Pub Date : 2016-05-01DOI: 10.1161/ATVBAHA.115.306973
M. Grandoch, Christina Kohlmorgen, A. Melchior-Becker, Kathrin Feldmann, S. Homann, Julia Müller, L. Kiene, Jinyang Zeng-Brouwers, Friederike Schmitz, N. Nagy, A. Polzin, N. Gowert, M. Elvers, P. Skroblin, X. Yin, M. Mayr, L. Schaefer, Lisa R Tannock, J. Fischer
OBJECTIVE Thrombin signaling promotes atherosclerosis by initiating inflammatory events indirectly through platelet activation and directly via protease-activated receptors. Therefore, endogenous thrombin inhibitors may be relevant modulators of atheroprogression and cardiovascular risk. In addition, endogenous thrombin inhibitors may affect the response to non-vitamin K-dependent oral anticoagulants. Here, the question was addressed whether the small leucine-rich proteoglycan biglycan acts as an endogenous thrombin inhibitor in atherosclerosis through activation of heparin cofactor II. APPROACH AND RESULTS Biglycan concentrations were elevated in the plasma of patients with acute coronary syndrome and in male Apolipoprotein E-deficient (ApoE(-/-)) mice. Biglycan was detected in the glycocalyx of capillaries and the subendothelial matrix of arterioles of ApoE(-/-) mice and in atherosclerotic plaques. Thereby a vascular compartment is provided that may mediate the endothelial and subendothelial activation of heparin cofactor II through biglycan. ApoE and Bgn double-deficient (ApoE(-/-)/Bgn(-/0)) mice showed higher activity of circulating thrombin, increased platelet activation and platelet adhesion in vivo, supporting a role of biglycan in balancing thrombin activity. Furthermore, concentrations of circulating cytokines and aortic macrophage content were elevated in ApoE(-/-)/Bgn(-/0) mice, suggesting a proinflammatory phenotype. Elevated platelet activation and macrophage accumulation were reversed by treating ApoE(-/-)/Bgn(-/0) mice with the thrombin inhibitor argatroban. Ultimately, ApoE(-/-)/Bgn(-/0) mice developed aggravated atherosclerosis. CONCLUSIONS The present results indicate that biglycan plays a previously unappreciated protective role during the progression of atherosclerosis by inhibiting thrombin activity, platelet activation, and finally macrophage-mediated plaque inflammation.
{"title":"Loss of Biglycan Enhances Thrombin Generation in Apolipoprotein E-Deficient Mice: Implications for Inflammation and Atherosclerosis.","authors":"M. Grandoch, Christina Kohlmorgen, A. Melchior-Becker, Kathrin Feldmann, S. Homann, Julia Müller, L. Kiene, Jinyang Zeng-Brouwers, Friederike Schmitz, N. Nagy, A. Polzin, N. Gowert, M. Elvers, P. Skroblin, X. Yin, M. Mayr, L. Schaefer, Lisa R Tannock, J. Fischer","doi":"10.1161/ATVBAHA.115.306973","DOIUrl":"https://doi.org/10.1161/ATVBAHA.115.306973","url":null,"abstract":"OBJECTIVE\u0000Thrombin signaling promotes atherosclerosis by initiating inflammatory events indirectly through platelet activation and directly via protease-activated receptors. Therefore, endogenous thrombin inhibitors may be relevant modulators of atheroprogression and cardiovascular risk. In addition, endogenous thrombin inhibitors may affect the response to non-vitamin K-dependent oral anticoagulants. Here, the question was addressed whether the small leucine-rich proteoglycan biglycan acts as an endogenous thrombin inhibitor in atherosclerosis through activation of heparin cofactor II.\u0000\u0000\u0000APPROACH AND RESULTS\u0000Biglycan concentrations were elevated in the plasma of patients with acute coronary syndrome and in male Apolipoprotein E-deficient (ApoE(-/-)) mice. Biglycan was detected in the glycocalyx of capillaries and the subendothelial matrix of arterioles of ApoE(-/-) mice and in atherosclerotic plaques. Thereby a vascular compartment is provided that may mediate the endothelial and subendothelial activation of heparin cofactor II through biglycan. ApoE and Bgn double-deficient (ApoE(-/-)/Bgn(-/0)) mice showed higher activity of circulating thrombin, increased platelet activation and platelet adhesion in vivo, supporting a role of biglycan in balancing thrombin activity. Furthermore, concentrations of circulating cytokines and aortic macrophage content were elevated in ApoE(-/-)/Bgn(-/0) mice, suggesting a proinflammatory phenotype. Elevated platelet activation and macrophage accumulation were reversed by treating ApoE(-/-)/Bgn(-/0) mice with the thrombin inhibitor argatroban. Ultimately, ApoE(-/-)/Bgn(-/0) mice developed aggravated atherosclerosis.