Abstract
High-density lipoprotein (HDL) has many protective activities against atherosclerosis, including its role in reverse cholesterol transport, and its antioxidant, anti-inflammatory, and endothelial cell maintenance functions. However, all HDL is not functionally equivalent. The authors of recent studies have shown that infection, inflammation, diabetes, and coronary artery disease are associated with dysfunctional HDL. HDL can lose its protective activities through a variety of mechanisms, including, but not limited to, altered protein composition, oxidative protein modification mediated by the enzyme myeloperoxidase, and lipid modification. Studies in which the authors used bacterial endotoxin in humans and mice have directly demonstrated changes in HDL composition, loss of HDL’s cholesterol acceptor activity, and decreased hepatic processing and secretion of cholesterol. Although a routine clinical assay for dysfunctional HDL is not currently available, the development of such an assay would be beneficial for a better understanding of the role that dysfunctional HDL plays as a risk factor for coronary artery disease and for the determination of how various drug therapies effect HDL functionality.
Journal of Lipidology: Volume 4, Issue 5, Pages 382-388 (September 2010)
Myeloperoxidase, inflammation, and dysfunctional high-density lipoprotein
Abstract
High-density lipoprotein (HDL) has many protective activities against atherosclerosis, including its role in reverse cholesterol transport, and its antioxidant, anti-inflammatory, and endothelial cell maintenance functions. However, all HDL is not functionally equivalent. The authors of recent studies have shown that infection, inflammation, diabetes, and coronary artery disease are associated with dysfunctional HDL. HDL can lose its protective activities through a variety of mechanisms, including, but not limited to, altered protein composition, oxidative protein modification mediated by the enzyme myeloperoxidase, and lipid modification. Studies in which the authors used bacterial endotoxin in humans and mice have directly demonstrated changes in HDL composition, loss of HDL’s cholesterol acceptor activity, and decreased hepatic processing and secretion of cholesterol. Although a routine clinical assay for dysfunctional HDL is not currently available, the development of such an assay would be beneficial for a better understanding of the role that dysfunctional HDL plays as a risk factor for coronary artery disease and for the determination of how various drug therapies effect HDL functionality.
Journal of Lipidology: Volume 4, Issue 5, Pages 382-388 (September 2010)
High-density lipoprotein (HDL) has many protective activities against atherosclerosis, including its role in reverse cholesterol transport, and its antioxidant, anti-inflammatory, and endothelial cell maintenance functions. However, all HDL is not functionally equivalent. The authors of recent studies have shown that infection, inflammation, diabetes, and coronary artery disease are associated with dysfunctional HDL. HDL can lose its protective activities through a variety of mechanisms, including, but not limited to, altered protein composition, oxidative protein modification mediated by the enzyme myeloperoxidase, and lipid modification. Studies in which the authors used bacterial endotoxin in humans and mice have directly demonstrated changes in HDL composition, loss of HDL’s cholesterol acceptor activity, and decreased hepatic processing and secretion of cholesterol. Although a routine clinical assay for dysfunctional HDL is not currently available, the development of such an assay would be beneficial for a better understanding of the role that dysfunctional HDL plays as a risk factor for coronary artery disease and for the determination of how various drug therapies effect HDL functionality.
Journal of Lipidology: Volume 4, Issue 5, Pages 382-388 (September 2010)
Plasma myeloperoxidase, NT-proBNP, and troponin-I in patients on CAPD compared with those on regular hemodialysis
Myeloperoxidase (MPO) is a hemoprotein that is released during inflammation and may lead to irreversible protein and lipid modification, increasing levels of oxidized low density lipoprotein, and promoting athrogenesis. Recently, it has been considered as a risk factor for cardiovascular diseases. Similarly, the measurement of carotid intima-media thickness gives an indication about the degree of atherosclerosis and prediction of clinical cardiovascular events.
Elevated white blood cells counts may indicate a state of acute inflammation and follow its progression. Dialysis patients are at a high risk of developing cardiovascular disease compared with healthy subjects. The role of N-terminal pro-brain natriuretic peptide and increased cardiac troponin in identification and prognostication of cardiovascular diseases in end-stage renal disease patients has been investigated. The current study aimed to evaluate plasma MPO and its possible relationship with carotid intima-media thickness, troponin I, N-terminal pro-brain natriuretic peptide (NT-proBNP), and insulin resistance as measured by homeostatic model assessment (HOMA index) in a cohort of Saudi patients who are undergoing hemodialysis (HD) vs. continuous ambulatory peritoneal dialysis for end-stage renal disease.
