Atherosclerosis最新文献

{"title":"ApoB-100: The guardian of LDL stability","authors":"Katariina Öörni , Lauri Äikäs","doi":"10.1016/j.atherosclerosis.2024.119096","DOIUrl":"10.1016/j.atherosclerosis.2024.119096","url":null,"abstract":"","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"410 ","pages":"Article 119096"},"PeriodicalIF":5.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145290825","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":"Reply to: Residual cardiovascular risk in CKD: Reaffirming the role of remnant cholesterol and inflammation","authors":"Daniel Elías-López , Camilla Jannie Kobylecki , Signe Vedel-Krogh , Takahito Doi , Børge Grønne Nordestgaard","doi":"10.1016/j.atherosclerosis.2025.120450","DOIUrl":"10.1016/j.atherosclerosis.2025.120450","url":null,"abstract":"","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"410 ","pages":"Article 120450"},"PeriodicalIF":5.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717284","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":"Fatty liver-index, systemic inflammation and cardiovascular mortality. Results from the LURIC study","authors":"Stephanie Wissel ,&nbsp;Hubert Scharnagl ,&nbsp;Marcus E. Kleber ,&nbsp;Graciela Delgado ,&nbsp;Angela Moissl ,&nbsp;Bernhard Krämer ,&nbsp;Winfried März","doi":"10.1016/j.atherosclerosis.2025.120557","DOIUrl":"10.1016/j.atherosclerosis.2025.120557","url":null,"abstract":"<div><h3>Background and aims</h3><div>The Fatty Liver Index (FLI) has emerged as an indicator of metabolic dysfunction and has been related to cardiovascular outcomes. This study aims to investigate if the association between FLI and cardiovascular mortality is modified by systemic inflammation.</div></div><div><h3>Methods</h3><div>The study population consisted of 3316 participants (mean age 63 years, 30,3 % female) of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. The FLI was calculated using triglycerides, BMI, waist circumference, and gamma-glutamyl transferase (GGT). Systemic inflammatory markers (hsCRP and IL-6) were measured with immunoturbidimetric and ELISA assays. The outcome of interest was cardiovascular mortality. Cox proportional hazard analyses accounting for confounding variables were used for statistical analyses.</div></div><div><h3>Results</h3><div>During a median follow-up of 9.9 years, 603 cardiovascular deaths occurred. Individuals in the highest compared to the lowest FLI tertile were at an increased risk of cardiovascular death (HR 1.39, 95 % CI 1.02–1.89). This association was significantly modified by elevated hsCRP (≥2 mg/L, HR 1.58, 95 % CI 1.10–2.26) and IL-6 (≥3.2 ng/L, (HR 1.93, 95 %CI 1.36–2.74).</div></div><div><h3>Conclusion</h3><div>The Fatty Liver Index is not associated with cardiovascular mortality. However, this relationship is modified by systemic inflammation. These results indicate that liver steatosis is particularly relevant in presence of systemic inflammation which suggests that risk assessment in individuals with steatosis needs to consider both metabolic and inflammatory markers.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120557"},"PeriodicalIF":5.7,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145501939","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 differences in mortality associated with physical activity before and after acute coronary syndrome","authors":"Sae Young Jae ,&nbsp;Dong-Hyuk Cho ,&nbsp;Setor K. Kunutsor ,&nbsp;Jimi Choi ,&nbsp;Barry A. Franklin ,&nbsp;Jun Gyo Gwon","doi":"10.1016/j.atherosclerosis.2025.120559","DOIUrl":"10.1016/j.atherosclerosis.2025.120559","url":null,"abstract":"<div><h3>Background and aims</h3><div>Sex differences have been suggested in the association between baseline physical activity (PA) and cardiovascular outcomes, with women potentially benefiting more. This study evaluated sex differences in survival benefits of changes in moderate-to-vigorous physical activity (MVPA) before and after acute coronary syndrome (ACS).