Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Time-Restricted Feeding Reduces Atherosclerosis in LDLR KO Mice but Not in ApoE Knockout Mice.","authors":"Amandine Chaix, Terry Lin, Bastian Ramms, Roy G Cutler, Tiffani Le, Catherine Lopez, Phuong Miu, Antonio F M Pinto, Alan Saghatelian, Martin P Playford, Nehal N Mehta, Mark P Mattson, Philip Gordts, Joseph L Witztum, Satchidananda Panda","doi":"10.1161/ATVBAHA.124.320998","DOIUrl":"10.1161/ATVBAHA.124.320998","url":null,"abstract":"<p><strong>Background: </strong>Dyslipidemia increases cardiovascular disease risk, the leading cause of death worldwide. Under time-restricted feeding (TRF), wherein food intake is restricted to a consistent window of <12 hours, weight gain, glucose intolerance, inflammation, dyslipidemia, and hypercholesterolemia are all reduced in mice fed an obesogenic diet. LDLR (low-density lipoprotein receptor) mutations are a major cause of familial hypercholesterolemia and early-onset cardiovascular disease.</p><p><strong>Methods: </strong>We subjected benchmark preclinical models, mice lacking LDLR-knockout or ApoE knockout to ad libitum feeding of an isocaloric atherogenic diet either ad libitum or 9 hours TRF for up to 13 weeks and assessed disease development, mechanism, and global changes in hepatic gene expression and plasma lipids. In a regression model, a subset of LDLR-knockout mice were ad libitum fed and then subject to TRF.</p><p><strong>Results: </strong>TRF could significantly attenuate weight gain, hypercholesterolemia, and atherosclerosis in mice lacking the LDLR-knockout mice under experimental conditions of both prevention and regression. In LDLR-knockout mice, increased hepatic expression of genes mediating β-oxidation during fasting is associated with reduced VLDL (very-low-density lipoprotein) secretion and lipid accumulation. Additionally, increased sterol catabolism coupled with fecal loss of cholesterol and bile acids contributes to the atheroprotective effect of TRF. Finally, TRF alone or combined with a cholesterol-free diet can reduce atherosclerosis in LDLR-knockout mice. However, mice lacking ApoE, which is an important protein for hepatic lipoprotein reuptake do not respond to TRF.</p><p><strong>Conclusions: </strong>In a preclinical animal model, TRF is effective in both the prevention and regression of atherosclerosis in LDLR knockout mice. The results suggest TRF alone or in combination with a low-cholesterol diet can be a lifestyle intervention for reducing cardiovascular disease risk in humans.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2069-2087"},"PeriodicalIF":7.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11409897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858933","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":"High-Dimensional Single-Cell Mass Cytometry Demonstrates Differential Platelet Functional Phenotypes in Infants With Congenital Heart Disease.","authors":"Sean X Gu, Brian S Marcus, Vivian W Gu, Adarsh P Varghese, John Hwa, E Vincent S Faustino","doi":"10.1161/ATVBAHA.124.321131","DOIUrl":"10.1161/ATVBAHA.124.321131","url":null,"abstract":"<p><strong>Background: </strong>Congenital heart disease (CHD) is a group of complex heart defects associated with hematologic abnormalities, including increased risk of thrombotic and bleeding events. Past studies have observed evidence of platelet hyperreactivity, while other studies showed decreased platelet activation in patients with CHD. The goal of this study was to develop a mass spectrometry approach to characterize single platelets in infants with CHD and identify potential etiology for such discrepant results.</p><p><strong>Methods: </strong>We enrolled 19 infants with CHD along with 21 non-CHD controls at Yale New Haven Children's Heart Center. A single-cell high-dimensional mass cytometry method was developed to quantitatively interrogate platelet surface markers in whole blood. Additionally, plasma cytokine analysis was performed through a multiplexed panel of 52 vascular and inflammatory markers to assess for platelet releasates.