Plasma MPO was significantly higher in patients on continuous ambulatory peritoneal dialysis (CAPD) than in those on HD and in normal subjects (P<0.001). Conversely, NT-proBNP plasma levels were significantly higher in patients on HD (both predialysis and postdialysis) than in those on CAPD (P<0.01) and than normal subjects. Similarly, plasma troponin-I levels were significantly higher in patients on HD compared with those of CAPD and than normal subjects (P<0.001). Plasma troponin-I and NT-proBNP levels were positively correlated in the 3 groups namely those on CAPD, Pre-HD, and post-HD (r: 0.464 and P=0.047; r: 0.330 and P=0.013; and r: 0.452 and P=0.024), respectively. There was no correlation between the MPO level and carotid intima-media thickness (P>0.05). However, plasma MPO level correlated positively with the white blood cell count in patients on CAPD and in those on HD (P <0.05).
Our findings suggest an increased oxidative stress in CAPD patients compared with HD patients, while the reported difference in plasma NT-proBNP and troponin-I may be related to the rapid decline of residual renal function in HD and type of membrane used in the HD dialysis procedure itself.
Hemodialysis International
Volume 14, Issue 3, pages 308–315, July 2010
Abdulla AL-HWEISH1, Sherif S. SULTAN2, Khaled MOGAZI3, Mohamed Y. ELSAMMAK4
Elevated white blood cells counts may indicate a state of acute inflammation and follow its progression. Dialysis patients are at a high risk of developing cardiovascular disease compared with healthy subjects. The role of N-terminal pro-brain natriuretic peptide and increased cardiac troponin in identification and prognostication of cardiovascular diseases in end-stage renal disease patients has been investigated. The current study aimed to evaluate plasma MPO and its possible relationship with carotid intima-media thickness, troponin I, N-terminal pro-brain natriuretic peptide (NT-proBNP), and insulin resistance as measured by homeostatic model assessment (HOMA index) in a cohort of Saudi patients who are undergoing hemodialysis (HD) vs. continuous ambulatory peritoneal dialysis for end-stage renal disease.
Plasma MPO was significantly higher in patients on continuous ambulatory peritoneal dialysis (CAPD) than in those on HD and in normal subjects (P<0.001). Conversely, NT-proBNP plasma levels were significantly higher in patients on HD (both predialysis and postdialysis) than in those on CAPD (P<0.01) and than normal subjects. Similarly, plasma troponin-I levels were significantly higher in patients on HD compared with those of CAPD and than normal subjects (P<0.001). Plasma troponin-I and NT-proBNP levels were positively correlated in the 3 groups namely those on CAPD, Pre-HD, and post-HD (r: 0.464 and P=0.047; r: 0.330 and P=0.013; and r: 0.452 and P=0.024), respectively. There was no correlation between the MPO level and carotid intima-media thickness (P>0.05). However, plasma MPO level correlated positively with the white blood cell count in patients on CAPD and in those on HD (P <0.05).
Our findings suggest an increased oxidative stress in CAPD patients compared with HD patients, while the reported difference in plasma NT-proBNP and troponin-I may be related to the rapid decline of residual renal function in HD and type of membrane used in the HD dialysis procedure itself.
Hemodialysis International
Volume 14, Issue 3, pages 308–315, July 2010
Abdulla AL-HWEISH1, Sherif S. SULTAN2, Khaled MOGAZI3, Mohamed Y. ELSAMMAK4
Myeloperoxidase Breaks Down Potentially Toxic Nanomaterials Identified
ScienceDaily (Apr. 8, 2010) — An international study based at the University of Pittsburgh provides the first identification of a human enzyme that can biodegrade carbon nanotubes-the superstrong materials found in products from electronics to plastics-and in laboratory tests offset the potentially damaging health effects of being exposed to the tiny components, according to findings published online in Nature Nanotechnology.
The results could open the door to the use of carbon nanotubes as a safe drug-delivery tool and also could lead to the development of a natural treatment for people exposed to nanotubes, either in the environment or the workplace, the team reported. The researchers found that carbon nanotubes degraded with the human enzyme myeloperoxidase (hMPO) did not produce the lung inflammation that intact nanotubes have been shown to cause. Furthermore, neutrophils, the white blood cells that contain and emit hMPO to kill invading microorganisms, can be directed to attack carbon nanotubes specifically.