</div></div><div><h3>Methods</h3><div>We analyzed 30,840 patients with an ACS diagnosis (mean age 60 years; men: 25,069, women: 5771) from the National Health Insurance Service. Changes in MVPA before and after ACS were self-reported and categorized as persistently inactive, MVPA initiation, MVPA cessation, or MVPA continuation. Outcomes included all-cause and cardiovascular disease (CVD) mortality.</div></div><div><h3>Results</h3><div>Over a median follow-up of 5.8 years, 1349 CVD deaths and 4379 all-cause deaths occurred. MVPA initiation was associated with reduced all-cause mortality in men (Hazard Ratio [HR] = 0.77, 95 % Confidence Interval [CI] 0.64–0.93) and women (HR = 0.57, 95 % CI 0.42–0.79). MVPA continuation was associated with reduced all-cause mortality in men and women: (HR = 0.74, 95 % CI 0.63–0.88) and (HR = 0.58, 95 % CI 0.44–0.77). For CVD mortality, MVPA initiation yielded HRs of 0.84 (95 % CI 0.59–1.19) in men and 0.53 (95 % CI 0.31–0.91) in women; MVPA continuation rendered HRs of 0.71 (95 % CI 0.51–0.99) in men and 0.46 (95 % CI 0.29–0.75) in women. Interaction analyses did not suggest significant sex differences in these associations.</div></div><div><h3>Conclusions</h3><div>Initiating or continuing MVPA post-ACS diagnosis is associated with a lower risk of all-cause and CVD mortality, with comparable benefits in men and women; this challenging the notion that women derive greater PA-induced mortality reductions than their male counterparts.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120559"},"PeriodicalIF":5.7,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145463693","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":"Nicotine induces m6A-modified eNOS dysregulation to aggravate endothelial injury in male mice","authors":"Guoxia Shi ,&nbsp;Ziquan Jiang ,&nbsp;Zhuo Du ,&nbsp;Sibo Sun ,&nbsp;Dongxu Huang ,&nbsp;Pingping Wan ,&nbsp;Shuang Li ,&nbsp;Manyu Du ,&nbsp;Qiuying Yan ,&nbsp;Bo Yu ,&nbsp;Caiying Tang ,&nbsp;Ping Sun ,&nbsp;Jiannan Dai","doi":"10.1016/j.atherosclerosis.2025.120558","DOIUrl":"10.1016/j.atherosclerosis.2025.120558","url":null,"abstract":"<div><h3>Background and aims</h3><div>Cigarette smoking is a well-established risk factor for vascular injury. However, the effects of nicotine alone remain poorly understood. This study aimed to investigate whether nicotine regulates endothelial nitric oxide synthase (<em>eNOS</em>) expression, thereby contributing to vascular endothelial injury, and to elucidate the critical involvement of N6-Methyladenosine (m6A) modification in this process.</div></div><div><h3>Methods</h3><div>Mice were exposed to 12 weeks of nicotine exposure, to examine its impact on vascular endothelial injury. Human coronary artery endothelial cells were stimulated with nicotine in vitro, and qRT-PCR and MeRIP-qPCR were performed to measure eNOS expression and its m6A modification levels, respectively. RNA pull-down assays were used to identify eNOS mRNA-interacting proteins, and an endothelial-specific methyltransferase-like protein 3 (Mettl3) knockout model and eNOS recombinant adenovirus were utilized to validate the role of eNOS m6A modification in nicotine-induced endothelial injury.</div></div><div><h3>Results</h3><div>Nicotine stimulation induced vascular endothelial injury by activating endothelial cells, thereby increasing their permeability and migration capacity through suppressing <em>eNOS</em> expression. These pathological changes were alleviated in both <em>eNOS</em>-overexpressing and endothelial-specific <em>Mettl3</em> knockout mice. Mechanistically, nicotine increased the m6A modification of <em>eNOS</em> through METTL3. METTL3 then interacted with the YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), which led to mRNA degradation and reduced protein levels via the m6A-dependent pathway.</div></div><div><h3>Conclusions</h3><div>We propose a novel mechanism by which nicotine promotes vascular endothelial injury via METTL3/YTHDF2-mediated m6A modification of <em>eNOS</em> in endothelial cells. This study offers a new insights for the formation of vascular endothelial injury.