Pub Date : 2019-12-01DOI: 10.1161/atv.0000000000000090
{"title":"Correction to: 18F-Sodium Fluoride Imaging of Coronary Atherosclerosis in Ambulatory Patients With Diabetes Mellitus.","authors":"","doi":"10.1161/atv.0000000000000090","DOIUrl":"https://doi.org/10.1161/atv.0000000000000090","url":null,"abstract":"","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89026218","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 : 2019-12-01DOI: 10.1161/ATVBAHA.119.313340
Annabelle Rodriguez, Bernardo L. Trigatti, C. Mineo, D. Knaack, John T. Wilkins, D. Sahoo, B. Asztalos, S. Mora, M. Cuchel, Henry J. Pownall, C. Rosales, P. Bernatchez, Amanda Ribeiro Martins da Silva, Godfrey S. Getz, Jacob L. Barber, Gregory C. Shearer, Angela M. Zivkovic, U. Tietge, Frank M. Sacks, M. Connelly, Michael N. Oda, W. Davidson, M. Sorci-Thomas, T. Vaisar, G. Ruotolo, K. Vickers, C. Martel
The HDL (high-density lipoprotein) Workshop was established in 2009 as a forum for candid discussions among academic basic scientists, clinical investigators, and industry researchers about the role of HDL in cardiovascular disease. This ninth HDL Workshop was held on May 16 to 17, 2019 in Boston, MA, and included outstanding oral presentations from established and emerging investigators. The Workshop featured 5 sessions with topics that tackled the role of HDL in the vasculature, its structural complexity, its role in health and disease states, and its interaction with the intestinal microbiome. The highlight of the program was awarding the Jack Oram Award to the distinguished professor emeritus G.S. Getz from the University of Chicago. The tenth HDL Workshop will be held on May 2020 in Chicago and will continue the focus on intellectually stimulating presentations by established and emerging investigators on novel roles of HDL in cardiovascular and noncardiovascular health and disease states.
{"title":"Proceedings of the Ninth HDL (High-Density Lipoprotein) Workshop: Focus on Cardiovascular Disease.","authors":"Annabelle Rodriguez, Bernardo L. Trigatti, C. Mineo, D. Knaack, John T. Wilkins, D. Sahoo, B. Asztalos, S. Mora, M. Cuchel, Henry J. Pownall, C. Rosales, P. Bernatchez, Amanda Ribeiro Martins da Silva, Godfrey S. Getz, Jacob L. Barber, Gregory C. Shearer, Angela M. Zivkovic, U. Tietge, Frank M. Sacks, M. Connelly, Michael N. Oda, W. Davidson, M. Sorci-Thomas, T. Vaisar, G. Ruotolo, K. Vickers, C. Martel","doi":"10.1161/ATVBAHA.119.313340","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.313340","url":null,"abstract":"The HDL (high-density lipoprotein) Workshop was established in 2009 as a forum for candid discussions among academic basic scientists, clinical investigators, and industry researchers about the role of HDL in cardiovascular disease. This ninth HDL Workshop was held on May 16 to 17, 2019 in Boston, MA, and included outstanding oral presentations from established and emerging investigators. The Workshop featured 5 sessions with topics that tackled the role of HDL in the vasculature, its structural complexity, its role in health and disease states, and its interaction with the intestinal microbiome. The highlight of the program was awarding the Jack Oram Award to the distinguished professor emeritus G.S. Getz from the University of Chicago. The tenth HDL Workshop will be held on May 2020 in Chicago and will continue the focus on intellectually stimulating presentations by established and emerging investigators on novel roles of HDL in cardiovascular and noncardiovascular health and disease states.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"71 36","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91549624","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 : 2019-12-01DOI: 10.1161/atvbaha.119.313461