\u0000\u0000\u0000CONCLUSIONS\u0000The present results indicate that biglycan plays a previously unappreciated protective role during the progression of atherosclerosis by inhibiting thrombin activity, platelet activation, and finally macrophage-mediated plaque inflammation.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"68 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87032841","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 : 2016-03-01DOI: 10.1161/ATVBAHA.115.307097
M. Vaduganathan, Deepak L. Bhatt
Human platelets possess 3 purinergic receptors (P2Y12, P2Y1, and P2X1), which collectively orchestrate key steps leading to platelet activation and aggregation (Figure). Until now, the selective blockade of the platelet P2Y12 ADP receptor, combined with the inhibition of thromboxane production by aspirin, has remained the backbone of pharmacotherapy for patients presenting with acute coronary syndrome or undergoing percutaneous coronary intervention.1 Figure. The investigational modified diadenosine tetraphosphate (Ap4A) derivative, GLS-409, in the context of major classes of currently approved antiplatelet therapies and their respective pharmacologic targets. COX indicates cyclooxygenase; F, fibrinogen; GP, glycoprotein; PAR, protease-activated receptor; and T, thrombin. See accompanying article on page 501 Despite significant progress in the attenuation of excess platelet activity in these high-risk settings, percutaneous coronary intervention–related thrombotic complications, including stent thrombosis, and severe bleeding continue to be major sources of morbidity and mortality. Early after acute coronary syndrome, patients may …
{"title":"Simultaneous Platelet P2Y12 and P2Y1 ADP Receptor Blockade: Are Two Better Than One?","authors":"M. Vaduganathan, Deepak L. Bhatt","doi":"10.1161/ATVBAHA.115.307097","DOIUrl":"https://doi.org/10.1161/ATVBAHA.115.307097","url":null,"abstract":"Human platelets possess 3 purinergic receptors (P2Y12, P2Y1, and P2X1), which collectively orchestrate key steps leading to platelet activation and aggregation (Figure). Until now, the selective blockade of the platelet P2Y12 ADP receptor, combined with the inhibition of thromboxane production by aspirin, has remained the backbone of pharmacotherapy for patients presenting with acute coronary syndrome or undergoing percutaneous coronary intervention.1\u0000\u0000\u0000\u0000Figure. \u0000The investigational modified diadenosine tetraphosphate (Ap4A) derivative, GLS-409, in the context of major classes of currently approved antiplatelet therapies and their respective pharmacologic targets. COX indicates cyclooxygenase; F, fibrinogen; GP, glycoprotein; PAR, protease-activated receptor; and T, thrombin.\u0000\u0000\u0000\u0000See accompanying article on page 501 \u0000\u0000Despite significant progress in the attenuation of excess platelet activity in these high-risk settings, percutaneous coronary intervention–related thrombotic complications, including stent thrombosis, and severe bleeding continue to be major sources of morbidity and mortality. Early after acute coronary syndrome, patients may …","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73320928","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 : 2016-01-01DOI: 10.1161/ATVBAHA.115.306561
O. Rider, R. Banerjee, J. Rayner, R. Shah, V. Murthy, M. Robson, S. Neubauer
OBJECTIVE To investigate the relationship between hepatic fat content, circulating triglyceride levels and aortic stiffness in adult and childhood obesity. APPROACH AND RESULTS Seventy-seven adults and 18 children across a wide range of body mass index (18.5-52.6 kg/m(2); percentile 8-100) with no identifiable cardiac risk factors underwent; 1H- magnetic resonance spectroscopy to quantify hepatic fat content and magnetic resonance imaging to assess aortic pulse wave velocity (PWV) and regional distensibility. In adults, multivariable regression showed age (β=0.09; P=0.02), liver fat (β=2.5; P=0.04), and serum triglyceride (β=0.47; P=0.01) to