Littérature scientifique sur le sujet « Blood lipoproteins Oxidation »

The purpose of the study was the content of lipid and protein peroxidation products, lipid spectrum parameters and the level of aminotransferases in obese, iodine deficient and obese rats in combination with iodine deficiency. Materials and methods. The study was performed on 45 white nonlinear rats weighing 120-180 g, which were divided into three experimental groups: obese rats (1st experimental group, n = 15), iodine-deficient animals (2nd experimental group), obese animals in combined with iodine deficiency (3rd experimental group, n = 15). The control group consisted of 15 intact rats. The content of products of lipid peroxidation and oxidative modification of proteins was determined in the blood and liver tissue of rats. Blood lipid spectrum was assessed by serum levels of triacylglycerols, total cholesterol, high-density lipoproteins and low-density lipoproteins, followed by calculation of the atherogenic factor. The activity of aspartate aminotransferase and alanine aminotransferase was determined in the blood. Results and discussion. It was found that in the liver tissue of rats and blood of experimental groups the content of lipid hydroperoxides and active products that react with thiobarbituric acid increases, which indicates the activation of lipoperoxidation processes. A variety of changes in protein peroxidation in both blood serum and liver tissue of animals of experimental groups was revealed. Regarding the lipid spectrum, the most pronounced differences in the indicators in relation to the control were found in obese animals in combination with iodine deficiency. In this group of animals, cholesterol was increased by 65% in reference to control, triacylglycerol content increased by 52%, low-density lipoprotein exceeded control by 60%, and high-density lipoprotein decreased by 61% in reference to control. The highest activity of aspartate aminotransferase was found in the group of animals with iodine deficiency, and alanine aminotransferase – in the group of obese animals. Conclusion. In the blood and liver tissue of rats with obesity, iodine deficiency and obesity in combination with iodine deficiency increases the content of products of free radical oxidation. The content of cholesterol, triacylglycerols, low-density lipoproteins increases in the blood, the content of high-density lipoproteins decreases, the activity of aspartate aminotransferase and alanine aminotransferase increases. The most pronounced differences in the indicators in reference to the control were found in obese animals in combination with iodine deficiency

Numerous studies have reported the presence of oxidatively modified high-density lipoprotein (OxHDL) within the intima of atheromatous plaques as well as in plasma; however, its role in the pathogenesis of thrombotic disease is not established. We now report that OxHDL, but not native HDL, is a potent inhibitor of platelet activation and aggregation induced by physiologic agonists. This antithrombotic effect was concentration and time dependent and positively correlated with the degree of lipoprotein oxidation. Oxidized lipoproteins are known ligands for scavenger receptors type B, CD36 and scavenger receptor B type I (SR-BI), both of which are expressed on platelets. Studies using murine CD36−/− or SR-BI−/− platelets demonstrated that the antithrombotic activity of OxHDL depends on platelet SR-BI but not CD36. Binding to SR-BI was required since preincubation of human and murine platelets with anti–SR-BI blocking antibody abrogated the inhibitory effect of OxHDL. Agonist-induced aggregation of platelets from endothelial nitric oxide synthase (eNOS)−/−, Akt-1−/−, and Akt-2−/− mice was inhibited by OxHDL to the same degree as platelets from wild-type (WT) mice, indicating that the OxHDL effect is mediated by a pathway different from the eNOS/Akt pathway. These novel findings suggest that contrary to the prothrombotic activity of oxidized low-density lipoprotein (OxLDL), HDL upon oxidation acquires antithrombotic activity that depends on platelet SR-BI.

Isoflavone intake is associated with various properties beneficial to human health which are related to their antioxidant activity, for example, to their ability to increase LDL oxidation resistance. However, the distribution of isoflavones among plasma lipoproteins has not yet been elucidated in vivo. Therefore, the objective of the present study was to investigate the association between daidzein (DAI) and lipoproteins in human plasma upon administration of the aglycone and glucoside form. Five men aged 22–30 years participated in a randomised, double-blind study in cross-over design. After ingestion of DAI and daidzein-7-O-β-d-glucoside (DG) (1 mg DAI aglycone equivalents/kg body weight) blood samples were drawn before isoflavone administration as well as 1, 2, 3, 4·5, 6, 8, 10, 12, 24 and 48 h post-dose. Concentrations of DAI in the different lipoprotein fractions (chylomicrons, VLDL, LDL, HDL) and in the non-lipoprotein fraction were analysed using isotope dilution capillary GC/MS. The lipoprotein fraction profiles were similar for all subjects and resembled those obtained for plasma in our previously published study. The lipoprotein distribution based on the area under the concentration–time profiles from 0 h to infinity in the different fractions were irrespective of the administered form: non-lipoprotein fraction (53 %) > LDL (20 %) > HDL (14 %) > VLDL (9·5 %) > chylomicrons (2·5 %). Of DAI present in plasma, 47 % was associated to lipoproteins. Concentrations in the different lipoprotein fractions as well as in the non-lipoprotein fraction were always higher after the ingestion of DG than of DAI. Taken together, these results demonstrate an association between isoflavones and plasma lipoproteins in vivo.

