Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Trem2/Tyrobp Signaling Protects Against Aortic Dissection and Rupture by Inhibiting Macrophage Activation in Mice.","authors":"Zenghui Zhang, Maoxiong Wu, Lei Yao, Weibin Zhou, Xiao Liu, Zhiteng Chen, Ping Hua, Leibo Xu, Lei Lv, Chiyu Liu, Chunling Huang, Sixu Chen, Zhaoqi Huang, Yuna Huang, Jiaqi He, Tingfeng Chen, Jingfeng Wang, Woliang Yuan, Zhaoyu Liu, Yangxin Chen","doi":"10.1161/ATVBAHA.124.321429","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321429","url":null,"abstract":"<p><strong>Background: </strong>The development of aortic dissection (AD) is closely associated with inflammation. The Trem2 (triggering receptor expressed on myeloid cells 2)/Tyrobp (TYRO protein tyrosine kinase-binding protein) signaling pathway critically regulates innate immunity and has emerged as an important target in cardiovascular diseases; however, its role in AD remains unclear.</p><p><strong>Methods: </strong>Transcriptome data from human and mouse ADs were used to perform differentially expressed gene-based protein-protein interaction network analyses. <i>Tyrobp</i> knockout (Tyrobp^-/-), myeloid cell-specific <i>Tyrobp</i>^-/- (Tyrobp^fl/fl Lyz2^cre), and <i>Trem2</i> knockout (Trem2^-/^-) mice were given β-aminopropionitrile monofumarate in drinking water to induce AD. To dissect the role of macrophages in <i>Tyrobp</i> deficiency-mediated AD progression, macrophages were depleted using clodronate liposomes. Bulk and single-cell RNA sequencing, immunofluorescence staining, and quantitative real-time polymerase chain reaction were performed to assess inflammation and the underlying mechanisms of Tyrobp in AD.</p><p><strong>Results: </strong>Network analysis identified <i>Tyrobp</i> as a hub gene of AD, with elevated levels observed in both human and mouse ADs. Global deletion and myeloid cell-specific deficiency of <i>Tyrobp</i> in mice significantly increased AD incidence and exacerbated extracellular matrix degradation and macrophage infiltration within the aortic wall. Macrophage depletion mitigated the adverse effects of <i>Tyrobp</i> deficiency on AD progression. Additionally, <i>Tyrobp</i> deficiency enhanced TLR (Toll-like receptor)-4 signaling and macrophage activation, which were abrogated by TLR4 inhibitors. Furthermore, deletion of the Tyrobp-associated receptor <i>Trem2</i> significantly aggravated mouse AD development, whereas Trem2 agonist treatment conferred protection against AD.</p><p><strong>Conclusions: </strong>Our findings suggest a novel role for the Trem2/Tyrobp axis in AD development in mice. Enhancement of Trem2/Tyrobp signaling may represent a promising strategy for the prevention and treatment of AD. Future studies to clarify the role of Trem2/Tyrobp in human AD are warranted.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589787","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":"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}

{"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":"https://doi.org/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":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SPA Promotes Atherosclerosis Through Mediating Macrophage Foam Cell Formation-Brief Report.","authors":"Skylar D King, Dunpeng Cai, Alisha Pillay, Mikayla M Fraunfelder, Lee-Ann H Allen, Shi-You Chen","doi":"10.1161/ATVBAHA.124.321460","DOIUrl":"10.1161/ATVBAHA.124.321460","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerosis is a progressive inflammatory disease in which macrophage foam cells play a central role in disease pathogenesis. SPA (surfactant protein A) is a lipid-associating protein involved with regulating macrophage function in various inflammatory diseases. However, the role of SPA in atherosclerosis and macrophage foam cell formation has not been investigated.</p><p><strong>Methods: </strong>SPA expression was assessed in healthy and atherosclerotic human coronary arteries and the brachiocephalic arteries of wild-type or ApoE-deficient mice fed high-fat diets for 4 weeks. Hypercholesteremic wild-type and SPA-deficient mice fed a high-fat diet for 6 weeks were investigated for atherosclerotic lesions in vivo. In vitro experiments using RAW264.7 macrophages, primary resident peritoneal macrophages extracted from wild-type or SPA-deficient mice, and human monocyte-derived macrophages from the peripheral blood of healthy donors determined the functional effects of SPA in macrophage foam cell formation.