher hazard ratios (HRs) of developing CAD events (HR, 6.44; 95 % confidence interval [CI], 2.64–10.24; <em>p</em> &lt; 0.001 and HR, 3.10; 95 % CI, 1.51–4.51; <em>p</em> &lt; 0.001, and HR, 1.88; 95 % CI, 1.08–2.60; <em>p</em> = 0.02, respectively).</div></div><div><h3>Conclusion</h3><div>Among patients with hypercholesterolemia, the JAS clinical diagnostic strata of FH are useful for risk discrimination beyond their diagnosis as FH.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"404 ","pages":"Article 119185"},"PeriodicalIF":4.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coronary artery calcium and all-cause mortality in the Multicenter AIDS Cohort Study.","authors":"Takahiro Suzuki, Sabina Haberlen, Tess E Peterson, Frank Palella, Matthew J Budoff, Mallory D Witt, Jared W Magnani, Wendy S Post","doi":"10.1016/j.atherosclerosis.2025.119181","DOIUrl":"https://doi.org/10.1016/j.atherosclerosis.2025.119181","url":null,"abstract":"<p><strong>Background and aims: </strong>People with HIV (PWH) have greater risk of subclinical cardiovascular disease than people without HIV, but few studies have evaluated risk for mortality based on coronary artery calcium (CAC) among PWH. We aimed to determine the association between CAC and all-cause mortality among men with (MWH) and without HIV (MWOH) and if it differs by HIV serostatus.</p><p><strong>Methods: </strong>We performed a longitudinal analysis in the Multicenter AIDS Cohort Study. We included men who underwent non-contrast cardiac computed tomography. Cox regression analyses were used to examine the associations between CAC presence (Agatston score>0), and with extent of CAC (log (CAC+1)), and subsequent mortality to calculate adjusted hazard ratios [aHR]. We evaluated differences by HIV serostatus using multiplicative CAC × HIV interaction terms.</p><p><strong>Results: </strong>Among 1344 men (mean age 50 years, CAC prevalence 45.7 %, 821 [61.1 %] MWH), we observed 108 deaths (13.2 %) among MWH and 43 deaths (8.2 %) among MWOH during follow-up (median:13.4 years). CAC presence was positively associated with mortality among all participants (aHR:1.46, 95 %CI:1.02-2.10, p = 0.04) and MWH (aHR:1.62, 1.05-2.49, p = 0.03). Among MWOH, we found no significant association (aHR:1.28, 0.63-2.58, p = 0.50). The extent of CAC was associated with mortality among all participants (aHR:1.37 per SD, 1.15-1.63, p < 0.001) and MWH (aHR:1.41,1.14-1.74, p = 0.002). Among MWOH, we found no significant association (aHR:1.35, 0.98-1.85, p = 0.07). There were no significant interactions by HIV serostatus for mortality for either the presence (p = 0.35) or extent of CAC (p = 0.51).</p><p><strong>Conclusions: </strong>CAC was positively associated with mortality in a large cohort of MWH, and the overall cohort including MWH and MWOH.</p>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":" ","pages":"119181"},"PeriodicalIF":4.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of the lymphangiogenic reelin is associated with sex-dependent calcific aortic stenosis in men","authors":"Eva Jover ,&nbsp;Mattie Garaikoetxea ,&nbsp;Ernesto Martín-Núñez ,&nbsp;Miriam Goñi-Olóriz ,&nbsp;Susana San-Ildefonso-García ,&nbsp;Adela Navarro ,&nbsp;Amaya Fernández-Celis ,&nbsp;Virginia Álvarez ,&nbsp;Rafael Sádaba ,&nbsp;Laurent Calvier ,&nbsp;Natalia López-Andrés","doi":"10.1016/j.atherosclerosis.2025.119162","DOIUrl":"10.1016/j.atherosclerosis.2025.119162","url":null,"abstract":"<div><h3>Background and aims</h3><div>Aortic stenosis is a major form of adult valvulopathy with strong sex-related phenotypes. Circulating reelin, a large extracellular glycoprotein, regulates lymphangiogenesis and inflammation and promotes atherosclerosis, a risk factor in aortic stenosis. We sought to investigate the sex-dependent expression of reelin in stenotic aortic valves to comprehend its role in aortic stenosis progression.</div></div><div><h3>Methods</h3><div>Reelin was studied in aortic valves and serum samples from severe aortic stenosis and aortic regurgitation patients. <em>In vitro</em> calcification modelling of human valve interstitial cells (VICs) (n = 18 donors, 50 % men) was conducted for 2, 4 and 8 days.</div></div><div><h3>Results</h3><div>Reelin (<em>RELN</em>) expression was enhanced within the fibrocalcific areas of stenotic aortic valves, especially in men. Expression of <em>RELN</em> was associated with angiogenic and lymphangiogenic, inflammation and osteogenic markers only in aortic stenosis but not in aortic regurgitation. The VIC, along with inflammatory cells and valve endothelial cells, expressed reelin. <em>In vitro</em>, we confirmed the VIC to display sex-dependent responses as those reported within the valve. Male VICs expressed higher <em>RELN</em> than women's, and that was significantly associated with enhanced Dab2/Akt/NFkB signaling as well as with lymphangiogenesis, inflammation, and osteogenesis markers.</div></div><div><h3>Conclusions</h3><div>This study suggests a sex-dependent expression of reelin in stenotic aortic valves. This observation is partly due to different responses in VIC between men and women. In men, reelin was associated with inflammation, angiogenesis, lymphangiogenesis, and osteogenesis, which contributes to more calcific phenotypes, clinically relevant in male patients. However, further mechanistic studies are necessary to fully understand these processes. It's important to note that these findings were not reflected in circulating levels of reelin.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"403 ","pages":"Article 119162"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143783155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}