The rate of lipid peroxidation and the parameters of antioxida- tive defense, including the activity of paraoxonase that is essen­tial for the prevention of low-density lipoprotein oxidation, was studied in 229female patients with type 2 diabetes mellitus with and without coronary heart disease (CHD) under varying glyc­emic control. Carbohydrate and lipid metabolisms were explored by unified biochemical studies, blood insulin levels were meas­ured by radioimmunological assay. The activity of paraoxonase associated with high-density lipoproteins of ester hydrolase was spectrophotometrically determined by using paraoxan as a sub­strate. Along with dyslipoproteinemia and insulin resistance, there was a drastically reduced paraoxonase activity that was as­sociated with the high-density lipoproteins of the antioxidant en­zyme and more pronounced in diabetics with CHD. A highly sig­nificant inverse correlation of the activity of the enzyme with the rate of lipid peroxidation and a less close relationship to basal glycemia have been verified, which substantiates the polygenic nature of decreased paraoxonase activity in diabetes mellitus.

Infiltration of red blood cells into atheromatous plaques and oxidation of hemoglobin (Hb) and lipoproteins are implicated in the pathogenesis of atherosclerosis. α1-microglobulin (A1M) is a radical-scavenging and heme-binding protein. In this work, we examined the origin and role of A1M in human atherosclerotic lesions. Using immunohistochemistry, we observed a significant A1M immunoreactivity in atheromas and hemorrhaged plaques of carotid arteries in smooth muscle cells (SMCs) and macrophages. The most prominent expression was detected in macrophages of organized hemorrhage. To reveal a possible inducer of A1M expression in ruptured lesions, we exposed aortic endothelial cells (ECs), SMCs and macrophages to heme, Oxy- and FerrylHb. Both heme and FerrylHb, but not OxyHb, upregulated A1M mRNA expression in all cell types. Importantly, only FerrylHb induced A1M protein secretion in aortic ECs, SMCs and macrophages. To assess the possible function of A1M in ruptured lesions, we analyzed Hb oxidation and heme-catalyzed lipid peroxidation in the presence of A1M. We showed that recombinant A1M markedly inhibited Hb oxidation and heme-driven oxidative modification of low-density lipoproteins as well plaque lipids derived from atheromas. These results demonstrate the presence of A1M in atherosclerotic plaques and suggest its induction by heme and FerrylHb in the resident cells.

Background Triglyceride-rich lipoproteins are considered to be independent predictors of atherosclerotic cardiovascular disease. The molecular basis of its atherogenicity is uncertain. Here, we aim to identify molecular species of phosphatidylcholine hydroperoxides (PCOOH) in triglyceride-rich lipoproteins. For comparison, copper-oxidized triglyceride-rich lipoproteins were investigated as well. Methods A fasting EDTA blood sample was collected from six healthy human volunteers to isolate two major triglyceride-rich lipoproteins fractions – very low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL) using sequential ultracentrifugation. Triglyceride-rich lipoproteins and plasma samples were studied for PCOOH by liquid chromatography (LC) coupled with Orbitrap mass spectrometry. Results Twelve molecular species of PCOOH in triglyceride-rich lipoproteins and/or plasma were identified using the following criteria: (1) high-resolution mass spectrometry (MS) with mass accuracy within 5 ppm, (2) retention time in LC and (3) fragmentation pattern in MS2 and MS3. PC36:4-OOH was most often detected in VLDL, IDL and plasma. The ratio of total PCOOH to phosphatidylcholine progressively increased with the duration of oxidation in both VLDL and IDL. Conclusion This study demonstrated the presence of 12 molecular species of PCOOH in native triglyceride-rich lipoproteins. The frequent detection of PCOOH in triglyceride-rich lipoproteins provides a molecular basis of the atherogenicity of triglyceride-rich lipoproteins. PCOOH in triglyceride-rich lipoproteins might serve as a molecular basis of the atherogenicity of triglyceride-rich lipoproteins.

