Atherosclerosis最新文献

{"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":"Real-world family planning and pregnancy practices in women with homozygous familial hypercholesterolemia","authors":"Janneke W.C.M. Mulder ,&nbsp;Willemijn A.M. Schonck ,&nbsp;Tycho R. Tromp ,&nbsp;M. Doortje Reijman ,&nbsp;Laurens F. Reeskamp ,&nbsp;G. Kees Hovingh ,&nbsp;Dirk J. Blom ,&nbsp;Jeanine E. Roeters van Lennep","doi":"10.1016/j.atherosclerosis.2025.119187","DOIUrl":"10.1016/j.atherosclerosis.2025.119187","url":null,"abstract":"<div><h3>Background and aims</h3><div>Homozygous familial hypercholesterolemia (HoFH) is characterized by extremely high plasma low-density lipoprotein cholesterol (LDL-C) levels and high premature atherosclerotic cardiovascular disease risk. During pregnancy LDL-C levels increase, while limited therapeutic options are available. This international study documented current approaches of healthcare professionals (HCPs) to family planning, pregnancy, and breastfeeding in HoFH.</div></div><div><h3>Methods</h3><div>An online HCP survey was distributed among the HoFH International Clinical Collaborators (HICC, NCT04815005). Responses were analyzed according to HCPs’ gender, medical specialty, country income status, and world region.</div></div><div><h3>Results</h3><div>In total, 87 HCPs (39.1 % women) from 48 countries participated (64.4 % practicing in high-income countries). Most HCPs (79.3 %) always discuss family planning with patients with HoFH. Most (72.4 %) recommend contraception, with intrauterine devices (50.8 %) and oral contraceptives (49.2 %) being most commonly recommended. One in three HCPs would advise against pregnancy if ASCVD risks were deemed too high. Except for lipoprotein apheresis and colesevelam, most HCPs would recommend discontinuing LLT during the conception, pregnancy, and breastfeeding periods. However, approximately 30 % advise continuation or reinitiation of statins and/or ezetimibe during pregnancy and breastfeeding despite labelled restrictions on use during pregnancy and breastfeeding. Nearly half (48.3 %) of HCPs would recommend that women with HoFH shorten the breastfeeding period to resume LLT earlier, with HCPs from high-income countries significantly more likely to do so (51.8 % vs. 41.9 %; <em>p</em> = 0.008).</div></div><div><h3>Conclusions</h3><div>This study highlights significant variability in the management of HoFH in women of childbearing age, especially concerning LLT use during conception, pregnancy, and breastfeeding. The findings underscore the need for further research to establish global evidence-based guidelines tailored to individual needs, to improve cardiovascular risk management and reproductive health outcomes for women with HoFH worldwide.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"404 ","pages":"Article 119187"},"PeriodicalIF":4.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143839410","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 ,&nbsp;Sabina Haberlen ,&nbsp;Tess E. Peterson ,&nbsp;Frank Palella ,&nbsp;Matthew J. Budoff ,&nbsp;Mallory D. Witt ,&nbsp;Jared W. Magnani ,&nbsp;Wendy S. Post","doi":"10.1016/j.atherosclerosis.2025.119181","DOIUrl":"10.1016/j.atherosclerosis.2025.119181","url":null,"abstract":"<div><h3>Background and aims</h3><div>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.</div></div><div><h3>Methods</h3><div>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&gt;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.</div></div><div><h3>Results</h3><div>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 &lt; 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).</div></div><div><h3>Conclusions</h3><div>CAC was positively associated with mortality in a large cohort of MWH, and the overall cohort including MWH and MWOH.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"404 ","pages":"Article 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":"Transportation noise and the cardiometabolic risk","authors":"Thomas Münzel ,&nbsp;Marin Kuntic ,&nbsp;Andreas Daiber ,&nbsp;Mette Sørensen","doi":"10.1016/j.atherosclerosis.2025.119148","DOIUrl":"10.1016/j.atherosclerosis.2025.119148","url":null,"abstract":"<div><div>Transportation noise is a widespread and often underestimated environmental pollutant, posing a substantial health risk particularly in urban areas. In contrast to air pollution, the health effects of noise pollution are less extensively documented. Defined as an unwanted and/or harmful sound, noise pollution affects over 20 % of the European Union (EU) population, contributing to an estimated 12,000 premature deaths and 48,000 new cases of ischemic heart disease annually.</div><div>Recent epidemiological evidence strengthens the link between transportation noise and cardiovascular disease (CVD). A 2024 Umbrella + review with subsequent meta-analyses found that road traffic noise was associated with risk of CVD, more specifically a 4.1 % higher risk for ischemic heart disease, 4.6 % for stroke, and 4.4 % for heart failure per 10 dB(A). Translational and experimental studies have investigated the biological mechanisms behind noise-induced cardiovascular damage, showing that noise impacts stress and sleep pathways. Human studies reveal that nighttime noise impairs vascular function, elevates stress hormone levels, and triggers inflammation and oxidative stress, particularly in individuals with pre-existing CVD. Animal research corroborates these findings, demonstrating that noise exposure leads to endothelial dysfunction, elevated blood pressure, and oxidative stress through mechanisms shared with traditional cardiovascular risk factors. Mitigation strategies are crucial to reducing the health impacts of environmental noise. For road traffic, transitioning to electric vehicles offers minimal noise reduction, necessitating measures such as noise-reducing asphalt, low-noise tyres, and changes in urban infrastructure, whereas for aircraft noise nighttime flight bans and optimized flight paths are important tools for reducing noise exposure. Addressing co-exposure to noise and air pollution is essential for a comprehensive approach to mitigating the environmental burden on cardiovascular health.