Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"SR-BI Models for Spontaneous Myocardial Infarction: High Unesterified/Total Cholesterol Ratio Not the Sole Piece of the Puzzle.","authors":"Miranda Van Eck","doi":"10.1161/ATVBAHA.124.321896","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321896","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"44 12","pages":"2489-2492"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738156","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":"ASGR1 Deficiency Inhibits Atherosclerosis in Western Diet-Fed <i>ApoE^-/-</i> Mice by Regulating Lipoprotein Metabolism and Promoting Cholesterol Efflux.","authors":"Yuyan Zhang, Xinhai Jiang, Weizhi Wang, Lijuan Lei, Ren Sheng, Shunwang Li, Jinque Luo, Huan Liu, Jing Zhang, Xiaowan Han, Yining Li, Yuhao Zhang, Chenyin Wang, Shuyi Si, Zheng-Gen Jin, Yanni Xu","doi":"10.1161/ATVBAHA.124.321076","DOIUrl":"10.1161/ATVBAHA.124.321076","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Atherosclerosis is the most common cause of cardiovascular diseases. Clinical studies indicate that loss-of-function ASGR1 (asialoglycoprotein receptor 1) is significantly associated with lower plasma cholesterol levels and reduces cardiovascular disease risk. However, the effect of ASGR1 on atherosclerosis remains incompletely understood; whether inhibition of ASGR1 causes liver injury remains controversial. Here, we comprehensively investigated the effects and the underlying molecular mechanisms of ASGR1 deficiency and overexpression on atherosclerosis and liver injury in mice.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We engineered &lt;i&gt;Asgr1&lt;/i&gt; knockout mice (&lt;i&gt;Asgr1&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt;), &lt;i&gt;Asgr1&lt;/i&gt; and &lt;i&gt;ApoE&lt;/i&gt; double-knockout mice (&lt;i&gt;Asgr1&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt;&lt;i&gt;ApoE&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt;), and ASGR1-overexpressing mice on an &lt;i&gt;ApoE&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt; background and then fed them different diets to assess the role of ASGR1 in atherosclerosis and liver injury.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;After being fed a Western diet for 12 weeks, &lt;i&gt;Asgr1&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt;&lt;i&gt;ApoE&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt; mice exhibited significantly decreased atherosclerotic lesion areas in the aorta and aortic root sections, reduced plasma VLDL (very-low-density lipoprotein) cholesterol and LDL (low-density lipoprotein) cholesterol levels, decreased VLDL production, and increased fecal cholesterol contents. Conversely, ASGR1 overexpression in &lt;i&gt;ApoE&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt; mice increased atherosclerotic lesions in the aorta and aortic root sections, augmented plasma VLDL cholesterol and LDL cholesterol levels and VLDL production, and decreased fecal cholesterol contents. Mechanistically, ASGR1 deficiency reduced VLDL production by inhibiting the expression of MTTP (microsomal triglyceride transfer protein) and ANGPTL3 (angiopoietin-like protein 3)/ANGPTL8 (angiopoietin-like protein 8) but increasing LPL (lipoprotein lipase) activity, increased LDL uptake by increasing LDLR (LDL receptor) expression, and promoted cholesterol efflux through increasing expression of LXRα (liver X receptor-α), ABCA1 (ATP-binding cassette subfamily A member 1), ABCG5 (ATP-binding cassette subfamily G member 5), and CYP7A1 (cytochrome P450 family 7 subfamily A member 1). These underlying alterations were confirmed in ASGR1-overexpressing &lt;i&gt;ApoE&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt; mice. In addition, ASGR1 deficiency exacerbates liver injury in Western diet-induced &lt;i&gt;Asgr1&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt;&lt;i&gt;ApoE&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt; mice and high-fat diet-induced but not normal laboratory diet-induced and high-fat and high-cholesterol diet-induced &lt;i&gt;Asgr1&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt; mice, while its overexpression mitigates liver injury in Western diet-induced ASGR1-overexpressing &lt;i&gt;ApoE&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt; mice.