Pub Date : 2019-08-29DOI: 10.1161/ATVBAHA.119.311574
Emma J Akers, S. Nicholls, B. D. Di Bartolo
Vascular calcification (VC) is strongly associated with all-cause mortality and is an independent predictor of cardiovascular events. Resulting from its complex, multifaceted nature, targeted treatments for VC have not yet been developed. Lipoproteins are well characterized in the pathogenesis of atherosclerotic plaques, leading to the development of plaque regressing therapeutics. Although their roles in plaque progression are well documented, their roles in VC, and calcification of a plaque, are not well understood. In this review, early in vitro data and clinical correlations suggest an inhibitory role for HDL (high-density lipoproteins) in VC, a stimulatory role for LDL (low-density lipoprotein) and VLDL (very low-density lipoprotein) and a potentially causal role for Lp(a) (lipoprotein [a]). Additionally, after treatment with a statin or PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, plaque calcification is observed to increase. With the notion that differing morphologies of plaque calcification associate with either a more stable or unstable plaque phenotype, uncovering the mechanisms of lipoprotein-artery wall interactions could produce targeted therapeutic options for VC.
{"title":"Plaque Calcification.","authors":"Emma J Akers, S. Nicholls, B. D. Di Bartolo","doi":"10.1161/ATVBAHA.119.311574","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.311574","url":null,"abstract":"Vascular calcification (VC) is strongly associated with all-cause mortality and is an independent predictor of cardiovascular events. Resulting from its complex, multifaceted nature, targeted treatments for VC have not yet been developed. Lipoproteins are well characterized in the pathogenesis of atherosclerotic plaques, leading to the development of plaque regressing therapeutics. Although their roles in plaque progression are well documented, their roles in VC, and calcification of a plaque, are not well understood. In this review, early in vitro data and clinical correlations suggest an inhibitory role for HDL (high-density lipoproteins) in VC, a stimulatory role for LDL (low-density lipoprotein) and VLDL (very low-density lipoprotein) and a potentially causal role for Lp(a) (lipoprotein [a]). Additionally, after treatment with a statin or PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, plaque calcification is observed to increase. With the notion that differing morphologies of plaque calcification associate with either a more stable or unstable plaque phenotype, uncovering the mechanisms of lipoprotein-artery wall interactions could produce targeted therapeutic options for VC.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"257 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90521330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-29DOI: 10.1161/ATVBAHA.119.312192
Yabing Chen, Xinyang Zhao, Hui Wu
Mammalian cells metabolize glucose primarily for energy production, biomass synthesis, and posttranslational glycosylation; and maintaining glucose metabolic homeostasis is essential for normal physiology of cells. Impaired glucose homeostasis leads to hyperglycemia, a hallmark of diabetes mellitus. Chronically increased glucose in diabetes mellitus promotes pathological changes accompanied by impaired cellular function and tissue damage, which facilitates the development of cardiovascular complications, the major cause of morbidity and mortality of patients with diabetes mellitus. Emerging roles of glucose metabolism via the hexosamine biosynthesis pathway (HBP) and increased protein modification via O-linked β-N-acetylglucosamine (O-GlcNAcylation) have been demonstrated in diabetes mellitus and implicated in the development of diabetic cardiovascular complications. This review will discuss the biological outcomes of the glucose metabolism via the hexosamine biogenesis pathway and protein O-GlcNAcylation in regulating cellular homeostasis, and highlight the regulations and contributions of elevated O-GlcNAcylation to the pathogenesis of diabetic cardiovascular disease.