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"403 ","pages":"Article 119148"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584435","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}

{"title":"Advancing atherosclerosis research: The Power of lipid imaging with MALDI-MSI","authors":"Christoph H.M. Bookmeyer ,&nbsp;F. Xavier Correig ,&nbsp;Luis Masana ,&nbsp;Paolo Magni ,&nbsp;Óscar Yanes ,&nbsp;Maria Vinaixa","doi":"10.1016/j.atherosclerosis.2025.119130","DOIUrl":"10.1016/j.atherosclerosis.2025.119130","url":null,"abstract":"<div><div>Atherosclerosis is a chronic inflammatory disease that is one of the leading causes of mortality globally. It is characterized by the formation of atheromatous plaques in the intima layer of larger arteries. The (fibro-)fatty plaques usually develop asymptomatically within the vessel until a serious event such as myocardial infarction or stroke occurs. Lipids play a pivotal role in disease progression, but while the causal role of cholesterol is beyond doubt, the distribution of numerous other lipids within the heterogeneous layers of atherosclerotic plaques, and their biological function remain unclear. A deeper understanding of the pathophysiological progression of the disease for prognostics, diagnostics, treatment, and prevention is of great need. Mass spectrometry imaging (MSI), in particular with matrix-assisted laser desorption/ionization (MALDI) offers an unprecedented untargeted characterization of the physiological microenvironment, unraveling the spatial distribution of numerous biochemical compounds. MALDI-MSI offers an advantageous balance of sample preparation, chemical sensitivity, and spatial resolution, and thus has been established as a key technology in modern biomedical analysis. This review focuses on the analysis of lipids in atherosclerotic lesions with MALDI-MSI, for which the past years showed major developments in the spatial characterization of lipids and their interaction within atherosclerotic plaques. We will cover main contributions with a focus on the recent decade, elaborate possibilities, limitations, main findings, and recent developments from sample handling to instrumentation, and estimate current challenges and potentials of MALDI-MSI with respect to a clinical application.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"403 ","pages":"Article 119130"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584433","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":"Functional interrogation of cellular Lp(a) uptake by genome-scale CRISPR screening","authors":"Taslima G. Khan ,&nbsp;Juliana Bragazzi Cunha ,&nbsp;Chinmay Raut ,&nbsp;Michael Burroughs ,&nbsp;Hitarthi S. Vyas ,&nbsp;Kyle Leix ,&nbsp;Sascha N. Goonewardena ,&nbsp;Alan V. Smrcka ,&nbsp;Elizabeth K. Speliotes ,&nbsp;Brian T. Emmer","doi":"10.1016/j.atherosclerosis.2025.119174","DOIUrl":"10.1016/j.atherosclerosis.2025.119174","url":null,"abstract":"<div><h3>Background and aims</h3><div>An elevated level of lipoprotein(a), or Lp(a), in the bloodstream has been causally linked to the development of atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Steady state levels of circulating lipoproteins are modulated by their rate of clearance, but the identity of the Lp(a) uptake receptor(s) has been controversial.</div></div><div><h3>Methods</h3><div>We performed a genome-scale CRISPR screen to functionally interrogate all potential Lp(a) uptake regulators in HuH7 cells. Screen validation was performed by single gene disruption and overexpression. Direct binding between purified lipoproteins and recombinant protein was tested using biolayer interferometry. An association between human genetic variants and circulating Lp(a) levels was analyzed in the UK Biobank cohort.</div></div><div><h3>Results</h3><div>The top positive and negative regulators of Lp(a) uptake in our screen were <em>LDLR</em> and <em>MYLIP</em>, encoding the LDL receptor and its ubiquitin ligase IDOL, respectively. We also found a significant correlation for other genes with established roles in LDLR regulation. No other gene products, including those previously proposed as Lp(a) receptors, exhibited a significant effect on Lp(a) uptake in our screen. We validated the functional influence of LDLR expression on HuH7 Lp(a) uptake, confirmed <em>in vitro</em> binding between the LDLR extracellular domain and purified Lp(a), and detected an association between loss-of-function <em>LDLR</em> variants and increased circulating Lp(a) levels in the UK Biobank cohort.</div></div><div><h3>Conclusions</h3><div>Our findings support a central role for the LDL receptor in mediating Lp(a) uptake by hepatocytes.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"403 ","pages":"Article 119174"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143748472","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}