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120558"},"PeriodicalIF":5.7,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145450718","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":"Common genetic variation in the APOE gene and risk of cancer: a systematic review and meta-analysis","authors":"Yousef A. Barakji ,&nbsp;Nanna B. Hupfeld ,&nbsp;Claus A. Bertelsen ,&nbsp;Ruth Frikke-Schmidt ,&nbsp;Sune F. Nielsen ,&nbsp;Katrine L. Rasmussen","doi":"10.1016/j.atherosclerosis.2025.120568","DOIUrl":"10.1016/j.atherosclerosis.2025.120568","url":null,"abstract":"<div><h3>Background and aims</h3><div>Already decades ago, apolipoprotein E (apoE) was suggested to be implemented in risk of cancer. The aim was to investigate the current evidence on the association between <em>APOE</em> ε2/ε3/ε4 carrier status and risk of cancer.</div></div><div><h3>Methods</h3><div>This systematic review and meta-analysis performed per PRISMA guidelines included a search of PubMed and Embase (PROSPERO CRD42024498793). Studies had to report <em>APOE</em> ε2/ε3/ε4 genotype/allele status, and ε33, non-ε4 or non-ε2 served as reference groups.</div></div><div><h3>Results</h3><div>Of 3189 screened records, we included 38 studies in the meta-analysis. For all cancer the risk increased from ε2 to ε3 to ε4 (<em>P</em> for trend: <em>p</em> = 0.01). For breast cancer ε4 was the risk allele (<em>p</em> = 0.03). The risk for colorectal cancer increased from ε2 to ε3 to ε4 (p for trend: <em>p</em> = 0.02). The Odds Ratio (OR) (95 % confidence interval (CI)) for colorectal cancer was 1.07 (1.00–1.13) for ε43 vs. ε33. For lung cancer the OR was 1.52 (1.04–2.2) for ε22 vs. ε33, and 2.80 (1.38–5.69) for ε4 vs. non-ε4. For the analyses for larynx and pharynx cancer, the OR was 0.72 (0.54–0.95) for ε2 vs. non-ε2.</div></div><div><h3>Conclusions</h3><div><em>APOE</em> ε2/ε3/ε4 genotype does not constitute a major risk factor for cancer. Effect sizes were overall small, and we did not find a clear pattern appearing throughout all cancer types with none of the comparisons (for individual alleles/genotypes) statistically significant for risk of all cancer. The study cannot exclude small but biologically interesting allele and genotype specific patterns for some cancer types with ε4 posing to be a risk factor and ε2 a protective factor.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120568"},"PeriodicalIF":5.7,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457431","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":"Loss of ADAM17 in smooth muscle cells enhances their transformation to macrophage-like cells leading to more severe atherosclerosis in mice","authors":"Ilamaran Meganathan ,&nbsp;Tolga Kilic ,&nbsp;Razoan Al Rimon ,&nbsp;Tushar Naiya ,&nbsp;Vidhya Krishnan ,&nbsp;Nikki Atanasova ,&nbsp;Anthony Wong ,&nbsp;Gavin Y. Oudit ,&nbsp;Slava Epelman ,&nbsp;Zamaneh Kassiri","doi":"10.1016/j.atherosclerosis.2025.120567","DOIUrl":"10.1016/j.atherosclerosis.2025.120567","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Atherosclerosis is a multicellular disease, and smooth muscle cells (SMCs) can contribute to plaque formation. ADAM17 (a distintegrin and metalloproteinase-17) is a membrane-bound proteinase that is upregulated in vascular disease and can regulate SMC functions. We investigated the role of ADAM17 in SMCs in atherosclerosis.</div></div><div><h3>Methods &amp; results</h3><div>Human coronary plaques showed a high number of macrophage-like SMCs and ADAM17 expression. Male and female mice with inducible ADAM17 knockdown in SMCs (<em>Ldlr</em>^−/−/<em>Adam17</em>^f/f/<em>Myh11</em>-Cre^ERT2; <em>Ldlr</em>^−/−/<em>Adam17</em>^SMC−KD), ADAM17-intact (<em>Ldlr</em>^−/−/<em>Adam17</em>^f/f; <em>Ldlr</em>^−/−), and genetic control (<em>Ldlr</em>^−/−/<em>Myh11</em>-Cre^ERT2) received Western diet (HCD) or regular chow. <em>Ldlr</em>^−/−/<em>Adam17</em>^SMC−KD-HCD mice developed significantly more plaques, higher aortic cholesterol content, and aortic valve plaque and stiffness compared to <em>Ldlr</em>^−/−-HCD mice, despite a comparable plasma lipid profile. SnRNAseq revealed a marked shift in SMC phenotypes from contractile to macrophage-like forms, and a greater population of proliferating inflammatory macrophages in <em>Ldlr</em>^−/−/<em>Adam17</em>^SMC−KD-HCD compared