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Inhibition of ASGR1 inhibits atherosclerosis in Western diet-fed &lt;i&gt;ApoE&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt; mi","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2428-2449"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11593992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387525","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":"Exploring Platelet Dysregulation in Congenital Heart Disease: Novel Findings From Mass Cytometry.","authors":"Roxane Darbousset","doi":"10.1161/ATVBAHA.124.321664","DOIUrl":"10.1161/ATVBAHA.124.321664","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2540-2542"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456858","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":"Gut Microbiome Diversity and Composition Correlates With Time in the Therapeutic Range in Patients on Warfarin Treatment: A Pilot Study.","authors":"Pasquale Agosti, Afroditi Kouraki, Tommaso Dionisi, Giovanni Addolorato, Luca D'Innocenzo, Silvia Sorrentino, Flavio De Maio, Erica De Candia, Aitor Blanco-Miguez, Davide Bazzani, Angela Bonadiman, Guendalina Tonidandel, Mattia Bolzan, Francesca Gianniello, Serena M Passamonti, Maria Abbattista, Ana M Valdes, Paolo Bucciarelli, Flora Peyvandi, Cristina Menni","doi":"10.1161/ATVBAHA.124.321490","DOIUrl":"10.1161/ATVBAHA.124.321490","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2659-2661"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543371","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":"<i>PARP15</i> Is a Susceptibility Locus for Clarkson Disease (Monoclonal Gammopathy-Associated Systemic Capillary Leak Syndrome).","authors":"Eunice C Chan, Ararat J Ablooglu, Chandra C Ghosh, Abhishek Desai, Niccole Schaible, Xiuying Chen, Ming Zhao, M Renee Olano, Sundar Ganesan, Justin B Lack, Ramaswamy Krishnan, Samir M Parikh, Kirk M Druey","doi":"10.1161/ATVBAHA.124.321522","DOIUrl":"10.1161/ATVBAHA.124.321522","url":null,"abstract":"<p><strong>Background: </strong>Vascular leakage is a deadly complication of severe infections, ranging from bacterial sepsis to malaria. Worldwide, septicemia is among the top 10 causes of lethality because of the shock and multiorgan dysfunction that arise from the host vascular response. In the monoclonal gammopathy-associated capillary leak syndrome (MG-CLS), even otherwise mundane infections induce recurrent septic-like episodes of profound microvascular hyperpermeability and shock. There are no defined genetic risk factors for MG-CLS or effective treatments for acute crises.</p><p><strong>Methods: </strong>We characterized predicted loss-of-function mutations in PARP15 (poly[ADP-ribose] polymerase 15), a protein of unknown function that is absent in mice, in patients with MG-CLS. We analyzed barrier function in PARP15-deficient vascular endothelial cells and vascular leakage in mice engineered to express wild-type or loss-of-function variant human PARP15.</p><p><strong>Results: </strong>We discovered several loss-of-function PARP15 variants associated with MG-CLS. These mutations severely reduced PARP15 enzymatic function. The presence of the most frequently detected variant (G628R) correlated with clinical markers of severe vascular leakage. In human microvascular endothelial cells, PARP15 suppressed cytokine-induced barrier disruption by ADP-ribosylating the scaffold protein JIP3 (c-Jun N-terminal kinase-interacting protein 3) and inhibiting p38 MAP (mitogen-activated protein) kinase activation. Mice expressing enzymatically inactive human PARP15(G628R) were significantly more prone to inflammation-associated vascular leakage than mice expressing wild-type PARP15 in a p38-dependent fashion.</p><p><strong>Conclusions: </strong><i>PARP15</i> represents a previously unrecognized genetic susceptibility factor for MG-CLS. PARP15-mediated ADP ribosylation is an essential and genetically determined mechanism of the human vascular response to inflammation.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2628-2646"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543369","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":"lncRNA VELRP Modulates Pulmonary Arterial Smooth Muscle Cell Proliferation and Promotes Vascular Remodeling in Pulmonary Hypertension.","authors":"Cuilian Liu, Jidong Chen, Xingtao Huang, Qinyi Xia, Lei Yang, Jiao Guo, Jinglin Tian, Jun Wang, Yanqin Niu, Li Li, Deming Gou","doi":"10.1161/ATVBAHA.124.321416","DOIUrl":"10.1161/ATVBAHA.124.321416","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary hypertension is a devastating vascular disorder characterized by extensive pulmonary vascular remodeling, ultimately leading to right ventricular failure and death. Activation of PDGF (platelet-derived growth factor) signaling promotes the hyperproliferation of pulmonary arterial smooth muscle cells (PASMCs), thus contributing to the pulmonary vascular remodeling. However, the molecular mechanisms that govern hyperproliferation of PASMCs induced by PDGF remain largely unknown, including the contribution of long noncoding RNAs (lncRNAs). In this study, we aimed to identify a novel lncRNA regulated by PDGF implicated in PASMC proliferation in pulmonary vascular remodeling.