Objective—Angiogenesis, the process of building complex vascular structures, begins with sprout formation on preexisting blood vessels, followed by extension of the vessels through proliferation and migration of endothelial cells. Based on the potential therapeutic benefits of preventing angiogenesis in pathological conditions, many studies have focused on the mechanisms of its initiation as well as control. However, how the extension of vessels is terminated remains obscure. Thus, we investigated the negative regulation mechanism. Approach and Results—We report that increased intracellular calcium can induce dephosphorylation of the endothelial receptor tyrosine kinase Tie2. The calcium-mediated dephosphorylation was found to be dependent on Tie2–calmodulin interaction. The Tyr1113 residue in the C-terminal end loop of the Tie2 kinase domain was mapped and found to be required for this interaction. Moreover, mutation of this residue into Phe impaired both the Tie2-calmodulin interaction and calcium-media...
{"title":"Correction to: Calmodulin Mediates Ca2+-Dependent Inhibition of Tie2 Signaling and Acts as a Developmental Brake During Embryonic Angiogenesis.","authors":"ChansikYang, JiyeonOhk, Ji YeunLee, Eun JinKim, JiyoonKim, SangyeulHan, DongeunPark, HosungJung, ChunghoKim","doi":"10.1161/ATV.0000000000000084","DOIUrl":"https://doi.org/10.1161/ATV.0000000000000084","url":null,"abstract":"Objective—Angiogenesis, the process of building complex vascular structures, begins with sprout formation on preexisting blood vessels, followed by extension of the vessels through proliferation and migration of endothelial cells. Based on the potential therapeutic benefits of preventing angiogenesis in pathological conditions, many studies have focused on the mechanisms of its initiation as well as control. However, how the extension of vessels is terminated remains obscure. Thus, we investigated the negative regulation mechanism. Approach and Results—We report that increased intracellular calcium can induce dephosphorylation of the endothelial receptor tyrosine kinase Tie2. The calcium-mediated dephosphorylation was found to be dependent on Tie2–calmodulin interaction. The Tyr1113 residue in the C-terminal end loop of the Tie2 kinase domain was mapped and found to be required for this interaction. Moreover, mutation of this residue into Phe impaired both the Tie2-calmodulin interaction and calcium-media...","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"59 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76127029","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 : 2019-01-01DOI: 10.1161/ATVBAHA.119.313200
Rajesh K. Singh, A. Haka, A. Asmal, V. C. Barbosa-Lorenzi, I. Grosheva, H. Chin, Yuquan Xiong, T. Hla, F. Maxfield
OBJECTIVE Aggregation and modification of LDLs (low-density lipoproteins) promote their retention and accumulation in the arteries. This is a critical initiating factor during atherosclerosis. Macrophage catabolism of agLDL (aggregated LDL) occurs using a specialized extracellular, hydrolytic compartment, the lysosomal synapse. Compartment formation by local actin polymerization and delivery of lysosomal contents by exocytosis promotes acidification of the compartment and degradation of agLDL. Internalization of metabolites, such as cholesterol, promotes foam cell formation, a process that drives atherogenesis. Furthermore, there is accumulating evidence for the involvement of TLR4 (Toll-like receptor 4) and its adaptor protein MyD88 (myeloid differentiation primary response 88) in atherosclerosis. Here, we investigated the role of TLR4 in catabolism of agLDL using the lysosomal synapse and foam cell formation. Approach and Results: Using bone marrow-derived macrophages from knockout mice, we find that TLR4 and MyD88 regulate compartment formation, lysosome exocytosis, acidification of the compartment, and foam cell formation. Using siRNA, pharmacological inhibition and knockout bone marrow-derived macrophages, we implicate SYK (spleen tyrosine kinase), PI3K (phosphoinositide 3-kinase), and Akt in agLDL catabolism using the lysosomal synapse. Using bone marrow transplantation of LDL receptor knockout mice with TLR4KO bone marrow, we show that deficiency of TLR4 protects macrophages from lipid accumulation during atherosclerosis. Finally, we demonstrate that macrophages in vivo form an extracellular compartment and exocytose lysosome contents similar to that observed in vitro for degradation of agLDL. CONCLUSIONS We present a mechanism in which interaction of macrophages with agLDL initiates a TLR4 signaling pathway, resulting in formation of the lysosomal synapse, catabolism of agLDL, and lipid accumulation in vitro and in vivo.