to <em>Ldlr</em>^−/−-HCD aortas. The plaques in <em>Ldlr</em>^−/−/<em>Adam17</em>^SMC−KD mice showed a higher number of macrophage-like SMCs, decreased expression of SMC proteins (calponin, α-SMA, SM22α) and increased SMC atherogenic marker (galectin-3). <em>In vitro</em>, under atherogenic conditions, <em>Adam17</em>^KD SMCs showed higher lipid content, increased lipid uptake and reduced efflux, associated with increased lipid uptake transporters (CD36, SRA1), and decreased efflux transporter, ABCA1, compared to control SMCs. In <em>Ldlr</em>^−/−/<em>Adam17</em>^SMC−KD-HCD aortas, membrane TNFR1 was stabilized, while the suppressed Ikkß-NFκB-LXRα pathway could underlie the decrease in ABCA1 expression.</div></div><div><h3>Conclusion</h3><div>ADAM17 is a novel regulator of SMC function in atherosclerosis. Its loss increases lipid content in SMCs, transformation into synthetic and macrophage-like states, and worsened atherosclerosis.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120567"},"PeriodicalIF":5.7,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145463692","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":"The role of ANGPTL8 in metabolism and cardiovascular diseases: Consensus and controversy","authors":"Yutong Lin ,&nbsp;Danan Wang ,&nbsp;Duanbin Li ,&nbsp;Fomin Zhang ,&nbsp;Qiongjun Zhu ,&nbsp;Xiaoyi Bao ,&nbsp;Ning Zhang ,&nbsp;Zakareya M. Alsalman ,&nbsp;Shengyu Chen ,&nbsp;Xiaolu Jiao ,&nbsp;Wenbin Zhang","doi":"10.1016/j.atherosclerosis.2025.120556","DOIUrl":"10.1016/j.atherosclerosis.2025.120556","url":null,"abstract":"<div><div>Angiopoietin-like protein 8 (ANGPTL8), a member of the angiopoietin-like protein (ANGPTL) family, is a physiological inhibitor of lipoprotein lipase (LPL), and plays a critical role in lipoprotein and triglyceride metabolism in response to nutritional cues. ANGPTL8 is implicated in a wide range of systemic and cellular processes and is closely associated with metabolic and cardiovascular diseases (CVD). Circulating ANGPTL8 is primarily secreted by the liver, with adipose tissue as a secondary source. Its expression is regulated by multiple transcription factors and microRNAs, and is responsive to fasting/refeeding states, hormonal signals, and stress conditions. In lipid metabolism, ANGPTL8 forms complexes with ANGPTL3 and ANGPTL4 to modulate LPL activity under fasting and feeding conditions. In glucose metabolism, ANGPTL8 plays a complex role. While some studies suggest it may improve glucose tolerance and insulin resistance, others indicate it could exacerbate glucose metabolism disorders and diabetes, or have no effect. Cardiovascular diseases are intricately linked to metabolic disorders and diseases. Increasing evidence also links ANGPTL8 to various cardiovascular pathologies, including atherosclerosis, hypertension, cardiomyopathy, cardiac hypertrophy, aortic aneurysm, and dissection. Given the strong interplay between metabolic dysregulation and CVDs, elucidating the role of ANGPTL8 in these processes is of significant interest. This review provides a balanced assessment of ANGPTL8's roles in key pathophysiological processes, highlighting its established functions in metabolism alongside its emerging involvement in CVDs. Understanding the diverse functions of ANGPTL8 in various tissues and metabolic states will lead to new opportunities for therapeutic intervention in cardiometabolic disorders.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"412 ","pages":"Article 120556"},"PeriodicalIF":5.7,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145555129","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":"Molecular mechanisms linking adipose tissue browning to reduced cardiovascular risk","authors":"Ana Checa-Ros ,&nbsp;Luis D'Marco","doi":"10.1016/j.atherosclerosis.2025.120564","DOIUrl":"10.1016/j.atherosclerosis.2025.120564","url":null,"abstract":"<div><div>Recent research elucidates the complex molecular mechanisms linking adipose tissue (AT) browning to improved metabolic and cardiovascular health. Pro-inflammatory signaling pathways, such as NLRP3 inflammasome, TLR4, and NF-κB, typically inhibit