</p><p><strong>Results: </strong>SPA expression was increased in atherosclerotic lesions in humans and ApoE-deficient mice and in response to a proatherosclerotic stimulus in vitro. SPA deficiency reduced the lipid profiles induced by hypercholesterolemia, attenuated atherosclerosis, and reduced the number of lesion-associated macrophage foam cells. In vitro studies revealed that SPA deficiency reduced intracellular cholesterol accumulation and macrophage foam cell formation. Mechanistically, SPA deficiency dramatically downregulated the expression of scavenger receptor CD36 (cluster of differentiation antigen 36) cellular and lesional expression. Importantly, SPA also increased CD36 expression in human monocyte-derived macrophages.</p><p><strong>Conclusions: </strong>Our results elucidate that SPA is a novel factor promoting atherosclerosis development. SPA enhances macrophage foam cell formation and atherosclerosis by increasing scavenger receptor CD36 expression, leading to increasing cellular OxLDL influx.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e277-e287"},"PeriodicalIF":7.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11499019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364169","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":"Spatial Transcriptomics: A New Frontier in Atherosclerosis Research?","authors":"Jennifer E Cole, Claudia Monaco","doi":"10.1161/ATVBAHA.124.321652","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321652","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"44 11","pages":"2291-2293"},"PeriodicalIF":7.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493717","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":"Ethnic Diversity and Distinctive Features of Familial Versus Multifactorial Chylomicronemia Syndrome: Insights From the UK FCS National Registry.","authors":"Bilal Bashir, Paul Downie, Natalie Forrester, Anthony S Wierzbicki, Charlotte Dawson, Alan Jones, Fiona Jenkinson, Michael Mansfield, Dev Datta, Hannah Delaney, Yee Teoh, Paul Hamilton, Maryam Ferdousi, See Kwok, Dawn O'Sullivan, Jian Wang, Robert A Hegele, Paul N Durrington, Handrean Soran","doi":"10.1161/ATVBAHA.124.320955","DOIUrl":"10.1161/ATVBAHA.124.320955","url":null,"abstract":"<p><strong>Background: </strong>Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to study the genotype distribution of FCS-causing genes in the United Kingdom, genotype-phenotype correlation, and clinical differences between FCS and multifactorial chylomicronemia syndrome (MCS).</p><p><strong>Methods: </strong>The study included 154 patients (FCS, 74; MCS, 80) from the UK FCS national registry and the UK arm of the FCS International Quality Improvement and Service Evaluation Project.</p><p><strong>Results: </strong>FCS was relatively common in non-Europeans and those with parental consanguinity (<i>P</i><0.001 for both). <i>LPL</i> variants were more common in European patients with FCS (European, 64%; non-European, 46%), while the genotype was more diverse in non-European patients with FCS. Patients with FCS had a higher incidence compared with patients with MCS of acute pancreatitis (84% versus 60%; <i>P</i>=0.001), recurrent pancreatitis (92% versus 63%; <i>P</i><0.001), unexplained abdominal pain (84% versus 52%; <i>P</i><0.001), earlier age of onset (median [interquartile range]) of symptoms (15.0 [5.5-26.5] versus 34.0 [25.2-41.7] years; <i>P</i><0.001), and of acute pancreatitis (24.0 [10.7-31.0] versus 33.5 [26.0-42.5] years; <i>P</i><0.001). Adverse cardiometabolic features and their co-occurrence was more common in individuals with MCS compared with those with FCS (<i>P</i><0.001 for each). Atherosclerotic cardiovascular disease was more prevalent in individuals with MCS than those with FCS (<i>P</i>=0.04). However, this association became nonsignificant after adjusting for age, sex, and body mass index. The prevalence of pancreatic complications and cardiometabolic profile of variant-positive MCS was intermediate between FCS and variant-negative MCS.</p><p><strong>Conclusions: </strong>The frequency of gene variant distribution varies based on the ethnic origin of patients with FCS. Patients with FCS are at a higher risk of pancreatic complications while the prevalence of atherosclerotic cardiovascular disease is lower in FCS compared with MCS. Carriers of heterozygous pathogenic variants have an intermediate phenotype between FCS and variant-negative MCS.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2334-2346"},"PeriodicalIF":7.