哺乳动物细胞代谢葡萄糖主要用于能量产生、生物质合成和翻译后糖基化;维持葡萄糖代谢稳态是细胞正常生理活动的必要条件。葡萄糖稳态受损导致高血糖，这是糖尿病的一个标志。糖尿病患者长期血糖升高，促进病理改变，并伴有细胞功能受损和组织损伤，易发生心血管并发症，是糖尿病患者发病和死亡的主要原因。葡萄糖代谢通过己糖胺生物合成途径(HBP)和通过o -连接β- n -乙酰氨基葡萄糖酰化(o - glcn酰化)增加的蛋白质修饰的新作用已经在糖尿病中得到证实，并涉及糖尿病心血管并发症的发展。本文将讨论己糖胺生物发生途径中葡萄糖代谢的生物学结果和o - glcnac酰化蛋白在调节细胞内稳态中的作用，并重点介绍o - glcnac酰化升高在糖尿病心血管疾病发病中的调节作用和贡献。
{"title":"Metabolic Stress and Cardiovascular Disease in Diabetes MellitusThe Role of Protein O-GlcNAc Modification.","authors":"Yabing Chen, Xinyang Zhao, Hui Wu","doi":"10.1161/ATVBAHA.119.312192","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.312192","url":null,"abstract":"Mammalian cells metabolize glucose primarily for energy production, biomass synthesis, and posttranslational glycosylation; and maintaining glucose metabolic homeostasis is essential for normal physiology of cells. Impaired glucose homeostasis leads to hyperglycemia, a hallmark of diabetes mellitus. Chronically increased glucose in diabetes mellitus promotes pathological changes accompanied by impaired cellular function and tissue damage, which facilitates the development of cardiovascular complications, the major cause of morbidity and mortality of patients with diabetes mellitus. Emerging roles of glucose metabolism via the hexosamine biosynthesis pathway (HBP) and increased protein modification via O-linked β-N-acetylglucosamine (O-GlcNAcylation) have been demonstrated in diabetes mellitus and implicated in the development of diabetic cardiovascular complications. This review will discuss the biological outcomes of the glucose metabolism via the hexosamine biogenesis pathway and protein O-GlcNAcylation in regulating cellular homeostasis, and highlight the regulations and contributions of elevated O-GlcNAcylation to the pathogenesis of diabetic cardiovascular disease.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84741493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-29DOI: 10.1161/ATVBAHA.119.313034
Allison B Herman, Milessa Silva Afonso, S. Kelemen, M. Ray, Christine N. Vrakas, A. Burke, R. Scalia, K. Moore, M. Autieri
OBJECTIVE Stress granules (SGs) are dynamic cytoplasmic aggregates containing mRNA, RNA-binding proteins, and translation factors that form in response to cellular stress. SGs have been shown to contribute to the pathogenesis of several human diseases, but their role in vascular diseases is unknown. This study shows that SGs accumulate in vascular smooth muscle cells (VSMCs) and macrophages during atherosclerosis. Approach and Results: Immunohistochemical analysis of atherosclerotic plaques from LDLR-/- mice revealed an increase in the stress granule-specific markers Ras-G3BP (GTPase-activating protein SH3 domain-binding protein) and PABP (poly-A-binding protein) in intimal macrophages and smooth muscle cells that correlated with disease progression. In vitro, PABP+ and G3BP+ SGs were rapidly induced in VSMC and bone marrow-derived macrophages in response to atherosclerotic stimuli, including oxidized low-density lipoprotein and mediators of mitochondrial or oxidative stress. We observed an increase in eIF2α phosphorylation, a requisite for stress granule formation, in cells exposed to these stimuli. Interestingly, SG formation, PABP expression, and eIF2α phosphorylation in VSMCs is reversed by treatment with the anti-inflammatory cytokine interleukin-19. Microtubule inhibitors reduced stress granule accumulation in VSMC, suggesting cytoskeletal regulation of stress granule formation. SG formation in VSMCs was also observed in other vascular disease pathologies, including vascular restenosis. Reduction of SG component G3BP1 by siRNA significantly altered expression profiles of inflammatory, apoptotic, and proliferative genes. CONCLUSIONS These results indicate that SG formation is a common feature of the vascular response to injury and disease, and that modification of inflammation reduces stress granule formation in VSMC.