"The successful medical application of carbon nanotubes rely on their effective breakdown in the body, but carbon nanotubes also are notoriously durable," said lead researcher Valerian Kagan, a professor and vice chair in the Department of Environmental and Occupational Health in Pitt's Graduate School of Public Health."The ability of hMPO to biodegrade carbon nanotubes reveals that this breakdown is part of a natural inflammatory response. The next step is to develop methods for stimulating that inflammatory response and reproducing the biodegradation process inside a living organism."
Kagan and his research group led the team of more than 20 researchers from four universities along with the laboratory groups of Alexander Star, an assistant professor of chemistry in Pitt's School of Arts and Sciences, and Judith Klein-Seethharaman, an assistant professor of structural biology in Pitt's School of Medicine. Additional Pitt researchers included Yulia Tyurina, a Pitt assistant professor of environmental and occupational health in the Graduate School of Public Health, and Donna Stolz, an associate professor of cell biology and physiology in Pitt's medical school; other researchers are from Sweden's Karolinska Institute, Trinity College in Ireland, the National Institute for Occupational Safety and Health, and West Virginia University.
Carbon nanotubes are one-atom thick rolls of graphite 100,000 times smaller than a human hair yet stronger than steel. They are used to reinforce plastics, ceramics, or concrete; are excellent conductors of electricity and heat; and are sensitive chemical sensors. However, a nanotube's surface also contains thousands of atoms that could react with the human body in unknown ways. Tests on mice have shown that nanotube inhalation results in severe lung inflammation coupled with an early onset of fibrosis. The tubes' durability raises additional concern about proper disposal and cleanup. In 2008, Star and Kagan reported in "Nano Letters" that carbon nanotubes deteriorate when exposed to the plant enzyme horseradish peroxidase, but their research focused on cleanup after accidental spills during manufacturing or in the environment.
For the current study, the researchers focused on human myeloperoxidase because it works via the release of strong acids and oxidants-similar to the chemicals used to break down carbon nanotubes. They first incubated short, single-walled nanotubes in an hMPO and hydrogen peroxide solution-the hydrogen peroxide sparks and sustains hMPO activity-for 24 hours, after which the structure and bulk of the tube had completely degenerated. The nanotubes degenerated even faster when sodium chloride was added to the solution to produce hypochlorite, a strong oxidizing compound known to break down nanotubes.
After establishing the effectiveness of myeloperoxidase in degrading carbon nanotubes, the team developed a technique to prompt neutrophils to attack nanotubes by capturing them and exposing them to the enzyme. They implanted a sample of nanotubes with antibodies known as immunoglobulin G (IgG), which made them specific neutrophil targets. After 12 hours, 100 percent of IgG nanotubes were degraded versus 30 percent of those without IgG. The researchers also tested the ability of macrophages, another white blood cell, to break down nanotubes, but after two days, only 50 percent of the tubes had degenerated.
In subsequent laboratory tests, lung tissue exposed to the degraded nanotubes for seven days exhibited negligible change when compared to unexposed tissue. On the other hand, tissue exposed to untreated nanotubes developed severe inflammation
The results could open the door to the use of carbon nanotubes as a safe drug-delivery tool and also could lead to the development of a natural treatment for people exposed to nanotubes, either in the environment or the workplace, the team reported. The researchers found that carbon nanotubes degraded with the human enzyme myeloperoxidase (hMPO) did not produce the lung inflammation that intact nanotubes have been shown to cause. Furthermore, neutrophils, the white blood cells that contain and emit hMPO to kill invading microorganisms, can be directed to attack carbon nanotubes specifically.
"The successful medical application of carbon nanotubes rely on their effective breakdown in the body, but carbon nanotubes also are notoriously durable," said lead researcher Valerian Kagan, a professor and vice chair in the Department of Environmental and Occupational Health in Pitt's Graduate School of Public Health."The ability of hMPO to biodegrade carbon nanotubes reveals that this breakdown is part of a natural inflammatory response. The next step is to develop methods for stimulating that inflammatory response and reproducing the biodegradation process inside a living organism."