{"title":"TLR4 (Toll-Like Receptor 4)-Dependent Signaling Drives Extracellular Catabolism of LDL (Low-Density Lipoprotein) Aggregates.","authors":"Rajesh K. Singh, A. Haka, A. Asmal, V. C. Barbosa-Lorenzi, I. Grosheva, H. Chin, Yuquan Xiong, T. Hla, F. Maxfield","doi":"10.1161/ATVBAHA.119.313200","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.313200","url":null,"abstract":"OBJECTIVE Aggregation and modification of LDLs (low-density lipoproteins) promote their retention and accumulation in the arteries. This is a critical initiating factor during atherosclerosis. Macrophage catabolism of agLDL (aggregated LDL) occurs using a specialized extracellular, hydrolytic compartment, the lysosomal synapse. Compartment formation by local actin polymerization and delivery of lysosomal contents by exocytosis promotes acidification of the compartment and degradation of agLDL. Internalization of metabolites, such as cholesterol, promotes foam cell formation, a process that drives atherogenesis. Furthermore, there is accumulating evidence for the involvement of TLR4 (Toll-like receptor 4) and its adaptor protein MyD88 (myeloid differentiation primary response 88) in atherosclerosis. Here, we investigated the role of TLR4 in catabolism of agLDL using the lysosomal synapse and foam cell formation. Approach and Results: Using bone marrow-derived macrophages from knockout mice, we find that TLR4 and MyD88 regulate compartment formation, lysosome exocytosis, acidification of the compartment, and foam cell formation. Using siRNA, pharmacological inhibition and knockout bone marrow-derived macrophages, we implicate SYK (spleen tyrosine kinase), PI3K (phosphoinositide 3-kinase), and Akt in agLDL catabolism using the lysosomal synapse. Using bone marrow transplantation of LDL receptor knockout mice with TLR4KO bone marrow, we show that deficiency of TLR4 protects macrophages from lipid accumulation during atherosclerosis. Finally, we demonstrate that macrophages in vivo form an extracellular compartment and exocytose lysosome contents similar to that observed in vitro for degradation of agLDL. CONCLUSIONS We present a mechanism in which interaction of macrophages with agLDL initiates a TLR4 signaling pathway, resulting in formation of the lysosomal synapse, catabolism of agLDL, and lipid accumulation in vitro and in vivo.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82485514","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 : 2019-01-01DOI: 10.1161/atv.0000000000000086
{"title":"Correction to: Apolipoprotein E4 Expression Causes Gain of Toxic Function in Isogenic Human Induced Pluripotent Stem Cell-Derived Endothelial Cells.","authors":"","doi":"10.1161/atv.0000000000000086","DOIUrl":"https://doi.org/10.1161/atv.0000000000000086","url":null,"abstract":"","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"67 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74489435","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 : 2019-01-01DOI: 10.1161/ATVBAHA.119.312934
Y. Katayama, A. Tanaka, A. Taruya, Manabu Kashiwagi, Tsuyoshi Nishiguchi, Y. Ozaki, Y. Matsuo, H. Kitabata, T. Kubo, Emi Shimda, T. Kondo, T. Akasaka
OBJECTIVE Cholesterol crystals (CCs) are frequently found at the site of acute myocardial infarctions (AMIs), but the role of CCs in the onset of AMI remains unclear due to the lack of validated in vivo imaging tools. The aim of this study was to validate the ability of optical coherence tomography (OCT) to detect CCs and to compare the prevalence and distribution of CCs in patients with AMIs and stable angina pectoris. Approach and Results: CC assessment using OCT were compared with histopathology results in 45 coronary samples. We investigated 152 consecutive patients with AMIs and 41 patients with single vessel-diseased stable angina pectoris. Based on the presence of plaque ruptures (PR), AMI patients were divided into 2 groups: those with PR (n=112) and those without PR (n=40). CCs invading fibrous caps were defined as superficial-type CCs. A multivariable logistic regression analysis was performed to determine PR predictors. The sensitivity and specificity of OCT for detecting CCs were 68% and 92%, respectively. The prevalence of plaques with CCs was higher in the AMI with PR group (AMI with PR 81%, AMI without PR 48%, stable angina pectoris 39%, P<0.01). A multivariable logistic model showed that superficial-type CCs and thin-cap fibroatheromas were positive predictors for PR. CONCLUSIONS OCT has a high specificity and modest sensitivity for the detection of CCs. The combination of CCs invading fibrous cap and thin-cap fibroatheromas detected by OCT may better identify rupture-prone plaques.