{"title":"Regulation of Stress Granule Formation by Inflammation, Vascular Injury, and Atherosclerosis.","authors":"Allison B Herman, Milessa Silva Afonso, S. Kelemen, M. Ray, Christine N. Vrakas, A. Burke, R. Scalia, K. Moore, M. Autieri","doi":"10.1161/ATVBAHA.119.313034","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.313034","url":null,"abstract":"OBJECTIVE\u0000Stress granules (SGs) are dynamic cytoplasmic aggregates containing mRNA, RNA-binding proteins, and translation factors that form in response to cellular stress. SGs have been shown to contribute to the pathogenesis of several human diseases, but their role in vascular diseases is unknown. This study shows that SGs accumulate in vascular smooth muscle cells (VSMCs) and macrophages during atherosclerosis. Approach and Results: Immunohistochemical analysis of atherosclerotic plaques from LDLR-/- mice revealed an increase in the stress granule-specific markers Ras-G3BP (GTPase-activating protein SH3 domain-binding protein) and PABP (poly-A-binding protein) in intimal macrophages and smooth muscle cells that correlated with disease progression. In vitro, PABP+ and G3BP+ SGs were rapidly induced in VSMC and bone marrow-derived macrophages in response to atherosclerotic stimuli, including oxidized low-density lipoprotein and mediators of mitochondrial or oxidative stress. We observed an increase in eIF2α phosphorylation, a requisite for stress granule formation, in cells exposed to these stimuli. Interestingly, SG formation, PABP expression, and eIF2α phosphorylation in VSMCs is reversed by treatment with the anti-inflammatory cytokine interleukin-19. Microtubule inhibitors reduced stress granule accumulation in VSMC, suggesting cytoskeletal regulation of stress granule formation. SG formation in VSMCs was also observed in other vascular disease pathologies, including vascular restenosis. Reduction of SG component G3BP1 by siRNA significantly altered expression profiles of inflammatory, apoptotic, and proliferative genes.\u0000\u0000\u0000CONCLUSIONS\u0000These results indicate that SG formation is a common feature of the vascular response to injury and disease, and that modification of inflammation reduces stress granule formation in VSMC.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73970557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-22DOI: 10.1161/ATVBAHA.119.313179
Koung Li Kim, Songyi Seo, Jee Taek Kim, Jaeteak Kim, Won Kim, Yeongju Yeo, Jong-Hyuk Sung, Sang Gyu Park, W. Suh
OBJECTIVE Aberrant neovascularization is a leading cause of blindness in several eye diseases, including age-related macular degeneration and proliferative diabetic retinopathy. The identification of key regulators of pathological ocular neovascularization has been a subject of extensive research and great therapeutic interest. Here, we explored the previously unrecognized role of cKIT and its ligand, SCF (stem cell factor), in the pathological ocular neovascularization process. Approach and Results: Compared with normoxia, hypoxia, a crucial driver of neovascularization, caused cKIT to be highly upregulated in endothelial cells, which significantly enhanced the angiogenic response of endothelial cells to SCF. In murine models of pathological ocular neovascularization, such as oxygen-induced retinopathy and laser-induced choroidal neovascularization models, cKIT and SCF expression was significantly increased in ocular tissues, and blockade of cKIT and SCF using cKit mutant mice and anti-SCF neutralizing IgG substantially suppressed pathological ocular neovascularization. Mechanistically, SCF/cKIT signaling induced neovascularization through phosphorylation of glycogen synthase kinase-3β and enhancement of the nuclear translocation of β-catenin and the transcription of β-catenin target genes related to angiogenesis. Inhibition of β-catenin-mediated transcription using chemical inhibitors blocked SCF-induced in vitro angiogenesis in hypoxia, and injection of a β-catenin agonist into cKit mutant mice with oxygen-induced retinopathy significantly enhanced pathological neovascularization in the retina. Conclusions; Our data reveal that SCF and cKIT are promising novel therapeutic targets for treating vision-threatening ocular neovascular diseases.