Chantal M Boulanger, O. Baretella, G. Blaise, R. Bond, Yin Cai, C. K. Chan, T. Chataigneau, Maggie Jie Chen, Hui Chen, Yanhua Cheng, D. Clement, R. Cohen, Michael J. Collis, A. Danser, J. D. De Mey, Charlotte M. S. Detremmerie, D. Duprez, M. Félétou, Nicolas Flavahan, Yuansheng Gao, Yumeng Guo, Ute Hoeffner, D. Houston, Ianto Boscheng Huang, Yu Huang, Stephane Iliano, D. Junquero, Z. Katusic, K. Komori, Mary Y.K. Lee, S. Leung, Zhuoming Li, Sophie Liang, Jacky Tsz Chiu Liu, T. Luscher, F. Michel, V. Miller, J. Mombouli, K. Morrison, S. Muldoon, S. O'Rourke, Louis Perrault, J. Quignard, N. Rusch, C. Sánchez-Ferrer, V. Schini-Kerth, K. Shen, Yi Shi, Erfei Song, Kiwi W Y Sun, S. Taddei, E. H. Tang, M. Tuncer, R. van den Ende, Y. Vedernikov, T. Verbeuren, C. Webb, A. Weigert, K. K. Wong, Cheng Xu, Kangmin Yang, Fan Ying, T. Zellers, Ying-Yong Zhao, Qian Zou, H. Shimokawa
{"title":"Tribute to Paul M. Vanhoutte, MD, PhD (1940-2019).","authors":"Chantal M Boulanger, O. Baretella, G. Blaise, R. Bond, Yin Cai, C. K. Chan, T. Chataigneau, Maggie Jie Chen, Hui Chen, Yanhua Cheng, D. Clement, R. Cohen, Michael J. Collis, A. Danser, J. D. De Mey, Charlotte M. S. Detremmerie, D. Duprez, M. Félétou, Nicolas Flavahan, Yuansheng Gao, Yumeng Guo, Ute Hoeffner, D. Houston, Ianto Boscheng Huang, Yu Huang, Stephane Iliano, D. Junquero, Z. Katusic, K. Komori, Mary Y.K. Lee, S. Leung, Zhuoming Li, Sophie Liang, Jacky Tsz Chiu Liu, T. Luscher, F. Michel, V. Miller, J. Mombouli, K. Morrison, S. Muldoon, S. O'Rourke, Louis Perrault, J. Quignard, N. Rusch, C. Sánchez-Ferrer, V. Schini-Kerth, K. Shen, Yi Shi, Erfei Song, Kiwi W Y Sun, S. Taddei, E. H. Tang, M. Tuncer, R. van den Ende, Y. Vedernikov, T. Verbeuren, C. Webb, A. Weigert, K. K. Wong, Cheng Xu, Kangmin Yang, Fan Ying, T. Zellers, Ying-Yong Zhao, Qian Zou, H. Shimokawa","doi":"10.1161/atvbaha.119.313461","DOIUrl":"https://doi.org/10.1161/atvbaha.119.313461","url":null,"abstract":"","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78535656","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 : 2019-12-01DOI: 10.1161/ATVBAHA.119.312707
Ya-ju Chang, Yi-Shuan J. Li, Chia-Ching Wu, Kuei‐Chun Wang, Tzu-chieh Huang, Z. Chen, S. Chien
OBJECTIVE Understanding message delivery among vascular cells is essential for deciphering the intercellular communicatios in cardiovascular diseases. MicroRNA (miR)-92a is enriched in endothelial cells (ECs) and circulation under atheroprone conditions. Macrophages are the primary immune cells in atherosclerotic lesions that modulate lesion development. Therefore, we hypothesize that, in response to atheroprone stimuli, ECs export miR-92a to macrophages to regulate their functions and enhance atherosclerotic progression. Approach and Results: We investigated the macrophage functions that are regulated by EC miR-92a under atheroprone microenvironments. We first determined the distributions of functional extracellular miR-92a by fractionating the intravesicular and extravesicular compartments from endothelial conditioned media and mice serum. The results indicate that extracellular vesicles are the primary vehicles for EC miR-92a transportation. Overexpression of miR-92a in ECs enhanced the proinflammatory responses and low-density lipoprotein uptake, while impaired the migration, of cocultured macrophage. Opposite effects were found in macrophages cocultured with ECs with miR-92a knockdown. Further analyses demonstrated that intravesicular miR-92a suppressed the expression of target gene Krüppel-like factor 4 (KLF4) in macrophages, suggesting a mechanism by which intravesicular miR-92a regulates recipient cell functions. Indeed, the overexpression of KLF4 rescued the EC miR-92a-induced macrophage atheroprone phenotypes. Furthermore, an inverse correlation of intravesicular miR-92a in blood serum and KLF4 expression in lesions was observed in atherosclerotic animals, indicating the potential function of extracellular miR-92a in regulating vascular diseases. CONCLUSIONS EC miR-92a can be transported to macrophages through extracellular vesicles to regulate KLF4 levels, thus leading to the atheroprone phenotypes of macrophage and, hence, atherosclerotic lesion formation.