</p><p><strong>Results: </strong>We found that infants with CHD had significant differences in platelet activation and functional markers by mass cytometry compared with non-CHD controls. Based on cell surface markers, we classified the platelets into 8 subpopulations (P0 to P7). Distinct subpopulations of platelets (P1, P4, and P5) exhibiting decreased aggregatory phenotype but altered secretory phenotypes were also identified and found to be more abundant in the blood of infants with CHD. Electron microscopy identified increased proportion of hypogranular platelets in CHD. Moreover, cytokine analysis demonstrated an overall increase in plasma cytokines and biomarkers in CHD, including IL (interleukin)-6, IL-8, IL-27, RANTES, and VWF (von Willebrand factor), which are expressed in platelet granules and can be released upon activation.</p><p><strong>Conclusions: </strong>We developed a robust mass cytometry approach to identify platelet phenotypic heterogeneity. Infants with CHD had alterations in distinct subpopulations of platelets with overall reduced aggregatory phenotype and secretory dysfunction. These findings suggest that platelets in infants with CHD may be exhausted due to persistent stimulation and may explain both bleeding and thrombotic vascular complications associated with CHD.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016223","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":"Cavβ3 Contributes to the Maintenance of the Blood-Brain Barrier and Alleviates Symptoms of Experimental Autoimmune Encephalomyelitis.","authors":"Damian Martus, Sarah K Williams, Kira Pichi, Stefanie Mannebach-Götz, Nicolas Kaiser, Barbara Wardas, Claudia Fecher-Trost, Markus R Meyer, Frank Schmitz, Andreas Beck, Richard Fairless, Ricarda Diem, Veit Flockerzi, Anouar Belkacemi","doi":"10.1161/ATVBAHA.124.321141","DOIUrl":"10.1161/ATVBAHA.124.321141","url":null,"abstract":"<p><strong>Background: </strong>Tight control of cytoplasmic Ca²⁺ concentration in endothelial cells is essential for the regulation of endothelial barrier function. Here, we investigated the role of Cavβ3, a subunit of voltage-gated Ca²⁺ (Cav) channels, in modulating Ca²⁺ signaling in brain microvascular endothelial cells (BMECs) and how this contributes to the integrity of the blood-brain barrier.</p><p><strong>Methods: </strong>We investigated the function of Cavβ3 in BMECs by Ca²⁺ imaging and Western blot, examined the endothelial barrier function in vitro and the integrity of the blood-brain barrier in vivo, and evaluated disease course after induction of experimental autoimmune encephalomyelitis in mice using Cavβ3^-/- (Cavβ3-deficient) mice as controls.</p><p><strong>Results: </strong>We identified Cavβ3 protein in BMECs, but electrophysiological recordings did not reveal significant Cav channel activity. In vivo, blood-brain barrier integrity was reduced in the absence of Cavβ3. After induction of experimental autoimmune encephalomyelitis, Cavβ3^-/- mice showed earlier disease onset with exacerbated clinical disability and increased T-cell infiltration. In vitro, the transendothelial resistance of Cavβ3^-/- BMEC monolayers was lower than that of wild-type BMEC monolayers, and the organization of the junctional protein ZO-1 (zona occludens-1) was impaired. Thrombin stimulates inositol 1,4,5-trisphosphate-dependent Ca²⁺ release, which facilitates cell contraction and enhances endothelial barrier permeability via Ca²⁺-dependent phosphorylation of MLC (myosin light chain). These effects were more pronounced in Cavβ3^-/- than in wild-type BMECs, whereas the differences were abolished in the presence of the MLCK (MLC kinase) inhibitor ML-7. Expression of <i>Cacnb3</i> cDNA in Cavβ3^-/- BMECs restored the wild-type phenotype. Coimmunoprecipitation and mass spectrometry demonstrated the association of Cavβ3 with inositol 1,4,5-trisphosphate receptor proteins.</p><p><strong>Conclusions: </strong>Independent of its function as a subunit of Cav channels, Cavβ3 interacts with the inositol 1,4,5-trisphosphate receptor and is involved in the tight control of cytoplasmic Ca²⁺ concentration and Ca²⁺-dependent MLC phosphorylation in BMECs, and this role of Cavβ3 in BMECs contributes to blood-brain barrier integrity and attenuates the severity of experimental autoimmune encephalomyelitis disease.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1833-1851"},"PeriodicalIF":7.