Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Role of Antibodies and Their Specificities in Atherosclerotic Cardiovascular Disease.","authors":"Justine Deroissart, Christoph J Binder, Florentina Porsch","doi":"10.1161/ATVBAHA.124.319843","DOIUrl":"10.1161/ATVBAHA.124.319843","url":null,"abstract":"<p><p>Atherosclerosis is a lipid-driven chronic inflammatory disease that is modulated by innate and adaptive immunity including humoral immunity. Importantly, antibody alterations achieved by genetic means or active and passive immunization strategies in preclinical studies can improve or aggravate atherosclerosis. Additionally, a wide range of epidemiological data demonstrate not only an association between the total levels of different antibody isotypes but also levels of antibodies targeting specific antigens with atherosclerotic cardiovascular disease. Here, we discuss the potential role of atherogenic dyslipidemia on the antibody repertoire and review potential antibody-mediated effector mechanisms involved in atherosclerosis development highlighting the major atherosclerosis-associated antigens that trigger antibody responses.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2154-2168"},"PeriodicalIF":7.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900813","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":"Glaucoma-Protective Human Single-Nucleotide Polymorphism in the <i>Angpt2</i> Locus Increased ANGPT2 Expression and Schlemm Canal Area in Mice-Brief Report.","authors":"Naoki Kiyota, Tuncer Onay, Phoebe Leeaw, Pan Liu, Dilip K Deb, Benjamin R Thomson, Ayellet V Segrè, Janey L Wiggs, Susan E Quaggin","doi":"10.1161/ATVBAHA.124.321555","DOIUrl":"10.1161/ATVBAHA.124.321555","url":null,"abstract":"<p><strong>Background: </strong>The ANGPT (angiopoietin)-TEK (tyrosine kinase, endothelial) vascular signaling pathway plays a key role in the formation of Schlemm canal, and loss-of-function mutations in the <i>TEK</i> or <i>ANGPT1</i> gene are associated with primary congenital glaucoma in children. In genome-wide association studies, an association was identified between protection from primary open-angle glaucoma and the single-nucleotide polymorphism rs76020419 (G>T), located within a predicted <i>miR-145</i>-binding site in the 3' untranslated region of <i>ANGPT2</i>. To date, the functional impact of this variant in the anterior chamber of the eye remains largely unexplored.</p><p><strong>Methods: </strong>MT (mutant) mice harboring an orthologous rs76020419 minor allele (T) were generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9). Plasma and tissue samples, including eyes, were collected, and ANGPT2 expression was quantified using ELISA. Anterior segments from eyes were collected from WT (wild-type) and MT mice, and Schlemm canal area was quantified.</p><p><strong>Results: </strong>In the MT group, higher ANGPT2 concentrations were observed in the plasma, lungs, kidneys, and eyes (<i>P</i>=0.0212, <i>P</i><0.001, <i>P</i>=0.0815, and <i>P</i>=0.0215, respectively). Additionally, the Schlemm canal was larger in MT mice compared with WT mice (<i>P</i>=0.0430).</p><p><strong>Conclusions: </strong>The rs76020419 minor allele (T) is associated with increased levels of ANGPT2 and a larger Schlemm canal in mice. These findings suggest a potential protective mechanism in glaucoma.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2207-2212"},"PeriodicalIF":7.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103904","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":"Cooperation Between Platelet β1 and β3 Integrins in the Arrest of Bleeding Under Inflammatory Conditions in Mice-Brief Report.","authors":"Emily Janus-Bell, Nicolas Receveur, Luc Mercier, Clarisse Mouriaux, Stéphanie Magnenat, Jochen Reiser, François Lanza, Béatrice Hechler, Benoit Ho-Tin-Noé, Pierre H Mangin","doi":"10.1161/ATVBAHA.124.321104","DOIUrl":"10.1161/ATVBAHA.124.321104","url":null,"abstract":"<p><strong>Background: </strong>Platelets prevent bleeding in a variety of inflammatory settings, the adhesion receptors and activation pathways involved being highly context-dependent and functionally redundant. In some situations, platelets recruited to inflammatory sites act independently of aggregation. The mechanisms underlying stable platelet adhesion in inflamed microvessels remain incompletely understood, in particular, whether and if so, how β1 and β3 integrins are involved.