{"title":"Feasibility and Clinical Significance of In Vivo Cholesterol Crystal Detection Using Optical Coherence Tomography.","authors":"Y. Katayama, A. Tanaka, A. Taruya, Manabu Kashiwagi, Tsuyoshi Nishiguchi, Y. Ozaki, Y. Matsuo, H. Kitabata, T. Kubo, Emi Shimda, T. Kondo, T. Akasaka","doi":"10.1161/ATVBAHA.119.312934","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.312934","url":null,"abstract":"OBJECTIVE Cholesterol crystals (CCs) are frequently found at the site of acute myocardial infarctions (AMIs), but the role of CCs in the onset of AMI remains unclear due to the lack of validated in vivo imaging tools. The aim of this study was to validate the ability of optical coherence tomography (OCT) to detect CCs and to compare the prevalence and distribution of CCs in patients with AMIs and stable angina pectoris. Approach and Results: CC assessment using OCT were compared with histopathology results in 45 coronary samples. We investigated 152 consecutive patients with AMIs and 41 patients with single vessel-diseased stable angina pectoris. Based on the presence of plaque ruptures (PR), AMI patients were divided into 2 groups: those with PR (n=112) and those without PR (n=40). CCs invading fibrous caps were defined as superficial-type CCs. A multivariable logistic regression analysis was performed to determine PR predictors. The sensitivity and specificity of OCT for detecting CCs were 68% and 92%, respectively. The prevalence of plaques with CCs was higher in the AMI with PR group (AMI with PR 81%, AMI without PR 48%, stable angina pectoris 39%, P<0.01). A multivariable logistic model showed that superficial-type CCs and thin-cap fibroatheromas were positive predictors for PR. CONCLUSIONS OCT has a high specificity and modest sensitivity for the detection of CCs. The combination of CCs invading fibrous cap and thin-cap fibroatheromas detected by OCT may better identify rupture-prone plaques.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85242200","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 : 2018-08-03DOI: 10.1161/ATVBAHA.119.313506
Federico Figliolini, A. Ranghino, C. Grange, Massimo Cedrino, Marta Tapparo, Claudia Cavallari, Andrea Rossi, G. Togliatto, S. Femminò, Maria Vittoria Gugliuzza, G. Camussi, M. Brizzi
OBJECTIVES Critical hindlimb ischemia is a severe consequence of peripheral artery disease. Surgical treatment does not prevent skeletal muscle impairment or improve long-term patient outcomes. The present study investigates the protective/regenerative potential and the mechanism of action of adipose stem cell-derived extracellular vesicles (ASC-EVs) in a mouse model of hindlimb ischemia. Approach and Results: We demonstrated that ASC-EVs exert a protective effect on muscle damage by acting both on tissue microvessels and muscle cells. The genes involved in muscle regeneration were up-regulated in the ischemic muscles of ASC-EV-treated animals. MyoD expression has also been confirmed in satellite cells. This was followed by a reduction in muscle function impairment in vivo. ASC-EVs drive myoblast proliferation and differentiation in the in vitro ischemia/reoxygenation model. Moreover, ASC-EVs have shown an anti-apoptotic effect both in vitro and in vivo. Transcriptomic analyses have revealed that ASC-EVs carry a variety of pro-angiogenic mRNAs, while proteomic analyses have demonstrated an enrichment of NRG1 (neuregulin 1). A NRG1 blocking antibody used in vivo demonstrated that NRG1 is relevant to ASC-EV-induced muscle protection, vascular growth, and recruitment of inflammatory cells. Finally, bioinformatic analyses on 18 molecules that were commonly detected in ASC-EVs, including mRNAs and proteins, confirmed the enrichment of pathways involved in vascular growth and muscle regeneration/protection. CONCLUSIONS This study demonstrates that ASC-EVs display pro-angiogenic and skeletal muscle protective properties that are associated with their NRG1/mRNA cargo. We, therefore, propose that ASC-EVs are a useful tool for therapeutic angiogenesis and muscle protection.