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131696","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":"Spatial Transcriptomic Approach to Understanding Coronary Atherosclerotic Plaque Stability.","authors":"Maria G Gastanadui, Camilla Margaroli, Silvio Litovsky, Robert P Richter, Dezhi Wang, Dongqi Xing, J Michael Wells, Amit Gaggar, Vivek Nanda, Rakesh P Patel, Gregory A Payne","doi":"10.1161/ATVBAHA.123.320330","DOIUrl":"10.1161/ATVBAHA.123.320330","url":null,"abstract":"<p><strong>Background: </strong>Coronary atherosclerotic plaques susceptible to acute coronary syndrome have traditionally been characterized by their surrounding cellular architecture. However, with the advent of intravascular imaging, novel mechanisms of coronary thrombosis have emerged, challenging our contemporary understanding of acute coronary syndrome. These intriguing findings underscore the necessity for a precise molecular definition of plaque stability. Considering this, our study aimed to investigate the vascular microenvironment in patients with stable and unstable plaques using spatial transcriptomics.</p><p><strong>Methods: </strong>Autopsy-derived coronary arteries were preserved and categorized by plaque stability (n=5 patients per group). We utilized the GeoMx spatial profiling platform and Whole Transcriptome Atlas to link crucial histological morphology markers in coronary lesions with differential gene expression in specific regions of interest, thereby mapping the vascular transcriptome. This innovative approach allowed us to conduct cell morphological and spatially resolved transcriptional profiling of atherosclerotic plaques while preserving crucial intercellular signaling.</p><p><strong>Results: </strong>We observed intriguing spatial and cell-specific transcriptional patterns in stable and unstable atherosclerotic plaques, showcasing regional variations within the intima and media. These regions exhibited differential expression of proinflammatory molecules (eg, IFN-γ [interferon-γ], MHC [major histocompatibility complex] class II, proinflammatory cytokines) and prothrombotic signaling pathways. By using lineage tracing through spatial deconvolution of intimal CD68⁺ (cluster of differentiation 68) cells, we characterized unique, intraplaque subpopulations originating from endothelial, smooth muscle, and myeloid lineages with distinct regional locations associated with plaque instability. In addition, unique transcriptional signatures were observed in vascular smooth muscle and CD68⁺ cells among plaques exhibiting coronary calcification.</p><p><strong>Conclusions: </strong>Our study illuminates distinct cell-specific and regional transcriptional alterations present in unstable plaques. Furthermore, we characterize spatially resolved, in situ evidence supporting cellular transdifferentiation and intraplaque plasticity as significant contributors to plaque instability in human coronary atherosclerosis. Our results provide a powerful resource for the identification of novel mediators of acute coronary syndrome, opening new avenues for preventative and therapeutic treatments.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e264-e276"},"PeriodicalIF":7.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11499036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131697","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":"Rap1A Modulates Store-Operated Calcium Entry in the Lung Endothelium: A Novel Mechanism Controlling NFAT-Mediated Vascular Inflammation and Permeability.","authors":"Ramoji Kosuru, Olivier Romito, Guru Prasad Sharma, Francesca Ferraresso, Behshid Ghadrdoost Nakhchi, Kai Yang, Tadanori Mammoto, Akiko Mammoto, Christian J Kastrup, David X Zhang, Paul H Goldspink, Mohamed Trebak, Magdalena Chrzanowska","doi":"10.1161/ATVBAHA.124.321458","DOIUrl":"10.1161/ATVBAHA.124.321458","url":null,"abstract":"<p><strong>Background: </strong>Store-operated calcium entry mediated by STIM (stromal interaction molecule)-1-Orai1 (calcium release-activated calcium modulator 1) is essential in endothelial cell (EC) functions, affecting signaling, NFAT (nuclear factor for activated T cells)-induced transcription, and metabolic programs. While the small GTPase Rap1 (Ras-proximate-1) isoforms, including the predominant Rap1B, are known for their role in cadherin-mediated adhesion, EC deletion of Rap1A after birth uniquely disrupts lung endothelial barrier function. Here, we elucidate the specific mechanisms by which Rap1A modulates lung vascular integrity and inflammation.