be independent predictors of PWV. Age and blood pressure-adjusted, moderated regression showed that 43% of the total negative effect of hepatic fat on PWV is attributable to indirect effects via increased triglyceride (P=0.005). In addition, regional distensibility was positively correlated with hepatic fat (ascending; r=-0.35; descending, r=-0.23; abdominal, r=-0.41; all P<0.001). Similar to that seen in adults, PWV (r=0.72; P<0.001) and abdominal regional distensibility (r=-0.52; P<0.001) were correlated with liver fat in children. CONCLUSIONS Increasing age, liver fat, and triglyceride are all related to increased aortic stiffness in adults. Even when controlling for the effects of age and blood pressure, hepatic fat has a negative effect on PWV, with substantial indirect effect occurring via increased circulating triglyceride level. This relationship between hepatic fat and aortic stiffness occurs early in the obesity process and is also seen in children. As such, hepatic fat content is a potential therapeutic target to treat the elevated vascular risk in obesity.
{"title":"Investigating a Liver Fat: Arterial Stiffening Pathway in Adult and Childhood Obesity.","authors":"O. Rider, R. Banerjee, J. Rayner, R. Shah, V. Murthy, M. Robson, S. Neubauer","doi":"10.1161/ATVBAHA.115.306561","DOIUrl":"https://doi.org/10.1161/ATVBAHA.115.306561","url":null,"abstract":"OBJECTIVE To investigate the relationship between hepatic fat content, circulating triglyceride levels and aortic stiffness in adult and childhood obesity. APPROACH AND RESULTS Seventy-seven adults and 18 children across a wide range of body mass index (18.5-52.6 kg/m(2); percentile 8-100) with no identifiable cardiac risk factors underwent; 1H- magnetic resonance spectroscopy to quantify hepatic fat content and magnetic resonance imaging to assess aortic pulse wave velocity (PWV) and regional distensibility. In adults, multivariable regression showed age (β=0.09; P=0.02), liver fat (β=2.5; P=0.04), and serum triglyceride (β=0.47; P=0.01) to be independent predictors of PWV. Age and blood pressure-adjusted, moderated regression showed that 43% of the total negative effect of hepatic fat on PWV is attributable to indirect effects via increased triglyceride (P=0.005). In addition, regional distensibility was positively correlated with hepatic fat (ascending; r=-0.35; descending, r=-0.23; abdominal, r=-0.41; all P<0.001). Similar to that seen in adults, PWV (r=0.72; P<0.001) and abdominal regional distensibility (r=-0.52; P<0.001) were correlated with liver fat in children. CONCLUSIONS Increasing age, liver fat, and triglyceride are all related to increased aortic stiffness in adults. Even when controlling for the effects of age and blood pressure, hepatic fat has a negative effect on PWV, with substantial indirect effect occurring via increased circulating triglyceride level. This relationship between hepatic fat and aortic stiffness occurs early in the obesity process and is also seen in children. As such, hepatic fat content is a potential therapeutic target to treat the elevated vascular risk in obesity.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73332775","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 : 2016-01-01DOI: 10.1161/ATVBAHA.116.308262
M. Hoekstra, T. V. Berkel
High-Density Lipoprotein: An Ambiguous Therapeutic Target in Atherosclerosis and Cardiovascular Disease A great majority of the morbidity and mortality worldwide can still be attributed to cardiovascular diseases, such as ischemic (coronary) heart disease, angina pectoris, and myocardial and cerebral infarction. Atherosclerosis, narrowing of the arteries because of arterial cholesterol deposition in macrophage foam cells, is the driving force behind the cardiovascular disease pathology. Water-soluble protein/lipid complexes called lipoproteins mediate the transport of cholesterol and other lipoid substances through the blood compartment. Relatively high levels of cholesterol associated with apolipoprotein B–containing low-density lipoprotein (LDL) particles predispose human subjects to the development of atherosclerosis and, thereby, increase the risk for cardiovascular disease. Apolipoprotein B–containing lipoproteins are, therefore, generally