{"title":"Extracellular Vesicles From Adipose Stem Cells Prevent Muscle Damage and Inflammation in a Mouse Model of Hind Limb Ischemia: Role of Neuregulin-1.","authors":"Federico Figliolini, A. Ranghino, C. Grange, Massimo Cedrino, Marta Tapparo, Claudia Cavallari, Andrea Rossi, G. Togliatto, S. Femminò, Maria Vittoria Gugliuzza, G. Camussi, M. Brizzi","doi":"10.1161/ATVBAHA.119.313506","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.313506","url":null,"abstract":"OBJECTIVES\u0000Critical hindlimb ischemia is a severe consequence of peripheral artery disease. Surgical treatment does not prevent skeletal muscle impairment or improve long-term patient outcomes. The present study investigates the protective/regenerative potential and the mechanism of action of adipose stem cell-derived extracellular vesicles (ASC-EVs) in a mouse model of hindlimb ischemia. Approach and Results: We demonstrated that ASC-EVs exert a protective effect on muscle damage by acting both on tissue microvessels and muscle cells. The genes involved in muscle regeneration were up-regulated in the ischemic muscles of ASC-EV-treated animals. MyoD expression has also been confirmed in satellite cells. This was followed by a reduction in muscle function impairment in vivo. ASC-EVs drive myoblast proliferation and differentiation in the in vitro ischemia/reoxygenation model. Moreover, ASC-EVs have shown an anti-apoptotic effect both in vitro and in vivo. Transcriptomic analyses have revealed that ASC-EVs carry a variety of pro-angiogenic mRNAs, while proteomic analyses have demonstrated an enrichment of NRG1 (neuregulin 1). A NRG1 blocking antibody used in vivo demonstrated that NRG1 is relevant to ASC-EV-induced muscle protection, vascular growth, and recruitment of inflammatory cells. Finally, bioinformatic analyses on 18 molecules that were commonly detected in ASC-EVs, including mRNAs and proteins, confirmed the enrichment of pathways involved in vascular growth and muscle regeneration/protection.\u0000\u0000\u0000CONCLUSIONS\u0000This study demonstrates that ASC-EVs display pro-angiogenic and skeletal muscle protective properties that are associated with their NRG1/mRNA cargo. We, therefore, propose that ASC-EVs are a useful tool for therapeutic angiogenesis and muscle protection.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"150 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75776569","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 : 2018-06-01DOI: 10.1161/atvbaha.118.311203
C. Edelstein, G. Getz, S. Marcovina, J. Albers, M. Koschinsky
Angelo Scanu spent almost the whole of his illustrious scientific career at the University of Chicago. Actually, he had 2 distinguished careers there: one devoted to plasma HDL (high-density lipoprotein) and the other to Lp(a) (lipoprotein(a)). Angelo had come to the United States in 1955 on a Fulbright Scholarship, working with Irvine Page at the Cleveland Clinic and with Walter Hughes at the Brookhaven National Laboratories. It was at this time he began his pioneering work on lipoproteins, developing a delipidation procedure that yielded apolipoproteins in essentially a lipidfree state. This breakthrough opened up the field of apolipoprotein research. He came to the University of Chicago in 1961 to do his American internship in internal medicine—a second internship, having done the first one in Italy, where he had graduated cum laude from Sassari University Medical School in 1949. Angelo then joined the faculty in the Department of Medicine at the University of Chicago, where he remained until his retirement in 2011. For the first 25 years of his research career, his focus was HDL, including the isolation and characterization of the structures of its 2 major apoproteins, A-I and A-II. Using innovative physicochemical methods, Angelo and his colleagues elucidated the role of the apolipoproteins in HDL structure. As a visiting investigator at CNRS (Centre National de la Recherche Scientifique), Gif-sur Yvette, France, he learned to apply small-angle X-ray scattering to the examination of lipoprotein structure. Along with Dr Vittorio Luzzati, these studies led to a series of important new findings on the structural organization of low-density lipoprotein and HDL. This venture highlighted Angelo’s