Kagan and his research group led the team of more than 20 researchers from four universities along with the laboratory groups of Alexander Star, an assistant professor of chemistry in Pitt's School of Arts and Sciences, and Judith Klein-Seethharaman, an assistant professor of structural biology in Pitt's School of Medicine. Additional Pitt researchers included Yulia Tyurina, a Pitt assistant professor of environmental and occupational health in the Graduate School of Public Health, and Donna Stolz, an associate professor of cell biology and physiology in Pitt's medical school; other researchers are from Sweden's Karolinska Institute, Trinity College in Ireland, the National Institute for Occupational Safety and Health, and West Virginia University.
Carbon nanotubes are one-atom thick rolls of graphite 100,000 times smaller than a human hair yet stronger than steel. They are used to reinforce plastics, ceramics, or concrete; are excellent conductors of electricity and heat; and are sensitive chemical sensors. However, a nanotube's surface also contains thousands of atoms that could react with the human body in unknown ways. Tests on mice have shown that nanotube inhalation results in severe lung inflammation coupled with an early onset of fibrosis. The tubes' durability raises additional concern about proper disposal and cleanup. In 2008, Star and Kagan reported in "Nano Letters" that carbon nanotubes deteriorate when exposed to the plant enzyme horseradish peroxidase, but their research focused on cleanup after accidental spills during manufacturing or in the environment.
For the current study, the researchers focused on human myeloperoxidase because it works via the release of strong acids and oxidants-similar to the chemicals used to break down carbon nanotubes. They first incubated short, single-walled nanotubes in an hMPO and hydrogen peroxide solution-the hydrogen peroxide sparks and sustains hMPO activity-for 24 hours, after which the structure and bulk of the tube had completely degenerated. The nanotubes degenerated even faster when sodium chloride was added to the solution to produce hypochlorite, a strong oxidizing compound known to break down nanotubes.
After establishing the effectiveness of myeloperoxidase in degrading carbon nanotubes, the team developed a technique to prompt neutrophils to attack nanotubes by capturing them and exposing them to the enzyme. They implanted a sample of nanotubes with antibodies known as immunoglobulin G (IgG), which made them specific neutrophil targets. After 12 hours, 100 percent of IgG nanotubes were degraded versus 30 percent of those without IgG. The researchers also tested the ability of macrophages, another white blood cell, to break down nanotubes, but after two days, only 50 percent of the tubes had degenerated.
In subsequent laboratory tests, lung tissue exposed to the degraded nanotubes for seven days exhibited negligible change when compared to unexposed tissue. On the other hand, tissue exposed to untreated nanotubes developed severe inflammation
Oxidation of apolipoprotein A-I by myeloperoxidase impairs the initial interactions with ABCA1 required for signaling and cholesterol export
A key cardioprotective effect of high-density lipoprotein (HDL) involves the interaction of its major protein, apolipoprotein A-I (apoA-I), with ATP-binding cassette transporter A1 (ABCA1), a macrophage cholesterol exporter. ApoA I is thought to remove cholesterol from macrophages by a cascade of events. First it binds directly to ABCA1, activating signaling pathways, and then it binds to and solubilizes lipid domains generated by ABCA1.
HDL isolated from human atherosclerotic lesions and blood of subjects with established coronary artery disease contains elevated levels of 3-chlorotyrosine and 3-nitrotyrosine, two characteristic products of myeloperoxidase (MPO), a heme protein secreted by macrophages. Here we show that chlorination--but not nitration--of apoA-I by the MPO pathway impairs its ability to interact directly with ABCA1, to activate the Janus kinase 2 signaling pathway, and to promote efflux of cellular cholesterol. In contrast, oxidation of apoA-I has little effect on its ability to stabilize ABCA1 protein or to solubilize phospholipids.
Our results indicate that chlorination of apoA-I by the MPO pathway selectively inhibits two critical early events in cholesterol efflux: the binding of apoA-I to ABCA1 and activation of a key signaling pathway. Therefore, oxidation of apoA-I in the artery wall by MPO-generated chlorinating intermediates may contribute to atherogenesis by impairing cholesterol efflux from macrophages
Baohai Shao1, Chongren Tang1, Jay W. Heinecke1 and John F. Oram2,*
1 University of Washington, United States;
2 University of Washington Medical Center, United States
HDL isolated from human atherosclerotic lesions and blood of subjects with established coronary artery disease contains elevated levels of 3-chlorotyrosine and 3-nitrotyrosine, two characteristic products of myeloperoxidase (MPO), a heme protein secreted by macrophages. Here we show that chlorination--but not nitration--of apoA-I by the MPO pathway impairs its ability to interact directly with ABCA1, to activate the Janus kinase 2 signaling pathway, and to promote efflux of cellular cholesterol. In contrast, oxidation of apoA-I has little effect on its ability to stabilize ABCA1 protein or to solubilize phospholipids.