{"title":"SCF (Stem Cell Factor) and cKIT Modulate Pathological Ocular Neovascularization.","authors":"Koung Li Kim, Songyi Seo, Jee Taek Kim, Jaeteak Kim, Won Kim, Yeongju Yeo, Jong-Hyuk Sung, Sang Gyu Park, W. Suh","doi":"10.1161/ATVBAHA.119.313179","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.313179","url":null,"abstract":"OBJECTIVE\u0000Aberrant neovascularization is a leading cause of blindness in several eye diseases, including age-related macular degeneration and proliferative diabetic retinopathy. The identification of key regulators of pathological ocular neovascularization has been a subject of extensive research and great therapeutic interest. Here, we explored the previously unrecognized role of cKIT and its ligand, SCF (stem cell factor), in the pathological ocular neovascularization process. Approach and Results: Compared with normoxia, hypoxia, a crucial driver of neovascularization, caused cKIT to be highly upregulated in endothelial cells, which significantly enhanced the angiogenic response of endothelial cells to SCF. In murine models of pathological ocular neovascularization, such as oxygen-induced retinopathy and laser-induced choroidal neovascularization models, cKIT and SCF expression was significantly increased in ocular tissues, and blockade of cKIT and SCF using cKit mutant mice and anti-SCF neutralizing IgG substantially suppressed pathological ocular neovascularization. Mechanistically, SCF/cKIT signaling induced neovascularization through phosphorylation of glycogen synthase kinase-3β and enhancement of the nuclear translocation of β-catenin and the transcription of β-catenin target genes related to angiogenesis. Inhibition of β-catenin-mediated transcription using chemical inhibitors blocked SCF-induced in vitro angiogenesis in hypoxia, and injection of a β-catenin agonist into cKit mutant mice with oxygen-induced retinopathy significantly enhanced pathological neovascularization in the retina. Conclusions; Our data reveal that SCF and cKIT are promising novel therapeutic targets for treating vision-threatening ocular neovascular diseases.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83107257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-22DOI: 10.1161/ATVBAHA.119.312826
Bronson Haynes, Li Fang Yang, Ryan Huyck, E. Lehrer, Joshua M. Turner, N. Barabutis, Vanessa L. Correll, Allison H. Mathiesen, W. McPheat, O. Semmes, A. Dobrian
OBJECTIVE Endothelial cells (EC) in obese adipose tissue (AT) are exposed to a chronic proinflammatory environment that may induce a mesenchymal-like phenotype and altered function. The objective of this study was to establish whether endothelial-to-mesenchymal transition (EndoMT) is present in human AT in obesity and to investigate the effect of such transition on endothelial function and the endothelial particulate secretome represented by extracellular vesicles (EV). Approach and Results: We identified EndoMT in obese human AT depots by immunohistochemical co-localization of CD31 or vWF and α-SMA. We showed that AT EC exposed in vitro to TGF-β (tumor growth factor-β), TNF-α (tumor necrosis factor-α), and IFN-γ (interferon-γ) undergo EndoMT with progressive loss of endothelial markers. The phenotypic change results in failure to maintain a tight barrier in culture, increased migration, and reduced angiogenesis. EndoMT also reduced mitochondrial oxidative phosphorylation and glycolytic capacity of EC. EVs produced by EC that underwent EndoMT dramatically reduced angiogenic capacity of the recipient naïve ECs without affecting their migration or proliferation. Proteomic analysis of EV produced by EC in the proinflammatory conditions showed presence of several pro-inflammatory and immune proteins along with an enrichment in angiogenic receptors. CONCLUSIONS We demonstrated the presence of EndoMT in human AT in obesity. EndoMT in vitro resulted in production of EV that transferred some of the functional and metabolic features to recipient naïve EC. This result suggests that functional and molecular features of EC that underwent EndoMT in vivo can be disseminated in a paracrine or endocrine fashion and may induce endothelial dysfunction in distant vascular beds.