recognition of the importance of physical chemistry to the full understanding of lipoprotein structure—a view highlighted by his collaboration with Francois Kezdy, who was a close collaborator at the University of Chicago. Angelo was also a principal investigator in the Specialized Center of Research on Atherosclerosis where he studied the lipoproteins, lowdensity lipoprotein, and HDL of nonhuman primates. In the mid 1980s, the focus of Angelo’s laboratory shifted to the second theme of his research, Lp(a). In 1984, the group reported on the heterogeneity of Lp(a) particle size, which they correctly attributed to differently sized apo(a) (apolipoprotein(a)) moieties. In 1987, through a collaboration with Genentech, Inc, Angelo and his colleagues provided the first report of the unexpected similarity between the apo(a) component of Lp(a) and the fibrinolytic proenzyme plasminogen. The partial protein sequence data indicated the presence in apo(a) of domains corresponding to plasminogen kringle IV, kringle V, and protease sequences; the latter domain was shown to be inactive in apo(a). This work led to a publication in Nature in 1989, where Angelo’s group showed that Lp(a) inhibits the binding of plasminogen to vascular cells—an important mechanism for the
{"title":"Angelo Scanu Memorial","authors":"C. Edelstein, G. Getz, S. Marcovina, J. Albers, M. Koschinsky","doi":"10.1161/atvbaha.118.311203","DOIUrl":"https://doi.org/10.1161/atvbaha.118.311203","url":null,"abstract":"Angelo Scanu spent almost the whole of his illustrious scientific career at the University of Chicago. Actually, he had 2 distinguished careers there: one devoted to plasma HDL (high-density lipoprotein) and the other to Lp(a) (lipoprotein(a)). Angelo had come to the United States in 1955 on a Fulbright Scholarship, working with Irvine Page at the Cleveland Clinic and with Walter Hughes at the Brookhaven National Laboratories. It was at this time he began his pioneering work on lipoproteins, developing a delipidation procedure that yielded apolipoproteins in essentially a lipidfree state. This breakthrough opened up the field of apolipoprotein research. He came to the University of Chicago in 1961 to do his American internship in internal medicine—a second internship, having done the first one in Italy, where he had graduated cum laude from Sassari University Medical School in 1949. Angelo then joined the faculty in the Department of Medicine at the University of Chicago, where he remained until his retirement in 2011. For the first 25 years of his research career, his focus was HDL, including the isolation and characterization of the structures of its 2 major apoproteins, A-I and A-II. Using innovative physicochemical methods, Angelo and his colleagues elucidated the role of the apolipoproteins in HDL structure. As a visiting investigator at CNRS (Centre National de la Recherche Scientifique), Gif-sur Yvette, France, he learned to apply small-angle X-ray scattering to the examination of lipoprotein structure. Along with Dr Vittorio Luzzati, these studies led to a series of important new findings on the structural organization of low-density lipoprotein and HDL. This venture highlighted Angelo’s recognition of the importance of physical chemistry to the full understanding of lipoprotein structure—a view highlighted by his collaboration with Francois Kezdy, who was a close collaborator at the University of Chicago. Angelo was also a principal investigator in the Specialized Center of Research on Atherosclerosis where he studied the lipoproteins, lowdensity lipoprotein, and HDL of nonhuman primates. In the mid 1980s, the focus of Angelo’s laboratory shifted to the second theme of his research, Lp(a). In 1984, the group reported on the heterogeneity of Lp(a) particle size, which they correctly attributed to differently sized apo(a) (apolipoprotein(a)) moieties. In 1987, through a collaboration with Genentech, Inc, Angelo and his colleagues provided the first report of the unexpected similarity between the apo(a) component of Lp(a) and the fibrinolytic proenzyme plasminogen. The partial protein sequence data indicated the presence in apo(a) of domains corresponding to plasminogen kringle IV, kringle V, and protease sequences; the latter domain was shown to be inactive in apo(a). This work led to a publication in Nature in 1989, where Angelo’s group showed that Lp(a) inhibits the binding of plasminogen to vascular cells—an important mechanism for the ","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"53 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91219211","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 : 2018-02-01DOI: 10.1161/ATVBAHA.117.310673