Our results indicate that chlorination of apoA-I by the MPO pathway selectively inhibits two critical early events in cholesterol efflux: the binding of apoA-I to ABCA1 and activation of a key signaling pathway. Therefore, oxidation of apoA-I in the artery wall by MPO-generated chlorinating intermediates may contribute to atherogenesis by impairing cholesterol efflux from macrophages
Baohai Shao1, Chongren Tang1, Jay W. Heinecke1 and John F. Oram2,*
1 University of Washington, United States;
2 University of Washington Medical Center, United States
Vascular Endothelial Function Is Related to White Blood Cell Count and Myeloperoxidase Among Healthy Middle-Aged and Older Adults
Abstract—Endothelium-dependent dilation (EDD) is impaired with aging, but there is significant variability among healthy middle-aged and older adults. We tested the hypothesis that EDD is related to white blood cell (WBC) count in healthy men and women aged 55 to 75 years (n=48) who have a WBC count within the clinically normal range. The peak forearm blood flow response to intrabrachial artery infusion of acetylcholine was inversely related to WBC count (r=-0.38; P=0.004) and was 34% smaller in subjects with higher versus lower WBC count (more versus less than the median of 5.0x109 cells per liter; P=0.001).
Vascular smooth muscle responsiveness to NO (peak forearm blood flow response to sodium nitroprusside) was inversely related to WBC count (r=-0.30; P=0.02) but did not fully explain the associations with EDD. Inhibition of NO with NG-monomethyl-L-arginine reduced EDD in subjects with lower (-56%; P=0.01) but not higher WBC count. Tetrahydrobiopterin selectively improved EDD in subjects with higher WBC count (+35%; P=0.01) by increasing NO bioavailability. EDD was related (P<0.05) to neutrophil, eosinophil, and monocyte but not lymphocyte or basophil counts.
Myeloperoxidase, which is secreted by neutrophils and monocytes, consumes NO and produces molecules that oxidize tetrahydrobiopterin, was inversely related to EDD (r=-0.35; P=0.02), and was 42% higher in subjects with a higher WBC count (P=0.02). No other factors contributed to the relation between EDD and WBC count. Among healthy middle-aged and older adults, impaired EDD is related to higher neutrophil, eosinophil, and monocyte-based WBC count mediated by reduced responsiveness to NO and increased myeloperoxidase-associated reductions in tetrahydrobiopterin and NO bioavailability.
Ashley E. Walker; Sara Marian Seibert; Anthony J. Donato; Gary L. Pierce; and Douglas R. Seals*
From the Department of Integrative Physiology, University of Colorado, Boulder, Colo
Vascular smooth muscle responsiveness to NO (peak forearm blood flow response to sodium nitroprusside) was inversely related to WBC count (r=-0.30; P=0.02) but did not fully explain the associations with EDD. Inhibition of NO with NG-monomethyl-L-arginine reduced EDD in subjects with lower (-56%; P=0.01) but not higher WBC count. Tetrahydrobiopterin selectively improved EDD in subjects with higher WBC count (+35%; P=0.01) by increasing NO bioavailability. EDD was related (P<0.05) to neutrophil, eosinophil, and monocyte but not lymphocyte or basophil counts.
Myeloperoxidase, which is secreted by neutrophils and monocytes, consumes NO and produces molecules that oxidize tetrahydrobiopterin, was inversely related to EDD (r=-0.35; P=0.02), and was 42% higher in subjects with a higher WBC count (P=0.02). No other factors contributed to the relation between EDD and WBC count. Among healthy middle-aged and older adults, impaired EDD is related to higher neutrophil, eosinophil, and monocyte-based WBC count mediated by reduced responsiveness to NO and increased myeloperoxidase-associated reductions in tetrahydrobiopterin and NO bioavailability.
Ashley E. Walker; Sara Marian Seibert; Anthony J. Donato; Gary L. Pierce; and Douglas R. Seals*
From the Department of Integrative Physiology, University of Colorado, Boulder, Colo
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