</p><p><strong>Methods: </strong>RNA-sequencing analysis was conducted to identify a novel lncRNA named vessel-enriched lncRNA regulated by PDGF-BB (platelet-derived growth factor-BB; VELRP). Functional investigations of VELRP were performed using knockdown and overexpression strategies along with RNA sequencing. Validation of the function and potential mechanisms of VELRP was performed through Western blot, RNA immunoprecipitation, and chromatin immunoprecipitation assays.</p><p><strong>Results: </strong>We identified a novel vessel-enriched lncRNA with an increased response to PDGF-BB stimulus. VELRP was identified as an evolutionarily conserved RNA molecule. Modulation of VELRP in PASMCs significantly altered cell proliferation. Mechanistically, VELRP enhances trimethylation of H3K4 (histone H3 lysine 4) by interacting with WDR5 (WD repeat-containing protein 5), leading to increased expression of CDK (cyclin-dependent kinase) 1, CDK2, and CDK4 and consequent hyperproliferation of PASMCs. The pathological relevance of VELRP upregulation in pulmonary artery was confirmed using rat pulmonary hypertension models in vivo, as well as in PASMCs from patients with idiopathic pulmonary arterial hypertension. Specific knockdown of VELRP in smooth muscle cells using adeno-associated virus type 9 SM22α (smooth muscle protein 22α) promoter-shRNA-mediated silencing of VELRP resulted in a significant decrease in right ventricular systolic pressure and vascular remodeling in rat pulmonary hypertension model.</p><p><strong>Conclusions: </strong>VELRP, as an lncRNA upregulated by PDGF-BB, mediates PASMC proliferation via WDR5/CDK signaling. In vivo studies demonstrate that targeted intervention of VELRP in smooth muscle cells can prevent the development of pulmonary hypertension.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2560-2576"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364168","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":"Radiation-Induced Macrovessel/Microvessel Disease.","authors":"Jun-Ichi Abe, Bryan G Allen, Andreas M Beyer, David Lewandowski, Kranti A Mapuskar, Vikram Subramanian, Michelle R Tamplin, Isabella M Grumbach","doi":"10.1161/ATVBAHA.124.319866","DOIUrl":"10.1161/ATVBAHA.124.319866","url":null,"abstract":"<p><p>Radiation therapy (RT) is a cornerstone in cancer treatment (used in 50% of cases), yet challenges persist because damage to normal tissue through direct impact of radiation or bystander effects is inevitable. Injury of macrovessels by RT manifests as obstructive disease, which is akin to atherosclerotic disease. Historically observed in coronary arteries of patients treated for breast cancer and lymphoma, it also affects patients receiving contemporary therapy for lung and chest cancers. Moreover, radiation at various sites can lead to peripheral vascular disease. An aspect of radiation-induced injury that has received little attention is microvascular injury, which typically results from damage to the endothelium and is considered the primary driver of RT-induced toxicity in the skin, kidney, and brain. This review delves into the clinical manifestations of RT-induced vascular disease, signaling pathways, cellular targets affected by radiation injury, and preclinical models of RT-induced vascular injury. The goal is to inspire the development of innovative strategies to prevent RT-related cardiovascular disease.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2407-2415"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493710","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":"COVID-19 Is a Coronary Artery Disease Risk Equivalent and Exhibits a Genetic Interaction With ABO Blood Type.","authors":"James R Hilser, Neal J Spencer, Kimia Afshari, Frank D Gilliland, Howard Hu, Arjun Deb, Aldons J Lusis, WH Wilson Tang, Jaana A Hartiala, Stanley L Hazen, Hooman Allayee","doi":"10.1161/ATVBAHA.124.321001","DOIUrl":"10.1161/ATVBAHA.124.321001","url":null,"abstract":"<p><strong>Background: </strong>COVID-19 is associated with acute risk of major adverse cardiac events (MACE), including myocardial infarction, stroke, and mortality (all-cause). However, the duration and underlying determinants of heightened risk of cardiovascular disease and MACE post-COVID-19 are not known.</p><p><strong>Methods: </strong>Data from the UK Biobank was used to identify COVID-19 cases (n=10 005) who were positive for polymerase chain reaction (PCR⁺)-based tests for SARS-CoV-2 infection (n=8062) or received hospital-based <i>International Classification of Diseases version-10 (ICD-10</i>) codes for COVID-19 (n=1943) between February 1, 2020 and December 31, 2020. Population controls (n=217 730) and propensity score-matched controls (n=38 860) were also drawn from the UK Biobank during the same period. Proportional hazard models were used to evaluate COVID-19 for association with long-term (>1000 days) risk of MACE and as a coronary artery disease risk equivalent. Additional analyses examined whether COVID-19 interacted with genetic determinants to affect the risk of MACE and its components.