目的:了解血管细胞间的信息传递对于解读心血管疾病的细胞间通讯至关重要。在动脉粥样硬化条件下，MicroRNA (miR)-92a在内皮细胞(ECs)和循环中富集。巨噬细胞是动脉粥样硬化病变中调节病变发展的主要免疫细胞。因此，我们假设，作为对动脉粥样硬化酮刺激的反应，内皮细胞将miR-92a输出到巨噬细胞，以调节巨噬细胞的功能并促进动脉粥样硬化的进展。方法和结果:我们研究了在动脉粥样硬化微环境下EC miR-92a调控的巨噬细胞功能。我们首先通过从内皮条件培养基和小鼠血清中分离泡内和泡外腔室来确定功能性细胞外miR-92a的分布。结果表明，细胞外囊泡是EC miR-92a运输的主要载体。在ECs中过表达miR-92a增强了共培养巨噬细胞的促炎反应和低密度脂蛋白摄取，同时损害了巨噬细胞的迁移。在与miR-92a敲低的内皮细胞共培养的巨噬细胞中发现相反的效果。进一步分析表明，囊泡内miR-92a抑制巨噬细胞中靶基因kr样因子4 (KLF4)的表达，提示囊泡内miR-92a调节受体细胞功能的机制。事实上，KLF4的过表达挽救了EC mir -92a诱导的巨噬细胞动脉粥样硬化表型。此外，在动脉粥样硬化动物中观察到血清囊内miR-92a与病变中KLF4表达呈负相关，表明细胞外miR-92a在调节血管疾病中的潜在功能。结论sec miR-92a可通过细胞外囊泡转运至巨噬细胞，调节KLF4水平，从而导致巨噬细胞的动脉粥样硬化表型，从而形成动脉粥样硬化病变。
{"title":"Extracellular MicroRNA-92a Mediates Endothelial Cell-Macrophage Communication.","authors":"Ya-ju Chang, Yi-Shuan J. Li, Chia-Ching Wu, Kuei‐Chun Wang, Tzu-chieh Huang, Z. Chen, S. Chien","doi":"10.1161/ATVBAHA.119.312707","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.312707","url":null,"abstract":"OBJECTIVE\u0000Understanding message delivery among vascular cells is essential for deciphering the intercellular communicatios in cardiovascular diseases. MicroRNA (miR)-92a is enriched in endothelial cells (ECs) and circulation under atheroprone conditions. Macrophages are the primary immune cells in atherosclerotic lesions that modulate lesion development. Therefore, we hypothesize that, in response to atheroprone stimuli, ECs export miR-92a to macrophages to regulate their functions and enhance atherosclerotic progression. Approach and Results: We investigated the macrophage functions that are regulated by EC miR-92a under atheroprone microenvironments. We first determined the distributions of functional extracellular miR-92a by fractionating the intravesicular and extravesicular compartments from endothelial conditioned media and mice serum. The results indicate that extracellular vesicles are the primary vehicles for EC miR-92a transportation. Overexpression of miR-92a in ECs enhanced the proinflammatory responses and low-density lipoprotein uptake, while impaired the migration, of cocultured macrophage. Opposite effects were found in macrophages cocultured with ECs with miR-92a knockdown. Further analyses demonstrated that intravesicular miR-92a suppressed the expression of target gene Krüppel-like factor 4 (KLF4) in macrophages, suggesting a mechanism by which intravesicular miR-92a regulates recipient cell functions. Indeed, the overexpression of KLF4 rescued the EC miR-92a-induced macrophage atheroprone phenotypes. Furthermore, an inverse correlation of intravesicular miR-92a in blood serum and KLF4 expression in lesions was observed in atherosclerotic animals, indicating the potential function of extracellular miR-92a in regulating vascular diseases.\u0000\u0000\u0000CONCLUSIONS\u0000EC miR-92a can be transported to macrophages through extracellular vesicles to regulate KLF4 levels, thus leading to the atheroprone phenotypes of macrophage and, hence, atherosclerotic lesion formation.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"53 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90079031","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 : 2019-12-01DOI: 10.1161/atv.0000000000000089
{"title":"Correction to: Role of LpL (Lipoprotein Lipase) in Macrophage Polarization In Vitro and In Vivo.","authors":"","doi":"10.1161/atv.0000000000000089","DOIUrl":"https://doi.org/10.1161/atv.0000000000000089","url":null,"abstract":"","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74815119","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 : 2019-11-26DOI: 10.1161/ATVBAHA.119.313535
O. Boucherat, R. Paulin, S. Provencher, S. Bonnet
Endothelial cell (EC) dysfunction, characterized by cell injury, ensuing apoptosis, and release of growth factors and cytokines, is a critical early event in the pathogenesis of many cardiovascular diseases, including pulmonary hypertension (PH). Indeed, excessive production of paracrine factors from damaged EC promotes the recruitment of circulating inflammatory cells and triggers vascular remodeling through stimulation of pulmonary artery (PA) smooth muscle cell (SMC) contraction and proliferation. Although endothelium injury is recognized to play a causative role in the development and progression of PH, the underlying mechanisms as well as the nature of the signaling molecules that mediates crosstalk between PAECs and adjacent SMCs remain poorly understood.