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490701","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":"Endothelial Autophagy Promotes Atheroprotective Communication Between Endothelial and Smooth Muscle Cells via Exosome-Mediated Delivery of miR-204-5p.","authors":"Zhen Tian, Hua Ning, Xinyue Wang, Yu Wang, Tianshu Han, Changhao Sun","doi":"10.1161/ATVBAHA.123.319993","DOIUrl":"10.1161/ATVBAHA.123.319993","url":null,"abstract":"<p><strong>Background: </strong>Cellular communication among different types of vascular cells is indispensable for maintaining vascular homeostasis and preventing atherosclerosis. However, the biological mechanism involved in cellular communication among these cells and whether this biological mechanism can be used to treat atherosclerosis remain unknown. We hypothesized that endothelial autophagy mediates the cellular communication in vascular tissue through exosome-mediated delivery of atherosclerosis-related genes.</p><p><strong>Methods: </strong>Rapamycin and adeno-associated virus carrying <i>Atg7</i> short hairpin RNA under the Tie (TEK receptor tyrosine kinase) promoter were used to activate and inhibit vascular endothelial autophagy in high-fat diet-fed <i>ApoE</i>^<i>-/-</i> mice, respectively. miRNA microarray, in vivo and in vitro experiments, and human vascular tissue were used to explore the effects of endothelial autophagy on endothelial function and atherosclerosis and its molecular mechanisms. Quantitative polymerase chain reaction and miRNA sequencing were performed to determine changes in miRNA expression in exosomes. Immunofluorescence and exosome coculture experiments were conducted to examine the role of endothelial autophagy in regulating the communication between endothelial cells and smooth muscle cells (SMCs) via exosomal miRNA.</p><p><strong>Results: </strong>Endothelial autophagy was inhibited in thoracic aortas of high-fat diet-fed <i>ApoE</i>^<i>-/</i>^<i>-</i> mice. Furthermore, rapamycin alleviated high-fat diet-induced atherosclerotic burden and endothelial dysfunction, while endothelial-specific <i>Atg7</i> depletion aggravated the atherosclerotic burden. miRNA microarray, in vivo and in vitro experiments, and human vascular tissue analysis revealed that miR-204-5p was significantly increased in endothelial cells after high-fat diet exposure, which directly targeted <i>Bcl2</i> to regulate endothelial cell apoptosis. Importantly, endothelial autophagy activation decreased excess miR-204-5p by loading miR-204-5p into multivesicular bodies and secreting it through exosomes. Moreover, exosomal miR-204-5p can effectively transport to SMCs, alleviating SMC calcification by regulating target proteins such as RUNX2 (runt-related transcription factor 2).</p><p><strong>Conclusions: </strong>Our study revealed the exosomal pathway by which endothelial autophagy protects atherosclerosis: endothelial autophagy activation transfers miR-204-5p from endothelial cells to SMCs via exosomes, both preventing endothelial apoptosis and alleviating SMC calcification.</p><p><strong>Registration: </strong>URL: https://www.chictr.org.cn/; Unique identifier: ChiCTR2200064155.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1813-1832"},"PeriodicalIF":7.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490702","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":"Molecular Changes Implicate Angiogenesis and Arterial Remodeling in Systemic Sclerosis-Associated and Idiopathic Pulmonary Hypertension.","authors":"Yuechen Zhou, Tracy Tabib, Mengqi Huang, Ke Yuan, Yunhye Kim, Christina Morse, John Sembrat, Eleanor Valenzi, Robert Lafyatis","doi":"10.1161/ATVBAHA.123.320005","DOIUrl":"10.1161/ATVBAHA.123.320005","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary hypertension (PH) is a common complication of systemic sclerosis (SSc) and a leading cause of mortality among patients with this disease. PH can also occur as an idiopathic condition (idiopathic pulmonary arterial hypertension). Investigation of transcriptomic alterations in vascular populations is critical to elucidating cellular mechanisms underlying pathobiology of SSc-associated and idiopathic PH.