{"title":"Endothelial-to-Mesenchymal Transition in Human Adipose Tissue Vasculature Alters the Particulate Secretome and Induces Endothelial Dysfunction.","authors":"Bronson Haynes, Li Fang Yang, Ryan Huyck, E. Lehrer, Joshua M. Turner, N. Barabutis, Vanessa L. Correll, Allison H. Mathiesen, W. McPheat, O. Semmes, A. Dobrian","doi":"10.1161/ATVBAHA.119.312826","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.312826","url":null,"abstract":"OBJECTIVE\u0000Endothelial cells (EC) in obese adipose tissue (AT) are exposed to a chronic proinflammatory environment that may induce a mesenchymal-like phenotype and altered function. The objective of this study was to establish whether endothelial-to-mesenchymal transition (EndoMT) is present in human AT in obesity and to investigate the effect of such transition on endothelial function and the endothelial particulate secretome represented by extracellular vesicles (EV). Approach and Results: We identified EndoMT in obese human AT depots by immunohistochemical co-localization of CD31 or vWF and α-SMA. We showed that AT EC exposed in vitro to TGF-β (tumor growth factor-β), TNF-α (tumor necrosis factor-α), and IFN-γ (interferon-γ) undergo EndoMT with progressive loss of endothelial markers. The phenotypic change results in failure to maintain a tight barrier in culture, increased migration, and reduced angiogenesis. EndoMT also reduced mitochondrial oxidative phosphorylation and glycolytic capacity of EC. EVs produced by EC that underwent EndoMT dramatically reduced angiogenic capacity of the recipient naïve ECs without affecting their migration or proliferation. Proteomic analysis of EV produced by EC in the proinflammatory conditions showed presence of several pro-inflammatory and immune proteins along with an enrichment in angiogenic receptors.\u0000\u0000\u0000CONCLUSIONS\u0000We demonstrated the presence of EndoMT in human AT in obesity. EndoMT in vitro resulted in production of EV that transferred some of the functional and metabolic features to recipient naïve EC. This result suggests that functional and molecular features of EC that underwent EndoMT in vivo can be disseminated in a paracrine or endocrine fashion and may induce endothelial dysfunction in distant vascular beds.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"59 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88574993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-21DOI: 10.1161/ATVBAHA.119.313110
Emily R. Legan, Renhao Li
Recent advances in mechanical circulatory support (MCS) devices and technology have provided life-saving treatment options for patients with advanced stage heart failure and other severe cardiac and respiratory complications. Some forms of MCS such as left ventricular assist devices (LVADs) provide longterm circulatory support to patients as a destination therapy option or as a temporary solution before heart transplantation. The Interagency Registry for Mechanically Assisted Circulatory Support estimates that 2500 patients receive MCS devices each year.1 The benefits of LVADs have been demonstrated, as marked by over 50% patient survival after 1 year with first-generation LVADs to >80% survival with more recent generations.1,2
{"title":"Gone With the Vane.","authors":"Emily R. Legan, Renhao Li","doi":"10.1161/ATVBAHA.119.313110","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.313110","url":null,"abstract":"Recent advances in mechanical circulatory support (MCS) devices and technology have provided life-saving treatment options for patients with advanced stage heart failure and other severe cardiac and respiratory complications. Some forms of MCS such as left ventricular assist devices (LVADs) provide longterm circulatory support to patients as a destination therapy option or as a temporary solution before heart transplantation. The Interagency Registry for Mechanically Assisted Circulatory Support estimates that 2500 patients receive MCS devices each year.1 The benefits of LVADs have been demonstrated, as marked by over 50% patient survival after 1 year with first-generation LVADs to >80% survival with more recent generations.1,2","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88108146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-21DOI: 10.1161/ATVBAHA.119.313016
M. Sasaki, Tomohiro Komatsu, K. Ikewaki