{"title":"New Insights Into HIMF (Hypoxia-Induced Mitogenic Factor)-Mediated Signaling Pathways in Pulmonary Hypertension.","authors":"O. Boucherat, R. Paulin, S. Provencher, S. Bonnet","doi":"10.1161/ATVBAHA.119.313535","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.313535","url":null,"abstract":"Endothelial cell (EC) dysfunction, characterized by cell injury, ensuing apoptosis, and release of growth factors and cytokines, is a critical early event in the pathogenesis of many cardiovascular diseases, including pulmonary hypertension (PH). Indeed, excessive production of paracrine factors from damaged EC promotes the recruitment of circulating inflammatory cells and triggers vascular remodeling through stimulation of pulmonary artery (PA) smooth muscle cell (SMC) contraction and proliferation. Although endothelium injury is recognized to play a causative role in the development and progression of PH, the underlying mechanisms as well as the nature of the signaling molecules that mediates crosstalk between PAECs and adjacent SMCs remain poorly understood.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78465674","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 : 2019-11-26DOI: 10.1161/ATVBAHA.119.313479
D. Nechipurenko, P. Mangin, M. Panteleev
{"title":"Response by Nechipurenko et al to Letter Regarding Article, \"Clot Contraction Drives the Translocation of Procoagulant Platelets to Thrombus Surface\".","authors":"D. Nechipurenko, P. Mangin, M. Panteleev","doi":"10.1161/ATVBAHA.119.313479","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.313479","url":null,"abstract":"","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"100 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85805054","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 : 2019-11-26DOI: 10.1161/ATVBAHA.119.313533
M. Rogers, E. Aikawa
Extracellular vesicles (EVs) function as mediators of cell-cell communication1 and organ crosstalk,2 but a complete understanding of the mechanistic roles this critical communication process plays in cardiovascular and associated diseases is lacking. In normal conditions, EV crosstalk is important for proper cell and organ function, but in diseased conditions EV cargos can be altered in a way that promotes disease pathology. Multiple cargos have been observed in EVs, including RNAs, such as microRNA, DNA, proteins, and lipids, which can be encased within EVs or associated with EV membranes. Given this critical function, identifying the communication roles of EVs in normal physiology and diseasedriving mechanisms holds great therapeutic promise. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Chang et al3 propose EV transport as a major pathway in which miR-92a is transported from endothelial cells to macrophages that, in turn, contributes to the development of atherosclerosis. This study identifies a key mechanism of how miR-92a cell-cell communication occurs in atherosclerotic vasculature and raises the potential of EV-associated miR-92a as a disease biomarker and therapeutic target.