</p><p><strong>Methods: </strong>The impact of isolated or combined platelet deficiency in β1 and β3 integrins on inflammation-associated hemostasis was investigated in 3 models of acute inflammation: immune complex-based cutaneous reverse passive Arthus reaction, intranasal lipopolysaccharide-induced lung inflammation, and cerebral ischemia-reperfusion following transient (2-hour) occlusion of the middle cerebral artery.</p><p><strong>Results: </strong>Mice with platelet-directed inactivation of <i>Itgb1</i> (PF4Cre-β1^-/-) displayed no bleeding in any of the inflammation models, while mice defective in platelet <i>Itgb3</i> (PF4Cre-β3^-/-) exhibited bleeding in all 3 models. Remarkably, the bleeding phenotype of PF4Cre-β3^-/- mice was exacerbated in the reverse passive Arthus model by the concomitant deletion of β1 integrins, PF4Cre-β1^-/-/β3^-/- animals presenting increased bleeding. Intravital microscopy in reverse passive Arthus experiments highlighted a major defect in the adhesion of PF4Cre-β1^-/-/β3^-/- platelets to inflamed microvessels. Unlike PF4Cre-β1^-/- and PF4Cre-β3^-/- mice, PF4Cre-β1^-/-/β3^-/- animals developed early hemorrhagic transformation 6 hours after transient middle cerebral artery occlusion. PF4Cre-β1^-/-/β3^-/- mice displayed no more bleeding in lipopolysaccharide-induced lung inflammation than PF4Cre-β3^-/- animals.</p><p><strong>Conclusions: </strong>Altogether, these results show that the requirement for and degree of functional redundancy between platelet β1 and β3 integrins in inflammation-associated hemostasis vary with the inflammatory situation.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2213-2222"},"PeriodicalIF":7.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981504","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":"Discordance Analysis of VLDL-C and ApoB in UK Biobank and Framingham Study: A Prospective Observational Study.","authors":"Selin Bilgic, Karol M Pencina, Michael J Pencina, Justine Cole, Line Dufresne, George Thanassoulis, Allan D Sniderman","doi":"10.1161/ATVBAHA.124.321165","DOIUrl":"10.1161/ATVBAHA.124.321165","url":null,"abstract":"<p><strong>Background: </strong>Recent observational and Mendelian randomization analyses have reported significant effects of VLDL-C (very-low density lipoprotein cholesterol) on risk that is independent of ApoB (apolipoprotein B). We aim to determine the independent association of VLDL-C and ApoB with the risk of new onset cardiovascular events in the UK Biobank and Framingham Heart Study cohorts.</p><p><strong>Methods: </strong>We included 294 289 UK Biobank participants with a median age of 56 years, 42% men, and 2865 Framingham Heart Study participants (median age, 53 years; 47% men). The residual resulting from regressing VLDL-C on ApoB expresses the portion of VLDL-C not explained by ApoB, while the residual from regressing ApoB on VLDL-C expresses the portion of ApoB not explained by VLDL-C. Cox proportional hazards models for atherosclerotic cardiovascular disease incidence were created for residual VLDL-C and residual ApoB. Models were analyzed with and without high-density lipoprotein cholesterol (HDL-C). Furthermore, we investigated the independent effects of VLDL-C after accounting for ApoB and HDL-C and of HDL-C after accounting for ApoB and VLDL-C.</p><p><strong>Results: </strong>In the UK Biobank, ApoB was highly correlated with VLDL-C (r=0.70; <i>P</i><0.001) but weakly negatively correlated with HDL-C (r=-0.11; <i>P</i><0.001). The ApoB residual and the VLDL-C residual were significantly associated with new-onset atherosclerotic cardiovascular disease (hazard ratio [HR], 1.08 and 1.05, respectively; <i>P</i><0.001). After adjusting for HDL-C, the ApoB residual remained similar in magnitude (HR, 1.10; <i>P</i><0.001), whereas the effect size of the VLDL-C residual was reduced (HR, 1.02; <i>P</i>=0.029). The independent effect of HDL-C (after accounting for ApoB and VLDL-C) remained robust (HR, 0.86; <i>P</i><0.0001), while the independent effect of VLDL-C (after accounting for ApoB and HDL-C) was modest (HR, 1.02; <i>P</i>=0.029). All results were consistent in the Framingham cohort.