</p><p><strong>Methods: </strong>We analyzed single-cell RNA sequencing profiles of endothelial and perivascular mesenchymal populations from explanted lung tissue of patients with SSc-associated PH (n=16), idiopathic pulmonary arterial hypertension (n=3), and healthy controls (n=15). Findings were validated by immunofluorescence staining of explanted human lung tissue.</p><p><strong>Results: </strong>Three disease-associated endothelial populations emerged. Two angiogenic endothelial cell (EC) subtypes markedly expanded in SSc-associated PH lungs: tip ECs expressing canonical tip markers <i>PGF</i> and <i>APLN</i> and phalanx ECs expressing genes associated with vascular development, endothelial barrier integrity, and Notch signaling. Gene regulatory network analysis suggested enrichment of Smad1 (SMAD family member 1) and PPAR-γ (peroxisome proliferator-activated receptor-γ) regulon activities in these 2 populations, respectively. Mapping of potential ligand-receptor interactions highlighted Notch, apelin-APJ (apelin receptor), and angiopoietin-Tie (tyrosine kinase with immunoglobulin-like and EGF-like domains 1) signaling pathways between angiogenic ECs and perivascular cells. Transitional cells, expressing both endothelial and pericyte/smooth muscle cell markers, provided evidence for the presence of endothelial-to-mesenchymal transition. Transcriptional programs associated with arterial endothelial dysfunction implicated VEGF-A (vascular endothelial growth factor-A), TGF-β1 (transforming growth factor beta-1), angiotensin, and TNFSF12 (tumor necrosis factor ligand superfamily member 12)/TWEAK (TNF-related weak inducer of apoptosis) in the injury/remodeling phenotype of PH arterial ECs.</p><p><strong>Conclusions: </strong>These data provide high-resolution insights into the complexity and plasticity of the pulmonary endothelium in SSc-associated PH and idiopathic pulmonary arterial hypertension and provide direct molecular insights into soluble mediators and transcription factors driving PH vasculopathy.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e210-e225"},"PeriodicalIF":7.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11269037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261312","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":"Deletion of Talin1 in Myeloid Cells Facilitates Atherosclerosis in Mice.","authors":"Huiping Shi, Jianhua Song, Liang Gao, Xindi Shan, Sumith R Panicker, Longbiao Yao, Michael McDaniel, Meixiang Zhou, Samuel McGee, Hui Zhong, Courtney T Griffin, Lijun Xia, Bojing Shao","doi":"10.1161/ATVBAHA.123.319677","DOIUrl":"10.1161/ATVBAHA.123.319677","url":null,"abstract":"<p><strong>Background: </strong>Integrin-regulated monocyte recruitment and cellular responses of monocyte-derived macrophages are critical for the pathogenesis of atherosclerosis. In the canonical model, talin1 controls ligand binding to integrins, a prerequisite for integrins to mediate leukocyte recruitment and induce immune responses. However, the role of talin1 in the development of atherosclerosis has not been studied. Our study investigated how talin1 in myeloid cells regulates the progression of atherosclerosis.</p><p><strong>Methods: </strong>On an <i>Apoe</i>^<i>-/-</i> background, myeloid talin1-deficient mice and the control mice were fed with a high-fat diet for 8 or 12 weeks to induce atherosclerosis. The atherosclerosis development in the aorta and monocyte recruitment into atherosclerotic lesions were analyzed.</p><p><strong>Results: </strong>Myeloid talin1 deletion facilitated the formation of atherosclerotic lesions and macrophage deposition in lesions. Talin1 deletion abolished integrin β2-mediated adhesion of monocytes but did not impair integrin α4β1-dependent cell adhesion in a flow adhesion assay. Strikingly, talin1 deletion did not prevent Mn²⁺- or chemokine-induced activation of integrin α4β1 to the high-affinity state for ligands. In an in vivo competitive homing assay, monocyte infiltration into inflamed tissues was prohibited by antibodies to integrin α4β1 but was not affected by talin1 deletion or antibodies to integrin β2. Furthermore, quantitative polymerase chain reaction and ELISA (enzyme-linked immunosorbent assay) analysis showed that macrophages produced cytokines to promote inflammation and the proliferation of smooth muscle cells. Ligand binding to integrin β3 inhibited cytokine generation in macrophages, although talin1 deletion abolished the negative effects of integrin β3.