</p><p><strong>Methods: </strong>The role of EC Rap1A in lung inflammation and permeability was examined using in vitro and in vivo approaches.</p><p><strong>Results: </strong>We explored Ca²⁺ signaling in human ECs following siRNA-mediated knockdown of Rap1A or Rap1B. Rap1A knockdown, unlike Rap1B, significantly increased store-operated calcium entry in response to a GPCR (G-protein-coupled receptor) agonist, ATP (500 µmol/L), or thapsigargin (250 nmol/L). This enhancement was attenuated by Orai1 channel blockers 10 μmol/L BTP2 (N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-4-methyl-1,2,3-thiadiazole-5-carboxamide), 10 μmol/L GSK-7975A, and 5 μmol/L Gd³⁺. Whole-cell patch clamp measurements revealed enhanced Ca²⁺ release-activated Ca²⁺ current density in siRap1A ECs. Rap1A depletion in ECs led to increased NFAT1 nuclear translocation and activity and elevated levels of proinflammatory cytokines (CXCL1 [C-X-C motif chemokine ligand 1], CXCL11 [C-X-C motif chemokine 11], CCL5 [chemokine (C-C motif) ligand 5], and IL-6 [interleukin-6]). Notably, reducing Orai1 expression in siRap1A ECs normalized store-operated calcium entry, NFAT activity, and endothelial hyperpermeability in vitro. EC-specific Rap1A knockout (Rap1A^iΔEC) mice displayed an inflammatory lung phenotype with increased lung permeability and inflammation markers, along with higher Orai1 expression. Delivery of siRNA against Orai1 to lung endothelium using lipid nanoparticles effectively normalized Orai1 levels in lung ECs, consequently reducing hyperpermeability and inflammation in Rap1A^iΔEC mice.</p><p><strong>Conclusions: </strong>Our findings uncover a novel role of Rap1A in regulating Orai1-mediated Ca²⁺ entry and expression, crucial for NFAT-mediated transcription and endothelial inflammation. This study distinguishes the unique function of Rap1A from that of the predominant Rap1B isoform and highlights the importance of normalizing Orai1 expression in maintaining lung vascular integrity and modulating endothelial functions.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2271-2287"},"PeriodicalIF":7.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340164","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":"What Is the Best Experimental Model for Developing Novel Therapeutics in Peripheral Artery Disease?","authors":"Anne Lejay, Winona W Wu, Salomé H Kuntz, Mark W Feinberg","doi":"10.1161/ATVBAHA.124.321163","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321163","url":null,"abstract":"<p><strong>Clinical problem: </strong>More than 200 million people worldwide have peripheral artery disease (PAD). PAD affects the quality of life and is associated with significant morbidity and mortality. Standard treatment for severe cases of PAD is surgical or endovascular revascularization. However, up to 30% of patients are not candidates for open or endovascular procedures, due to high operative risk or unfavorable vascular involvement. Furthermore, revascularization procedures may be insufficient to adequately improve microvascular tissue perfusion, wound healing, or limb salvage. Accordingly, regardless of advances in treatment modalities, outcomes of patients with PAD have remained unfavorable. Therefore, new medical therapeutic approaches are much needed. Small animal models are indispensable tools for the understanding of PAD physiopathology and the development of novel medical therapies.</p><p><strong>Recommendations for increasing translation from animal models: </strong>Development of animal models that more closely mimic the pathophysiology (with occlusive atherothrombosis and chronic development of limb ischemia) can incorporate the cardiovascular risk factors associated with this disease state, and focus on more clinically relevant outcomes is critical. In practice, this means using both animals that develop atherosclerosis and methods for the application of gradual arterial occlusion to induce hind limb ischemia. Doing so will likely help identify novel targets for intervention and overcome some principal challenges confronted by previous clinical trials. While various rodent models are discussed, the optimal animal model is yet to be defined.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"44 11","pages":"2264-2270"},"PeriodicalIF":7.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11501046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493718","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}