{"title":"Impact of Hepatic ABCA1 (ATP-Binding Cassette Transporter A1) Deletion on Reverse Cholesterol Transport A New Clue in Solving Complex HDL (High-Density Lipoprotein) Metabolism.","authors":"M. Sasaki, Tomohiro Komatsu, K. Ikewaki","doi":"10.1161/ATVBAHA.119.313016","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.313016","url":null,"abstract":"","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87418118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-15DOI: 10.1161/ATVBAHA.119.312705
J. Valdivielso, D. Rodríguez‐Puyol, J. Pascual, C. Barrios, M. Bermúdez-López, M. Sánchez-Niño, M. Pérez-Fernández, A. Ortiz
Patients with chronic kidney disease (CKD) are at an increased risk of premature mortality, mainly from cardiovascular causes. The association between CKD on hemodialysis and accelerated atherosclerosis was described >40 years ago. However, more recently, it has been suggested that the increase in atherosclerosis risk is actually observed in early CKD stages, remaining stable thereafter. In this regard, interventions targeting the pathogenesis of atherosclerosis, such as statins, successful in the general population, have failed to benefit patients with very advanced CKD. This raises the issue of the relative contribution of atherosclerosis versus other forms of cardiovascular injury such as arteriosclerosis or myocardial injury to the increased cardiovascular risk in CKD. In this review, the pathophysiogical contributors to atherosclerosis in CKD that are shared with the general population, or specific to CKD, are discussed. The NEFRONA study prospectively assessed the prevalence and progression of subclinical atherosclerosis (plaque in vascular ultrasound), confirming an increased prevalence of atherosclerosis in patients with moderate CKD. However, the adjusted odds ratio for subclinical atherosclerosis increased with CKD stage, suggesting a contribution of CKD itself to subclinical atherosclerosis. Progression of atherosclerosis was closely related to CKD progression as well as to the baseline presence of atheroma plaque, and to higher phosphate, uric acid, and ferritin and lower 25(OH) vitamin D levels. These insights may help design future clinical trials of stratified personalized medicine targeting atherosclerosis in patients with CKD. Future primary prevention trials should enroll patients with evidence of subclinical atherosclerosis and should provide a comprehensive control of all known risk factors in addition to testing any additional intervention or placebo.
{"title":"Atherosclerosis in Chronic Kidney Disease.","authors":"J. Valdivielso, D. Rodríguez‐Puyol, J. Pascual, C. Barrios, M. Bermúdez-López, M. Sánchez-Niño, M. Pérez-Fernández, A. Ortiz","doi":"10.1161/ATVBAHA.119.312705","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.312705","url":null,"abstract":"Patients with chronic kidney disease (CKD) are at an increased risk of premature mortality, mainly from cardiovascular causes. The association between CKD on hemodialysis and accelerated atherosclerosis was described >40 years ago. However, more recently, it has been suggested that the increase in atherosclerosis risk is actually observed in early CKD stages, remaining stable thereafter. In this regard, interventions targeting the pathogenesis of atherosclerosis, such as statins, successful in the general population, have failed to benefit patients with very advanced CKD. This raises the issue of the relative contribution of atherosclerosis versus other forms of cardiovascular injury such as arteriosclerosis or myocardial injury to the increased cardiovascular risk in CKD. In this review, the pathophysiogical contributors to atherosclerosis in CKD that are shared with the general population, or specific to CKD, are discussed. The NEFRONA study prospectively assessed the prevalence and progression of subclinical atherosclerosis (plaque in vascular ultrasound), confirming an increased prevalence of atherosclerosis in patients with moderate CKD. However, the adjusted odds ratio for subclinical atherosclerosis increased with CKD stage, suggesting a contribution of CKD itself to subclinical atherosclerosis. Progression of atherosclerosis was closely related to CKD progression as well as to the baseline presence of atheroma plaque, and to higher phosphate, uric acid, and ferritin and lower 25(OH) vitamin D levels. These insights may help design future clinical trials of stratified personalized medicine targeting atherosclerosis in patients with CKD. Future primary prevention trials should enroll patients with evidence of subclinical atherosclerosis and should provide a comprehensive control of all known risk factors in addition to testing any additional intervention or placebo.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"87 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80618226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-15DOI: 10.1161/ATVBAHA.119.313215