</p><p><strong>Conclusions: </strong>When adjusted for HDL-C, the association of VLDL-C with cardiovascular risk was no longer clinically meaningful. Our residual discordance analysis suggests that adjustment for HDL-C cannot be ignored.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2244-2251"},"PeriodicalIF":7.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981505","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":"Endothelium as a Source of Cardiovascular Toxicity From Antitumor Kinase Inhibitors.","authors":"Richard J Travers, Alec Stepanian, Iris Z Jaffe","doi":"10.1161/ATVBAHA.124.319864","DOIUrl":"10.1161/ATVBAHA.124.319864","url":null,"abstract":"<p><p>Kinase inhibitors (KIs) targeting oncogenic molecular pathways have revolutionized cancer therapy. By directly targeting specific tumor-driving kinases, targeted therapies have fewer side effects compared with chemotherapy. Despite the enhanced specificity, cardiovascular side effects have emerged with many targeted cancer therapies that limit long-term outcomes in patients with cancer. Endothelial cells lining all blood vessels are critical to cardiovascular health and are also exposed to circulating levels of systemic anticancer therapies. Both on- and off-target perturbation of signaling pathways from KIs can cause endothelial dysfunction, resulting in cardiovascular toxicity. As such, the endothelium is a potential source, and also a therapeutic target for prevention, of cardiovascular toxicity. In this review, we examine the evidence for KI-induced endothelial cell dysfunction as a mechanism for the cardiovascular toxicities of vascular endothelial growth factor inhibitors, BCR-Abl (breakpoint cluster region-Abelson proto-oncogene) KIs, Bruton tyrosine inhibitors, and emerging information regarding endothelial toxicity of newer classes of KIs.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2143-2153"},"PeriodicalIF":7.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11424247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981506","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":"Sex Dimorphism in Pulmonary Arterial Hypertension Associated With Autoimmune Diseases.","authors":"Anna Krzyżewska, Kondababu Kurakula","doi":"10.1161/ATVBAHA.124.320886","DOIUrl":"10.1161/ATVBAHA.124.320886","url":null,"abstract":"<p><p>Pulmonary hypertension is a rare, incurable, and progressive disease. Although there is increasing evidence that immune disorders, particularly those associated with connective tissue diseases, are a strong predisposing factor in the development of pulmonary arterial hypertension (PAH), there is currently a lack of knowledge about the detailed molecular mechanisms responsible for this phenomenon. Exploring this topic is crucial because patients with an immune disorder combined with PAH have a worse prognosis and higher mortality compared with patients with other PAH subtypes. Moreover, data recorded worldwide show that the prevalence of PAH in women is 2× to even 4× higher than in men, and the ratio of PAH associated with autoimmune diseases is even higher (9:1). Sexual dimorphism in the pathogenesis of cardiovascular disease was explained for many years by the action of female sex hormones. However, there are increasing reports of interactions between sex hormones and sex chromosomes, and differences in the pathogenesis of cardiovascular disease may be controlled not only by sex hormones but also by sex chromosome pathways that are not dependent on the gonads. This review discusses the role of estrogen and genetic factors including the role of genes located on the X chromosome, as well as the potential protective role of the Y chromosome in sexual dimorphism, which is prominent in the occurrence of PAH associated with autoimmune diseases. Moreover, an overview of animal models that could potentially play a role in further investigating the aforementioned link was also reviewed.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2169-2190"},"PeriodicalIF":7.