regarded as being proatherogenic factors. Cholesterol ester–rich high-density lipoprotein (HDL) particles use apolipoprotein A1 (apoA1) as their primary protein component. In sharp contrast to LDL, HDL is considered a potent anti-atherogenic agent. This notion is based on the fact that, in the general population, a strong inverse correlation exists between plasma levels of HDL cholesterol and the risk of cardiovascular disease. Of note, this inverse association seems to be independent of the level of cholesterol associated with proatherogenic LDL particles. As such, increasing plasma levels of HDL cholesterol has long been regarded a promising alternative therapy to supplement classical statin–based LDL cholesterol–lowering strategies that are able to reduce cardiovascular disease by only ≈30%. However, over the last decade, the enthusiasm for HDL as an interesting therapeutic target has been challenged by the HDL hypothesis critics because genetic association studies have excluded HDL cholesterol levels as determinants for cardiovascular disease risk. Furthermore, several therapeutic HDL-targeting approaches have proven insufficient to secure benefit for cardiovascular disease patients. Niacin is the most effective drug available in the clinic to raise plasma HDL cholesterol levels. Despite the fact that niacin is able to effectively raise plasma HDL cholesterol levels in patients who are treated with statins, the recent AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) testing the effect of niacin treatment on cardiovascular disease outcome in humans was stopped because of futility. Among patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of <70 mg/dL, addition of niacin to statin therapy did not reduce the composite risk of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral
{"title":"High-Density Lipoprotein: An Ambiguous Therapeutic Target in Atherosclerosis and Cardiovascular Disease","authors":"M. Hoekstra, T. V. Berkel","doi":"10.1161/ATVBAHA.116.308262","DOIUrl":"https://doi.org/10.1161/ATVBAHA.116.308262","url":null,"abstract":"High-Density Lipoprotein: An Ambiguous Therapeutic Target in Atherosclerosis and Cardiovascular Disease A great majority of the morbidity and mortality worldwide can still be attributed to cardiovascular diseases, such as ischemic (coronary) heart disease, angina pectoris, and myocardial and cerebral infarction. Atherosclerosis, narrowing of the arteries because of arterial cholesterol deposition in macrophage foam cells, is the driving force behind the cardiovascular disease pathology. Water-soluble protein/lipid complexes called lipoproteins mediate the transport of cholesterol and other lipoid substances through the blood compartment. Relatively high levels of cholesterol associated with apolipoprotein B–containing low-density lipoprotein (LDL) particles predispose human subjects to the development of atherosclerosis and, thereby, increase the risk for cardiovascular disease. Apolipoprotein B–containing lipoproteins are, therefore, generally regarded as being proatherogenic factors. Cholesterol ester–rich high-density lipoprotein (HDL) particles use apolipoprotein A1 (apoA1) as their primary protein component. In sharp contrast to LDL, HDL is considered a potent anti-atherogenic agent. This notion is based on the fact that, in the general population, a strong inverse correlation exists between plasma levels of HDL cholesterol and the risk of cardiovascular disease. Of note, this inverse association seems to be independent of the level of cholesterol associated with proatherogenic LDL particles. As such, increasing plasma levels of HDL cholesterol has long been regarded a promising alternative therapy to supplement classical statin–based LDL cholesterol–lowering strategies that are able to reduce cardiovascular disease by only ≈30%. However, over the last decade, the enthusiasm for HDL as an interesting therapeutic target has been challenged by the HDL hypothesis critics because genetic association studies have excluded HDL cholesterol levels as determinants for cardiovascular disease risk. Furthermore, several therapeutic HDL-targeting approaches have proven insufficient to secure benefit for cardiovascular disease