Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Nanoparticle-Directed Antioxidant Therapy Can Ameliorate Disease Progression in a Novel, Diet-Inducible Model of Coronary Artery Disease.","authors":"Shi Su, Zhifen Chen, Qingen Ke, Olivier Kocher, Monty Krieger, Peter M Kang","doi":"10.1161/ATVBAHA.124.321030","DOIUrl":"10.1161/ATVBAHA.124.321030","url":null,"abstract":"<p><strong>Background: </strong>Oxidative stress plays a crucial role in the pathogenesis of coronary artery disease. In cardiovascular research using murine models, the generation and maintenance of models with robust coronary arterial atherosclerosis has been challenging.</p><p><strong>Methods: </strong>We characterized a new mouse model in which the last 3 amino acids of the carboxyl terminus of the HDL (high-density lipoprotein) receptor (SR-B1 [scavenger receptor, class B, type 1]) were deleted in a low-density lipoprotein receptor knockout (LDLR^-/-) mouse model (SR-B1ΔCT/LDLR^-/-) fed an atherogenic diet. We also tested the therapeutic effects of an oxidative stress-targeted nanoparticle in atherogenic diet-fed SR-B1ΔCT/LDLR^-/- mice.</p><p><strong>Results: </strong>The SR-B1ΔCT/LDLR^-/- mice fed an atherogenic diet had occlusive coronary artery atherosclerosis, impaired cardiac function, and a dramatically lower survival rate, compared with LDLR^-/- mice fed the same diet. As SR-B1ΔCT/LDLR^-/- mice do not exhibit female infertility or low pup yield, they are far easier and less costly to use than the previously described SR-B1-based models of coronary artery disease. We found that treatment with the targeted nanoparticles improved the cardiac functions and corrected hematologic abnormalities caused by the atherogenic diet in SR-B1ΔCT/LDLR^-/- mice but did not alter the distinctive plasma lipid levels.</p><p><strong>Conclusions: </strong>The SR-B1ΔCT/LDLR^-/- mice developed diet-inducible, fatal atherosclerotic coronary artery disease, which could be ameliorated by targeted nanoparticle therapy. Our study provides new tools for the development of cardiovascular therapies.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2476-2488"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456859","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":"Immunoregulatory Macrophages Modify Local Pulmonary Immunity and Ameliorate Hypoxic Pulmonary Hypertension.","authors":"Angeles Fernandez-Gonzalez, Amit Mukhia, Janhavi Nadkarni, Gareth R Willis, Monica Reis, Kristjan Zhumka, Sally Vitali, Xianlan Liu, Alexandra Galls, S Alex Mitsialis, Stella Kourembanas","doi":"10.1161/ATVBAHA.124.321264","DOIUrl":"10.1161/ATVBAHA.124.321264","url":null,"abstract":"<p><strong>Background: </strong>Macrophages play a significant role in the onset and progression of vascular disease in pulmonary hypertension, and cell-based immunotherapies aimed at treating vascular remodeling are lacking. We aimed to evaluate the effect of pulmonary administration of macrophages modified to have an anti-inflammatory/proresolving phenotype in attenuating early pulmonary inflammation and progression of experimentally induced pulmonary hypertension.</p><p><strong>Methods: </strong>Mouse bone marrow-derived macrophages were polarized in vitro to a regulatory (M2_reg) phenotype. M2_reg profile and anti-inflammatory capacity were assessed in vitro upon lipopolysaccharide/IFNγ (interferon-γ) restimulation, before their administration to 8- to 12-week-old mice. M2_reg protective effect was evaluated at early (2-4 days) and late (4 weeks) time points during hypoxia (8.5% O₂) exposure. Levels of inflammatory markers were quantified in alveolar macrophages and whole lung, while pulmonary hypertension development was ascertained by right ventricular systolic pressure (RVSP) and right ventricular hypertrophy measurements. Bronchoalveolar lavage from M2_reg-transplanted hypoxic mice was collected and its inflammatory potential evaluated on naive bone marrow-derived macrophages.</p><p><strong>Results: </strong>M2_reg macrophages expressing <i>Tgf</i>β, <i>Il10</i>, and <i>Cd206</i> demonstrated a stable anti-inflammatory phenotype in vitro, by downregulating the induction of proinflammatory cytokines and surface molecules (<i>Cd86</i>, <i>Il6</i>, and <i>Tnf</i>α) upon a subsequent proinflammatory stimulus. A single dose of M2_regs attenuated hypoxic monocytic recruitment and perivascular inflammation. Early hypoxic lung and alveolar macrophage inflammation leading to pulmonary hypertension development was significantly reduced, and, importantly, M2_regs attenuated right ventricular hypertrophy, right ventricular systolic pressure, and vascular remodeling at 4 weeks post-treatment.