</p><p><strong>Conclusions: </strong>Integrin α4β1 controls monocyte recruitment during atherosclerosis. Talin1 is dispensable for integrin α4β1 activation to the high-affinity state and integrin α4β1-mediated monocyte recruitment. Yet, talin1 is required for integrin β3 to inhibit the production of inflammatory cytokines in macrophages. Thus, intact monocyte recruitment and elevated inflammatory responses cause enhanced atherosclerosis in talin1-deficient mice. Our study provides novel insights into the roles of myeloid talin1 and integrins in the progression of atherosclerosis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1799-1812"},"PeriodicalIF":7.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426181","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":"Hypertriglyceridemia Results From an Impaired Catabolism of Triglyceride-Rich Lipoproteins in <i>PLIN1</i>-Related Lipodystrophy.","authors":"Bruno Vergès, Marie-Christine Vantyghem, Yves Reznik, Laurence Duvillard, Alexia Rouland, Emilie Capel, Corinne Vigouroux","doi":"10.1161/ATVBAHA.124.320774","DOIUrl":"10.1161/ATVBAHA.124.320774","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic variants in <i>PLIN1</i>-encoding PLIN1 (perilipin-1) are responsible for an autosomal dominant form of familial partial lipodystrophy (FPL) associated with severe insulin resistance, hepatic steatosis, and important hypertriglyceridemia. This study aims to decipher the mechanisms of hypertriglyceridemia associated with <i>PLIN1</i>-related FPL.</p><p><strong>Methods: </strong>We performed an in vivo lipoprotein kinetic study in 6 affected patients compared with 13 healthy controls and 8 patients with type 2 diabetes. Glucose and lipid parameters, including plasma LPL (lipoprotein lipase) mass, were measured. <i>LPL</i> mRNA and protein expression were evaluated in abdominal subcutaneous adipose tissue from patients with 5 <i>PLIN1</i>-mutated FPL and 3 controls.</p><p><strong>Results: </strong>Patients with <i>PLIN1</i>-mutated FPL presented with decreased fat mass, insulin resistance, and diabetes (glycated hemoglobin A1c, 6.68±0.70% versus 7.48±1.63% in patients with type 2 diabetes; mean±SD; <i>P</i>=0.27). Their plasma triglycerides were higher (5.96±3.08 mmol/L) than in controls (0.76±0.27 mmol/L; <i>P</i><0.0001) and patients with type 2 diabetes (2.94±1.46 mmol/L, <i>P</i>=0.006). Compared with controls, patients with <i>PLIN1</i>-related FPL had a significant reduction of the indirect fractional catabolic rate of VLDL (very-low-density lipoprotein)-apoB100 toward IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein; 1.79±1.38 versus 5.34±2.45 pool/d; <i>P</i>=0.003) and the indirect fractional catabolic rate of IDL-apoB100 toward LDL (2.14±1.44 versus 7.51±4.07 pool/d; <i>P</i>=0.005). VLDL-apoB100 production was not different between patients with <i>PLIN1</i>-related FPL and controls. Compared with patients with type 2 diabetes, patients with <i>PLIN1</i>-related FPL also showed a significant reduction of the catabolism of both VLDL-apoB100 (<i>P</i>=0.031) and IDL-apoB100 (<i>P</i>=0.031). Plasma LPL mass was significantly lower in patients with <i>PLIN1</i>-related FPL than in controls (21.03±10.08 versus 55.76±13.10 ng/mL; <i>P</i><0.0001), although the LPL protein expression in adipose tissue was similar. VLDL-apoB100 and IDL-apoB100 indirect fractional catabolic rates were negatively correlated with plasma triglycerides and positively correlated with LPL mass.</p><p><strong>Conclusions: </strong>We show that hypertriglyceridemia associated with <i>PLIN1</i>-related FPL results from a marked decrease in the catabolism of triglyceride-rich lipoproteins (VLDL and IDL). This could be due to a pronounced reduction in LPL availability, related to the decreased adipose tissue mass.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1873-1883"},"PeriodicalIF":7.