Jingjing Tang
The scientific community of atherosclerosis and related inflammatory diseases research has lost a lifelong member with the passing of Elaine W. Raines on July 16, 2017. Elaine died at her home in Burien Washington after losing her battle to metastasized breast cancer. Those of us who are familiar with Elaine’s passion for science, her perseverance in everyday research and her ultimate optimistic perspective for life are greatly saddened. We feel fortunate to have experienced Elaine’s mentorship, friendship, love of science, and love of Northwest living; we mourn deeply the loss of a very unique and inspirational personality. Elaine was born in Seattle and grew up in Renton Washington. After graduating from Whitman College where she double majored in Chemistry and Economics, she spent 5 years in California where she completed her Master of Science at the University of California at San Francisco and did research at the Salk Institute. On her return to Seattle, Elaine landed the job …
随着Elaine W. Raines于2017年7月16日去世，动脉粥样硬化及相关炎症性疾病研究科学界失去了一位终身成员。伊莱恩在与转移性乳腺癌的斗争中失败后，在华盛顿布里恩的家中去世。我们当中熟悉伊莱恩对科学的热情，对日常研究的坚持以及对生活的乐观态度的人都感到非常难过。我们感到很幸运，经历了伊莱恩的指导，友谊，对科学的热爱，以及对西北生活的热爱;我们对失去一位非常独特和鼓舞人心的人物深表哀悼。伊莱恩出生于西雅图，在华盛顿州伦顿长大。从惠特曼学院(Whitman College)化学和经济学双学位毕业后，她在加州待了5年，在加州大学旧金山分校(University of California at San Francisco)完成了理学硕士学位，并在索尔克研究所(Salk Institute)做了研究。回到西雅图后，伊莱恩得到了那份工作。
{"title":"Elaine W. Raines (1948–2017)","authors":"Jingjing Tang","doi":"10.1161/ATVBAHA.117.310673","DOIUrl":"https://doi.org/10.1161/ATVBAHA.117.310673","url":null,"abstract":"The scientific community of atherosclerosis and related inflammatory diseases research has lost a lifelong member with the passing of Elaine W. Raines on July 16, 2017. Elaine died at her home in Burien Washington after losing her battle to metastasized breast cancer. Those of us who are familiar with Elaine’s passion for science, her perseverance in everyday research and her ultimate optimistic perspective for life are greatly saddened. We feel fortunate to have experienced Elaine’s mentorship, friendship, love of science, and love of Northwest living; we mourn deeply the loss of a very unique and inspirational personality.\u0000\u0000Elaine was born in Seattle and grew up in Renton Washington. After graduating from Whitman College where she double majored in Chemistry and Economics, she spent 5 years in California where she completed her Master of Science at the University of California at San Francisco and did research at the Salk Institute. On her return to Seattle, Elaine landed the job …","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75584523","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 : 2018-01-01DOI: 10.1161/ATVBAHA.118.310859
A. Daugherty
{"title":"Recipients of the 2018 Early Career Investigator Awards","authors":"A. Daugherty","doi":"10.1161/ATVBAHA.118.310859","DOIUrl":"https://doi.org/10.1161/ATVBAHA.118.310859","url":null,"abstract":"","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"2009 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90335780","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 : 2017-11-01DOI: 10.1161/ATV.0000000000000043
L. Curtiss, G. Hansson, P. Libby, M. Correia, W. Haynes, A. Lichtenstein, L. Appel, M. Brands, M. Carnethon, S. Daniels, H. Franch, B. Franklin, P. Kris-Etherton, W. Harris, B. Howard, N. Karanja, M. Lefevre, L. Rudel, F. Sacks, L. Horn, M. Winston, J. Wylie-Rosett