K. S. Baker, A. Kopec, Asmita Pant, Lauren G Poole, Holly M. Cline-Fedewa, Dora Ivkovich, M. Olyaee, B. Woolbright, A. Miszta, H. Jaeschke, A. Wolberg, J. Luyendyk
OBJECTIVE Regulation of TF (tissue factor):FVIIa (coagulation factor VIIa) complex procoagulant activity is especially critical in tissues where plasma can contact TF-expressing cells. One example is the liver, where hepatocytes are routinely exposed to plasma because of the fenestrated sinusoidal endothelium. Although liver-associated TF contributes to coagulation, the mechanisms controlling the TF:FVIIa complex activity in this tissue are not known. Approach and Results: Common bile duct ligation in mice triggered rapid hepatocyte TF-dependent intrahepatic coagulation coincident with increased plasma bile acids, which occurred at a time before observable liver damage. Similarly, plasma TAT (thrombin-antithrombin) levels increased in cholestatic patients without concurrent hepatocellular injury. Pathologically relevant concentrations of the bile acid glycochenodeoxycholic acid rapidly increased hepatocyte TF-dependent procoagulant activity in vitro, independent of de novo TF synthesis and necrotic or apoptotic cell death. Glycochenodeoxycholic acid increased hepatocyte TF activity even in the presence of the phosphatidylserine-blocking protein lactadherin. Interestingly, glycochenodeoxycholic acid and taurochenodeoxycholic acid increased the procoagulant activity of the TF:FVIIa complex relipidated in unilamellar phosphatidylcholine vesicles, which was linked to an apparent decrease in the Km for FX (coagulation factor X). Notably, the zwitterionic detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, a bile acid structural analog, did not increase relipidated TF:FVIIa activity. Bile acids directly enhanced factor X activation by recombinant soluble TF:FVIIa complex but had no effect on FVIIa alone. CONCLUSIONS The results indicate that bile acids directly accelerate TF:FVIIa-driven coagulation reactions, suggesting a novel mechanism whereby elevation in a physiological mediator can directly increase TF:FVIIa procoagulant activity.
{"title":"Direct Amplification of TF (Tissue Factor).","authors":"K. S. Baker, A. Kopec, Asmita Pant, Lauren G Poole, Holly M. Cline-Fedewa, Dora Ivkovich, M. Olyaee, B. Woolbright, A. Miszta, H. Jaeschke, A. Wolberg, J. Luyendyk","doi":"10.1161/ATVBAHA.119.313215","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.313215","url":null,"abstract":"OBJECTIVE\u0000Regulation of TF (tissue factor):FVIIa (coagulation factor VIIa) complex procoagulant activity is especially critical in tissues where plasma can contact TF-expressing cells. One example is the liver, where hepatocytes are routinely exposed to plasma because of the fenestrated sinusoidal endothelium. Although liver-associated TF contributes to coagulation, the mechanisms controlling the TF:FVIIa complex activity in this tissue are not known. Approach and Results: Common bile duct ligation in mice triggered rapid hepatocyte TF-dependent intrahepatic coagulation coincident with increased plasma bile acids, which occurred at a time before observable liver damage. Similarly, plasma TAT (thrombin-antithrombin) levels increased in cholestatic patients without concurrent hepatocellular injury. Pathologically relevant concentrations of the bile acid glycochenodeoxycholic acid rapidly increased hepatocyte TF-dependent procoagulant activity in vitro, independent of de novo TF synthesis and necrotic or apoptotic cell death. Glycochenodeoxycholic acid increased hepatocyte TF activity even in the presence of the phosphatidylserine-blocking protein lactadherin. Interestingly, glycochenodeoxycholic acid and taurochenodeoxycholic acid increased the procoagulant activity of the TF:FVIIa complex relipidated in unilamellar phosphatidylcholine vesicles, which was linked to an apparent decrease in the Km for FX (coagulation factor X). Notably, the zwitterionic detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, a bile acid structural analog, did not increase relipidated TF:FVIIa activity. Bile acids directly enhanced factor X activation by recombinant soluble TF:FVIIa complex but had no effect on FVIIa alone.\u0000\u0000\u0000CONCLUSIONS\u0000The results indicate that bile acids directly accelerate TF:FVIIa-driven coagulation reactions, suggesting a novel mechanism whereby elevation in a physiological mediator can directly increase TF:FVIIa procoagulant activity.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73423060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-08-15DOI: 10.1161/ATVBAHA.119.313195