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426182","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":"Correction to: Inhibition of the Plasma SCUBE1, a Novel Platelet Adhesive Protein, Protects Mice Against Thrombosis.","authors":"","doi":"10.1161/ATV.0000000000000175","DOIUrl":"https://doi.org/10.1161/ATV.0000000000000175","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"44 8","pages":"e226"},"PeriodicalIF":7.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756866","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":"Cerebrovascular Endothelial Dysfunction: Role of BACE1.","authors":"Zvonimir S Katusic, Livius V d'Uscio, Tongrong He","doi":"10.1161/ATVBAHA.124.320798","DOIUrl":"10.1161/ATVBAHA.124.320798","url":null,"abstract":"<p><p>Dysfunctional endothelium is increasingly recognized as a mechanistic link between cardiovascular risk factors and dementia, including Alzheimer disease. BACE1 (β-site amyloid-β precursor protein-cleaving enzyme 1) is responsible for β-processing of APP (amyloid-β precursor protein), the first step in the production of Aβ (amyloid-β) peptides, major culprits in the pathogenesis of Alzheimer disease. Under pathological conditions, excessive activation of BACE1 exerts detrimental effects on endothelial function by Aβ-dependent and Aβ-independent mechanisms. High local concentration of Aβ in the brain blood vessels is responsible for the loss of key vascular protective functions of endothelial cells. More recent studies recognized significant contribution of Aβ-independent proteolytic activity of endothelial BACE1 to the pathogenesis of endothelial dysfunction. This review critically evaluates existing evidence supporting the concept that excessive activation of BACE1 expressed in the cerebrovascular endothelium impairs key homeostatic functions of the brain blood vessels. This concept has important therapeutic implications. Indeed, improved understanding of the mechanisms of endothelial dysfunction may help in efforts to develop new approaches to the protection and preservation of healthy cerebrovascular function.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1737-1747"},"PeriodicalIF":7.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11269044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141309923","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":"Ying and Yang of Ceramide in the Vascular Endothelium.","authors":"Gopika SenthilKumar, Zachary Zirgibel, Katie E Cohen, Boran Katunaric, Alyssa M Jobe, Carolyn G Shult, Rachel H Limpert, Julie K Freed","doi":"10.1161/ATVBAHA.124.321158","DOIUrl":"10.1161/ATVBAHA.124.321158","url":null,"abstract":"<p><p>Ceramides, a group of biologically active sphingolipids, have been described as the new cholesterol given strong evidence linking high plasma ceramide with endothelial damage, risk for early adverse cardiovascular events, and development of cardiometabolic disease. This relationship has sparked great interest in investigating therapeutic targets with the goal of suppressing ceramide formation. However, the growing data challenge this paradigm of ceramide as solely eliciting detrimental effects to the cardiovascular system. Studies show that ceramides are necessary for maintaining proper endothelial redox states, mechanosensation, and membrane integrity. Recent work in preclinical models and isolated human microvessels highlights that the loss of ceramide formation can in fact propagate vascular endothelial dysfunction. Here, we delve into these conflicting findings to evaluate how ceramide may be capable of exerting both beneficial and damaging effects within the vascular endothelium. We propose a unifying theory that while basal levels of ceramide in response to physiological stimuli are required for the production of vasoprotective metabolites such as S1P (sphingosine-1-phosphate), the chronic accumulation of ceramide can promote activation of pro-oxidative stress pathways in endothelial cells. Clinically, the evidence discussed here highlights the potential challenges associated with therapeutic suppression of ceramide formation as a means of reducing cardiovascular disease risk.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1725-1736"},"PeriodicalIF":7.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11269027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426217","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}