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981507","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: Dysfunctional APPL1-Mediated Epigenetic Regulation in Diabetic Vascular Injury.","authors":"","doi":"10.1161/ATV.0000000000000178","DOIUrl":"https://doi.org/10.1161/ATV.0000000000000178","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"44 10","pages":"e262"},"PeriodicalIF":7.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340166","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":"Targeting Vascular Stiffness.","authors":"Christopher P Mack","doi":"10.1161/ATVBAHA.124.321334","DOIUrl":"10.1161/ATVBAHA.124.321334","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2204-2206"},"PeriodicalIF":7.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11424245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900814","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":"Correction to: XBP 1-Deficiency Abrogates Neointimal Lesion of Injured Vessels Via Cross Talk With the PDGF Signaling.","authors":"","doi":"10.1161/ATV.0000000000000179","DOIUrl":"https://doi.org/10.1161/ATV.0000000000000179","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"44 10","pages":"e263"},"PeriodicalIF":7.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340167","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":"PAI-1 Regulates the Cytoskeleton and Intrinsic Stiffness of Vascular Smooth Muscle Cells.","authors":"Hekmat B Khoukaz, Manisha Vadali, Alex Schoenherr, Francisco I Ramirez-Perez, Mariana Morales-Quinones, Zhe Sun, Shumpei Fujie, Christopher A Foote, Zhen Lyu, Shuai Zeng, Marc A Augenreich, Dunpeng Cai, Shi-You Chen, Trupti Joshi, Yan Ji, Michael A Hill, Luis A Martinez-Lemus, William P Fay","doi":"10.1161/ATVBAHA.124.320938","DOIUrl":"10.1161/ATVBAHA.124.320938","url":null,"abstract":"<p><strong>Background: </strong>Plasma concentration of PAI-1 (plasminogen activator inhibitor-1) correlates with arterial stiffness. Vascular smooth muscle cells (SMCs) express PAI-1, and the intrinsic stiffness of SMCs is a major determinant of total arterial stiffness. We hypothesized that PAI-1 promotes SMC stiffness by regulating the cytoskeleton and that pharmacological inhibition of PAI-1 decreases SMC and aortic stiffness.</p><p><strong>Methods: </strong>PAI-039, a specific inhibitor of PAI-1, and small interfering RNA were used to inhibit PAI-1 expression in cultured human SMCs. Effects of PAI-1 inhibition on SMC stiffness, F-actin (filamentous actin) content, and cytoskeleton-modulating enzymes were assessed. WT (wild-type) and PAI-1-deficient murine SMCs were used to determine PAI-039 specificity. RNA sequencing was performed to determine the effects of PAI-039 on SMC gene expression. In vivo effects of PAI-039 were assessed by aortic pulse wave velocity.</p><p><strong>Results: </strong>PAI-039 significantly reduced intrinsic stiffness of human SMCs, which was accompanied by a significant decrease in cytoplasmic F-actin content. PAI-1 gene knockdown also decreased cytoplasmic F-actin. PAI-1 inhibition significantly increased the activity of cofilin, an F-actin depolymerase, in WT murine SMCs, but not in PAI-1-deficient SMCs. RNA-sequencing analysis suggested that PAI-039 upregulates AMPK (AMP-activated protein kinase) signaling in SMCs, which was confirmed by Western blotting. Inhibition of AMPK prevented activation of cofilin by PAI-039. In mice, PAI-039 significantly decreased aortic stiffness and tunica media F-actin content without altering the elastin or collagen content.</p><p><strong>Conclusions: </strong>PAI-039 decreases intrinsic SMC stiffness and cytoplasmic stress fiber content. These effects are mediated by AMPK-dependent activation of cofilin. PAI-039 also decreases aortic stiffness in vivo. These findings suggest that PAI-1 is an important regulator of the SMC cytoskeleton and that pharmacological inhibition of PAI-1 has the potential to prevent and treat cardiovascular diseases involving arterial stiffening.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2191-2203"},"PeriodicalIF":7.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11424258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141309925","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}