patients. Niacin is the most effective drug available in the clinic to raise plasma HDL cholesterol levels. Despite the fact that niacin is able to effectively raise plasma HDL cholesterol levels in patients who are treated with statins, the recent AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) testing the effect of niacin treatment on cardiovascular disease outcome in humans was stopped because of futility. Among patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of <70 mg/dL, addition of niacin to statin therapy did not reduce the composite risk of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"309 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74517637","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 : 1900-01-01DOI: 10.1161/ATVBAHA.116.308637
H. Ait-Oufella, A. Sage
Atherosclerosis is a pathological condition of the arterial wall that underlies adverse vascular events, including myocardial infarction, stroke, and ischemic gangrene, and is responsible for most of the cardiovascular morbidity and mortality in the Western world. The past 2 decades have witnessed major advances in our understanding of the pathophysiology of atherosclerosis especially the identification of a central role for innate and adaptive immune responses in arterial disease development and potentially disease complications.1 Among CD4+ T lymphocytes, interferon (IFN)-γ-producing T helper type 1 cells have been shown to exert proatherogenic effects, whereas regulatory T cells (Tregs) display atheroprotective properties.2 Tregs act through several pathways, including provision of interleukin (IL)-10 or transforming growth factor (TGF)-β, control of IL-2 availability, or cell–cell contact-dependent inhibitory mechanisms, for example, CTLA-4 expression and transendocytosis of costimulatory molecules.3,4 The identification of a critical protective role of Tregs in atherosclerosis5 has led to studies aimed at promoting Treg responses in vivo to tame disease development. Both antigen-specific and nonspecific strategies have been tested successfully in mouse models of atherosclerosis. Among the antigen-nonspecific approaches, treatment with selective anti-CD3 antibodies6 or treatment with IL-2,7 which substantially increased endogenous Tregs levels and halted disease …
{"title":"The Sunlight: A New Immunomodulatory Approach of Atherosclerosis.","authors":"H. Ait-Oufella, A. Sage","doi":"10.1161/ATVBAHA.116.308637","DOIUrl":"https://doi.org/10.1161/ATVBAHA.116.308637","url":null,"abstract":"Atherosclerosis is a pathological condition of the arterial wall that underlies adverse vascular events, including myocardial infarction, stroke, and ischemic gangrene, and is responsible for most of the cardiovascular morbidity and mortality in the Western world. The past 2 decades have witnessed major advances in our understanding of the pathophysiology of atherosclerosis especially the identification of a central role for innate and adaptive immune responses in arterial disease development and potentially disease complications.1 Among CD4+ T lymphocytes, interferon (IFN)-γ-producing T helper type 1 cells have been shown to exert proatherogenic effects, whereas regulatory T cells (Tregs) display atheroprotective properties.2 Tregs act through several pathways, including provision of interleukin (IL)-10 or transforming growth factor (TGF)-β, control of IL-2 availability, or cell–cell contact-dependent inhibitory mechanisms, for example, CTLA-4 expression and transendocytosis of costimulatory molecules.3,4 The identification of a critical protective role of Tregs in atherosclerosis5 has led to studies aimed at promoting Treg responses in vivo to tame disease development. Both antigen-specific and nonspecific strategies have been tested successfully in mouse models of atherosclerosis. Among the antigen-nonspecific approaches, treatment with selective anti-CD3 antibodies6 or treatment with IL-2,7 which substantially increased endogenous Tregs levels and halted disease …","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"34 1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77670768","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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