</p><p><strong>Conclusions: </strong>Adoptive transfer of M2_regs halts the recruitment of monocytes and modifies the hypoxic lung microenvironment, potentially changing the immunoreactivity of recruited macrophages and restoring normal immune functionality of the lung. These findings provide new mechanistic insights into the diverse role of macrophage phenotype on lung vascular homeostasis that can be explored as novel therapeutic targets.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e288-e303"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387527","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":"Real-Time Imaging Assessment of Stress-Induced Vascular Inflammation Using Heartbeat-Synchronized Motion Compensation.","authors":"Minseok A Jang, Joon Woo Song, Ryeong Hyun Kim, Dong Oh Kang, Ungyo Kang, Hyun Jung Kim, Jin Hyuk Kim, Eun Jin Park, Ye Hee Park, Bo-Hyung Lee, Chi Kyung Kim, Kyeongsoon Park, Jin Won Kim, Hongki Yoo","doi":"10.1161/ATVBAHA.124.321566","DOIUrl":"10.1161/ATVBAHA.124.321566","url":null,"abstract":"<p><strong>Background: </strong>Chronic mental stress accelerates atherosclerosis through complicated neuroimmune pathways, needing for advanced imaging techniques to delineate underlying cellular mechanisms. While histopathology, ex vivo imaging, and snapshots of in vivo images offer promising evidence, they lack the ability to capture real-time visualization of blood cell dynamics within pulsatile arteries in longitudinal studies.</p><p><strong>Methods: </strong>An electrically tunable lens was implemented in intravital optical microscopy, synchronizing the focal plane with heartbeats to follow artery movements. ApoE^-/- mice underwent 2 weeks of restraint stress before baseline imaging followed by 2 weeks of stress exposure in the longitudinal imaging, while nonstressed mice remained undisturbed. The progression of vascular inflammation was assessed in the carotid arteries through intravital imaging and histological analyses.</p><p><strong>Results: </strong>A 4-fold reduction of motion artifact, assessed by interframe SD, and an effective temporal resolution of 25.2 Hz were achieved in beating murine carotid arteries. Longitudinal intravital imaging showed chronic stress led to a 6.09-fold (<i>P</i>=0.017) increase in myeloid cell infiltration compared with nonstressed mice. After 3 weeks, we observed that chronic stress intensified vascular inflammation, increasing adhered myeloid cells by 2.45-fold (<i>P</i>=0.031), while no significant changes were noted in nonstressed mice. Microcirculation imaging revealed increased circulating, rolling, and adhered cells in stressed mice's venules. Histological analysis of the carotid arteries confirmed the in vivo findings that stress augmented plaque area, myeloid cell and macrophage accumulation, and necrotic core volume while reducing fibrous cap thickness indicating accelerated plaque formation. We visualized the 3-dimensional structure of the carotid artery and 4-dimensional dynamics of the venules in the cremaster muscle.</p><p><strong>Conclusions: </strong>Dynamic focusing motion compensation intravital microscopy enabled subcellular resolution in vivo imaging of blood cell dynamics in beating arteries under chronic restraint stress in real time. This novel technique emphasizes the importance of advanced in vivo imaging for understanding cardiovascular disease.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2493-2506"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387529","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":"NETosis in Cardiovascular Disease: An Opportunity for Personalized Antithrombotic Treatments?","authors":"Constance C F M J Baaten, Magdolna Nagy, Henri M H Spronk, Hugo Ten Cate, Bas L J H Kietselaer","doi":"10.1161/ATVBAHA.124.320150","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.320150","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"44 12","pages":"2366-2370"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738154","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":"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}