BACKGROUND: Reactive oxygen species (ROS) contribute to platelet hyperactivation during aging. Several oxidative pathways and antioxidant enzymes have been implicated; however, their mechanistic contributions during aging remain elusive. We hypothesized that mitochondria are an important source of platelet ROS and that mitochondrial SOD2 (superoxide dismutase) protects against mitochondrial ROS-driven platelet activation and thrombosis during aging. METHODS: We studied littermates of platelet-specific SOD2-knockout (SOD2 fl/fl Pf4Cre, pSOD2-KO) and control (SOD2 fl/fl ) mice at young (4–5 months) or old (18–20 months) ages. We examined agonist-induced platelet activation, platelet-dependent thrombin generation potential, and susceptibility to in vivo thrombosis. RESULTS: Platelet α IIb β 3 activation, aggregation, and adhesion were increased to similar extents in aged mice of both genotypes compared with young mice. In contrast, the age-dependent increases in mitochondrial and total cellular ROS, calcium elevation, and phosphatidylserine exposure were augmented in platelets from pSOD2-KO mice compared with control mice. Aged pSOD2-KO mice showed increased platelet-dependent thrombin generation compared with aged control mice. In vivo, aged pSOD2-KO mice exhibited enhanced susceptibility to carotid artery and pulmonary thrombosis compared to aged control mice. Adoptive transfer of platelets from aged pSOD2-KO but not aged control mice increased thrombotic susceptibility in aged host mice, suggesting a prothrombotic effect of platelet pSOD2 deficiency. Treatment with avasopasem manganese (GC4419), a SOD mimetic, decreased platelet mitochondrial pro-oxidants, cellular ROS levels, and inhibited procoagulant platelet formation and arterial thrombosis in aged mice. CONCLUSIONS: Platelet mitochondrial ROS contributes to age-related thrombosis and endogenous SOD2 protects from platelet-dependent thrombin generation and thrombosis during aging. GRAPHIC ABSTRACT: A graphic abstract is available for this article.
{"title":"Arteriosclerosis, Thrombosis, and Vascular Biology.","authors":"L. Curtiss, G. Hansson, P. Libby, M. Correia, W. Haynes, A. Lichtenstein, L. Appel, M. Brands, M. Carnethon, S. Daniels, H. Franch, B. Franklin, P. Kris-Etherton, W. Harris, B. Howard, N. Karanja, M. Lefevre, L. Rudel, F. Sacks, L. Horn, M. Winston, J. Wylie-Rosett","doi":"10.1161/ATV.0000000000000043","DOIUrl":"https://doi.org/10.1161/ATV.0000000000000043","url":null,"abstract":"BACKGROUND: Reactive oxygen species (ROS) contribute to platelet hyperactivation during aging. Several oxidative pathways and antioxidant enzymes have been implicated; however, their mechanistic contributions during aging remain elusive. We hypothesized that mitochondria are an important source of platelet ROS and that mitochondrial SOD2 (superoxide dismutase) protects against mitochondrial ROS-driven platelet activation and thrombosis during aging. METHODS: We studied littermates of platelet-specific SOD2-knockout (SOD2 fl/fl Pf4Cre, pSOD2-KO) and control (SOD2 fl/fl ) mice at young (4–5 months) or old (18–20 months) ages. We examined agonist-induced platelet activation, platelet-dependent thrombin generation potential, and susceptibility to in vivo thrombosis. RESULTS: Platelet α IIb β 3 activation, aggregation, and adhesion were increased to similar extents in aged mice of both genotypes compared with young mice. In contrast, the age-dependent increases in mitochondrial and total cellular ROS, calcium elevation, and phosphatidylserine exposure were augmented in platelets from pSOD2-KO mice compared with control mice. Aged pSOD2-KO mice showed increased platelet-dependent thrombin generation compared with aged control mice. In vivo, aged pSOD2-KO mice exhibited enhanced susceptibility to carotid artery and pulmonary thrombosis compared to aged control mice. Adoptive transfer of platelets from aged pSOD2-KO but not aged control mice increased thrombotic susceptibility in aged host mice, suggesting a prothrombotic effect of platelet pSOD2 deficiency. Treatment with avasopasem manganese (GC4419), a SOD mimetic, decreased platelet mitochondrial pro-oxidants, cellular ROS levels, and inhibited procoagulant platelet formation and arterial thrombosis in aged mice. CONCLUSIONS: Platelet mitochondrial ROS contributes to age-related thrombosis and endogenous SOD2 protects from platelet-dependent thrombin generation and thrombosis during aging. GRAPHIC ABSTRACT: A graphic abstract is available for this article.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"27 1","pages":"1"},"PeriodicalIF":0.0,"publicationDate":"2017-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83615080","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：