browning, whereas their disruption promotes it. Conversely, anti-inflammatory pathways mediated by IL-4, IL-13, and M2 macrophages stimulate browning and are associated with enhanced glucose tolerance and insulin sensitivity. Mitochondrial regulation is central to this process, with UCP-1 and PGC1-α as key effectors. Interventions like ASK-1 knockout, nitrate, and melatonin have increased thermogenesis and improved metabolic outcomes in preclinical models. A limited number of studies directly measuring cardiovascular endpoints report improved endothelial function, reduced hypertension, reduced atherosclerotic plaque inflammation with attenuated atherosclerosis progression and decreased liver steatosis, suggesting significant cardioprotective potential.</div><div>However, most evidence remains preclinical, derived from in vitro and animal studies. Interpretations are complicated by context-dependent effects, such as variable responses in IL-6 signaling. The current literature indicates that white AT browning mitigates inflammation and improves cardiometabolic health through multiple pathways that include key atherosclerosis-related risk factors; direct clinical confirmation is needed. Future research should prioritize human validation of preclinical findings to determine sex-specific responses, identify target patient populations, particularly those at high risk of atherosclerotic cardiovascular disease, and develop AT-targeted therapies with fewer off-target cardiovascular and systemic adverse effects.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120564"},"PeriodicalIF":5.7,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443871","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":"Mechanisms of matrix stiffness affecting calcific aortic valve disease by regulating Piezo1","authors":"Naifang Cao ,&nbsp;Si Cheng ,&nbsp;Haochang Hu ,&nbsp;Yi Qian ,&nbsp;Juan Fang ,&nbsp;Ningjing Qian ,&nbsp;Jinyong Chen ,&nbsp;Dilin Xu ,&nbsp;Shuangshuang Yang ,&nbsp;Wangxing Hu ,&nbsp;Junhui Xue ,&nbsp;Dao Zhou ,&nbsp;Jin Lu ,&nbsp;Hanyi Dai ,&nbsp;Jian'an Wang ,&nbsp;Xianbao Liu","doi":"10.1016/j.atherosclerosis.2025.120553","DOIUrl":"10.1016/j.atherosclerosis.2025.120553","url":null,"abstract":"<div><h3>Background and aims</h3><div>Mechanical factors have been found to trigger and promote calcific aortic valve disease (CAVD). Extracellular matrix (ECM) stiffness, one of the main mechanical factors, plays an important role in valve calcification. However, the specific mechanisms underlying ECM stiffness during CAVD progression remain unclear and require further investigation.</div></div><div><h3>Methods</h3><div>Atomic force microscopy was used to analyze the Young's modulus of the human aortic valves. Western blotting was performed to detect the COL4A3, COL1A1, ALP, RUNX2, and Piezo1 protein levels in valvular interstitial cells (VICs) cultured on a soft matrix. After Piezo1 was silenced <em>in vitro</em>, we evaluated ECM remodeling and osteogenic differentiation of VICs. We established an aortic valve calcification model in LDLR^−/− mice by a high-fat/cholesterol diet and evaluated the effect of AAV2-sh-Piezo1 on CAVD. RNA-seq was used to explore the mechanism by which Piezo1 affects CAVD.</div></div><div><h3>Results</h3><div>The Young's modulus of human calcified aortic valves was higher than that of normal aortic valves. Increased matrix stiffness upregulated Piezo1 and promoted ECM remodeling and osteogenic differentiation of VICs. <em>In vitro</em>, silencing of Piezo1 decreased COL4A3 expression and prevented the osteogenic differentiation of VICs. <em>In vivo</em>, Piezo1 knockdown ameliorated mouse aortic valve ECM remodeling and calcification. We found that Piezo1 may influence the Wnt pathway.</div></div><div><h3>Conclusion</h3><div>A Piezo1-mediated feedback loop may interconnect ECM stiffening, VIC osteogenic differentiation, and pathological ECM remodeling during CAVD progression.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120553"},"PeriodicalIF":5.7,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145501899","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}