{"title":"MicroRNA Extracellular Vesicle Stowaways in Cell-Cell Communication and Organ Crosstalk.","authors":"M. Rogers, E. Aikawa","doi":"10.1161/ATVBAHA.119.313533","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.313533","url":null,"abstract":"Extracellular vesicles (EVs) function as mediators of cell-cell communication1 and organ crosstalk,2 but a complete understanding of the mechanistic roles this critical communication process plays in cardiovascular and associated diseases is lacking. In normal conditions, EV crosstalk is important for proper cell and organ function, but in diseased conditions EV cargos can be altered in a way that promotes disease pathology. Multiple cargos have been observed in EVs, including RNAs, such as microRNA, DNA, proteins, and lipids, which can be encased within EVs or associated with EV membranes. Given this critical function, identifying the communication roles of EVs in normal physiology and diseasedriving mechanisms holds great therapeutic promise. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Chang et al3 propose EV transport as a major pathway in which miR-92a is transported from endothelial cells to macrophages that, in turn, contributes to the development of atherosclerosis. This study identifies a key mechanism of how miR-92a cell-cell communication occurs in atherosclerotic vasculature and raises the potential of EV-associated miR-92a as a disease biomarker and therapeutic target.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80596177","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 : 2019-11-26DOI: 10.1161/ATVBAHA.119.313503
M. Visser, R. van Oerle, H. ten Cate, V. Laux, N. Mackman, S. Heitmeier, H. Spronk
OBJECTIVES FXIa (factor XIa) induces clot formation, and human congenital FXI deficiency protects against venous thromboembolism and stroke. In contrast, the role of FXI in hemostasis is rather small, especially compared with FIX deficiency. Little is known about the cause of the difference in phenotypes associated with FIX deficiency and FXI deficiency. We speculated that activation of FIX via the intrinsic coagulation is not solely dependent on FXI(a; activated FXI) and aimed at identifying an FXI-independent FIX activation pathway. Approach and Results: We observed that ellagic acid and long-chain polyphosphates activated the coagulation system in FXI-deficient plasma, as could be demonstrated by measurement of thrombin generation, FIXa-AT (antithrombin), and FXa-AT complex levels, suggesting an FXI bypass route of FIX activation. Addition of a specific PKa (plasma kallikrein) inhibitor to FXI-deficient plasma decreased thrombin generation, prolonged activated partial thromboplastin time, and diminished FIXa-AT and FXa-AT complex formation, indicating that PKa plays a role in the FXI bypass route of FIX activation. In addition, FIXa-AT complex formation was significantly increased in F11-/- mice treated with ellagic acid or long-chain polyphosphates compared with controls and this increase was significantly reduced by inhibition of PKa. CONCLUSIONS We demonstrated that activation of FXII leads to thrombin generation via FIX activation by PKa in the absence of FXI. These findings may, in part, explain the different phenotypes associated with FIX and FXI deficiencies.
{"title":"PKa (Plasma Kallikrein) Contributes to Coagulation in the Absence of FXI (Factor XI) by Activating FIX (Factor IX).","authors":"M. Visser, R. van Oerle, H. ten Cate, V. Laux, N. Mackman, S. Heitmeier, H. Spronk","doi":"10.1161/ATVBAHA.119.313503","DOIUrl":"https://doi.org/10.1161/ATVBAHA.119.313503","url":null,"abstract":"OBJECTIVES\u0000FXIa (factor XIa) induces clot formation, and human congenital FXI deficiency protects against venous thromboembolism and stroke. In contrast, the role of FXI in hemostasis is rather small, especially compared with FIX deficiency. Little is known about the cause of the difference in phenotypes associated with FIX deficiency and FXI deficiency. We speculated that activation of FIX via the intrinsic coagulation is not solely dependent on FXI(a; activated FXI) and aimed at identifying an FXI-independent FIX activation pathway. Approach and Results: We observed that ellagic acid and long-chain polyphosphates activated the coagulation system in FXI-deficient plasma, as could be demonstrated by measurement of thrombin generation, FIXa-AT (antithrombin), and FXa-AT complex levels, suggesting an FXI bypass route of FIX activation. Addition of a specific PKa (plasma kallikrein) inhibitor to FXI-deficient plasma decreased thrombin generation, prolonged activated partial thromboplastin time, and diminished FIXa-AT and FXa-AT complex formation, indicating that PKa plays a role in the FXI bypass route of FIX activation. In addition, FIXa-AT complex formation was significantly increased in F11-/- mice treated with ellagic acid or long-chain polyphosphates compared with controls and this increase was significantly reduced by inhibition of PKa.\u0000\u0000\u0000CONCLUSIONS\u0000We demonstrated that activation of FXII leads to thrombin generation via FIX activation by PKa in the absence of FXI. These findings may, in part, explain the different phenotypes associated with FIX and FXI deficiencies.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90594859","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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