R. Retnakaran, C. Ye, P. Connelly, A. Hanley, M. Sermer, B. Zinman
OBJECTIVE apoA1 (apolipoprotein A-1) is the main lipoprotein associated with HDL (high-density lipoprotein) cholesterol. It was recently reported that intravenous infusion of apoA1 could lower insulin resistance in pregnant rats, leading to the suggestion that apoA1 could provide a target for reducing pregnancy-induced insulin resistance and the risk of gestational diabetes mellitus (GDM) in humans. However, the effects of apoA1 on insulin resistance and risk of GDM in human pregnancy are not known. Thus, we sought to systematically evaluate the relationships of apoA1 with glucose homeostasis and metabolic function in pregnant women. Approach and Results: In this study, 870 pregnant women were recruited in late second trimester and underwent metabolic characterization, including an oral glucose tolerance test on which 214 were diagnosed with GDM. Metabolic characterization included assessment of glucose tolerance, insulin sensitivity/resistance (Matsuda index, homeostasis model assessment of insulin resistance), pancreatic β-cell function, lipids (LDL [low-density lipoprotein] cholesterol, HDL cholesterol, triglycerides, apoB [apolipoprotein B], and apoA1), CRP (C-reactive protein), and adiponectin. Serum apoA1 was strongly correlated with HDL (r=0.79, P<0.0001) and weakly so with adiponectin (r=0.12, P=0.0004) but showed no association with measures of insulin sensitivity/resistance, β-cell function, glycemia, or CRP. There were no significant differences across apoA1 tertiles in mean adjusted Matsuda index (P=0.24), homeostasis model assessment of insulin resistance (P=0.08), or area under the glucose curve on the oral glucose tolerance test (P=0.96). Moreover, there were no differences in risk of GDM across tertiles of apoA1, both before (P=0.67) and after covariate adjustment (P=0.78). CONCLUSIONS Serum apoA1 is not associated with insulin resistance or the risk of GDM in human pregnancy.
{"title":"Serum apoA1 (Apolipoprotein A-1), Insulin Resistance, and the Risk of Gestational Diabetes Mellitus in Human Pregnancy.","authors":"R. Retnakaran, C. Ye, P. Connelly, A. Hanley, M. Sermer, B. Zinman","doi":"10.1161/ATVBAHA.119.313195","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.313195","url":null,"abstract":"OBJECTIVE\u0000apoA1 (apolipoprotein A-1) is the main lipoprotein associated with HDL (high-density lipoprotein) cholesterol. It was recently reported that intravenous infusion of apoA1 could lower insulin resistance in pregnant rats, leading to the suggestion that apoA1 could provide a target for reducing pregnancy-induced insulin resistance and the risk of gestational diabetes mellitus (GDM) in humans. However, the effects of apoA1 on insulin resistance and risk of GDM in human pregnancy are not known. Thus, we sought to systematically evaluate the relationships of apoA1 with glucose homeostasis and metabolic function in pregnant women. Approach and Results: In this study, 870 pregnant women were recruited in late second trimester and underwent metabolic characterization, including an oral glucose tolerance test on which 214 were diagnosed with GDM. Metabolic characterization included assessment of glucose tolerance, insulin sensitivity/resistance (Matsuda index, homeostasis model assessment of insulin resistance), pancreatic β-cell function, lipids (LDL [low-density lipoprotein] cholesterol, HDL cholesterol, triglycerides, apoB [apolipoprotein B], and apoA1), CRP (C-reactive protein), and adiponectin. Serum apoA1 was strongly correlated with HDL (r=0.79, P<0.0001) and weakly so with adiponectin (r=0.12, P=0.0004) but showed no association with measures of insulin sensitivity/resistance, β-cell function, glycemia, or CRP. There were no significant differences across apoA1 tertiles in mean adjusted Matsuda index (P=0.24), homeostasis model assessment of insulin resistance (P=0.08), or area under the glucose curve on the oral glucose tolerance test (P=0.96). Moreover, there were no differences in risk of GDM across tertiles of apoA1, both before (P=0.67) and after covariate adjustment (P=0.78).\u0000\u0000\u0000CONCLUSIONS\u0000Serum apoA1 is not associated with insulin resistance or the risk of GDM in human pregnancy.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76183462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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