</p><p><strong>Results: </strong>The risk of MACE was elevated in COVID-19 cases at all levels of severity (HR, 2.09 [95% CI, 1.94-2.25]; <i>P</i><0.0005) and to a greater extent in cases hospitalized for COVID-19 (HR, 3.85 [95% CI, 3.51-4.24]; <i>P</i><0.0005). Hospitalization for COVID-19 represented a coronary artery disease risk equivalent since incident MACE risk among cases without history of cardiovascular disease was even higher than that observed in patients with cardiovascular disease without COVID-19 (HR, 1.21 [95% CI, 1.08-1.37]; <i>P</i><0.005). A significant genetic interaction was observed between the <i>ABO</i> locus and hospitalization for COVID-19 (<i>P</i>_interaction=0.01), with risk of thrombotic events being increased in subjects with non-O blood types (HR, 1.65 [95% CI, 1.29-2.09]; <i>P</i>=4.8×10^-5) to a greater extent than subjects with blood type O (HR, 0.96 [95% CI, 0.66-1.39]; <i>P</i>=0.82).</p><p><strong>Conclusions: </strong>Hospitalization for COVID-19 represents a coronary artery disease risk equivalent, with post-acute myocardial infarction and stroke risk particularly heightened in non-O blood types. These results may have important clinical implications and represent, to our knowledge, one of the first examples of a gene-pathogen exposure interaction for thrombotic events.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2321-2333"},"PeriodicalIF":7.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387526","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":"Decoding Macrophage Heterogeneity to Unravel Vascular Inflammation as a Path to Precision Medicine.","authors":"Sarvesh Chelvanambi, Julius L Decano, Holger Winkels, Chiara Giannarelli, Masanori Aikawa","doi":"10.1161/ATVBAHA.124.319571","DOIUrl":"10.1161/ATVBAHA.124.319571","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"44 11","pages":"2253-2257"},"PeriodicalIF":7.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11715277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493715","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":"GP VI-Mediated Platelet Activation and Procoagulant Activity Aggravate Inflammation and Aortic Wall Remodeling in Abdominal Aortic Aneurysm.","authors":"Tobias Feige, Agnes Bosbach, Kim J Krott, Joscha Mulorz, Madhumita Chatterjee, Julia Ortscheid, Evelyn Krüger, Irena Krüger, Niloofar Salehzadeh, Silvia Goebel, Wiebke Ibing, Maria Grandoch, Götz Münch, Markus U Wagenhäuser, Hubert Schelzig, Margitta Elvers","doi":"10.1161/ATVBAHA.123.320615","DOIUrl":"10.1161/ATVBAHA.123.320615","url":null,"abstract":"<p><strong>Background: </strong>Platelets play an important role in cardiovascular and cerebrovascular diseases. Abdominal aortic aneurysm (AAA) is a highly lethal, atherosclerosis-related disease with characteristic features of progressive dilatation of the abdominal aorta and degradation of the vessel wall, accompanied by chronic inflammation. Platelet activation and procoagulant activity play a decisive role in the AAA pathology as they might trigger AAA development in both mice and humans.</p><p><strong>Methods: </strong>The present study investigated the impact of the major platelet collagen receptor GP (platelet glycoprotein) VI in pathophysiological processes underlying AAA initiation and progression. For experimental AAA induction in mice, PPE (porcine pancreatic elastase) and the external PPE model were used.</p><p><strong>Results: </strong>Genetic deletion of GP VI offered protection of mice against aortic diameter expansion in experimental AAA. Mechanistically, GP VI deficiency resulted in decreased inflammation with reduced infiltration of neutrophils and platelets into the aortic wall. Furthermore, remodeling of the aortic wall was improved in the absence of GP VI, as indicated by reduced MMP (matrix metalloproteinase)-2/9 and OPN (osteopontin) plasma levels and an enhanced α-SMA (α-smooth muscle actin) content within the aortic wall, accompanied by reduced cell apoptosis. Consequently, an elevation in intima/media thickness and elastin content was observed in GP VI-deficient PPE mice, resulting in a significantly reduced aortic diameter expansion and reduced aneurysm incidence. In patients with AAA, enhanced plasma levels of soluble GP VI and fibrin, as well as fibrin accumulation within the intraluminal thrombus might serve as new biomarkers to detect AAA early. Moreover, we hypothesize that GP VI might play a role in procoagulant activity and thrombus stabilization via binding to fibrin.</p><p><strong>Conclusions: </strong>In conclusion, our results emphasize the potential need for a GP VI-targeted antiplatelet therapy to reduce AAA initiation and progression, as well as to protect patients with AAA from aortic rupture.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2294-2317"},"PeriodicalIF":7.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103905","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}