Cigarette smoke (CS) is known to contain a large number of oxidants. In order to assess the oxidative effects of CS on biological fluids, we exposed human blood plasma to filtered (gas phase) and unfiltered (whole) CS, and determined the rate of utilization of endogenous antioxidants in relation to the appearance of lipid hydroperoxides. Lipid peroxidation was measured with a specific and sensitive assay that can detect lipid hydroperoxides at plasma levels as low as 10 nM. We found that exposure of plasma to the gas phase of CS, but not to whole CS, induces lipid peroxidation once endogenous ascorbic acid has been oxidized completely. In addition, CS exposure caused oxidation of plasma protein thiols and albumin-bound bilirubin, whereas uric acid and alpha-tocopherol were not consumed at significant rates. In plasma exposed to the gas phase of CS, low-density lipoprotein exhibited slightly increased electrophoretic mobility, but there was no apparent degradation of apolipoprotein B. Our results support the concept of an increased vitamin C utilization in smokers, and suggest that lipid peroxidation induced by oxidants present in the gas phase of CS leads to potentially atherogenic changes in lipoproteins.

Atherosclerosis is a chronic inflammatory disease, in which the immune system has a prominent role in its development and progression. Inflammation-induced endothelial dysfunction results in an increased permeability to lipoproteins and their subendothelial accumulation, leukocyte recruitment, and platelets activation. Recruited monocytes differentiate into macrophages which develop pro- or anti-inflammatory properties according to their microenvironment. Atheroma progression or healing is determined by the balance between these functional phenotypes. Macrophages and smooth muscle cells secrete inflammatory cytokines including interleukins IL-1β, IL-12, and IL-6. Within the arterial wall, low-density lipoprotein cholesterol undergoes an oxidation. Additionally, triglyceride-rich lipoproteins and remnant lipoproteins exert pro-inflammatory effects. Macrophages catabolize the oxidized lipoproteins and coalesce into a lipid-rich necrotic core, encapsulated by a collagen fibrous cap, leading to the formation of fibro-atheroma. In the conditions of chronic inflammation, macrophages exert a catabolic effect on the fibrous cap, resulting in a thin-cap fibro-atheroma which makes the plaque vulnerable. However, their morphology may change over time, shifting from high-risk lesions to more stable calcified plaques. In addition to conventional cardiovascular risk factors, an exposure to acute and chronic psychological stress may increase the risk of cardiovascular disease through inflammation mediated by an increased sympathetic output which results in the release of inflammatory cytokines. Inflammation is also the link between ageing and cardiovascular disease through increased clones of leukocytes in peripheral blood. Anti-inflammatory interventions specifically blocking the cytokine pathways reduce the risk of myocardial infarction and stroke, although they increase the risk of infections.

Background: Polyphenols are bioactive compounds that can be found mostly in foods like fruits, cereals, vegetables, dry legumes, chocolate and beverages such as coffee, tea and wine. They are extensively used in the prevention and treatment of cardiovascular disease (CVD) providing protection against many chronic illnesses. Their effects on human health depend on the amount consumed and on their bioavailability. Many studies have demonstrated that polyphenols have also good effects on the vascular system by lowering blood pressure, improving endothelial function, increasing antioxidant defences, inhibiting platelet aggregation and low-density lipoprotein oxidation, and reducing inflammatory responses. Methods: This review is focused on some groups of polyphenols and their effects on several cardiovascular risk factors such as hypertension, oxidative stress, atherogenesis, endothelial dysfunction, carotid artery intima-media thickness, diabetes and lipid disorders. Results: It is proved that these compounds have many cardio protective functions: they alter hepatic cholesterol absorption, triglyceride biosynthesis and lipoprotein secretion, the processing of lipoproteins in plasma, and inflammation. In some cases, human long-term studies did not show conclusive results because they lacked in appropriate controls and in an undefined polyphenol dosing regimen. Conclusion: Rigorous evidence is necessary to demonstrate whether or not polyphenols beneficially impact CVD prevention and treatment.

Includes bibliographical references (leaves 172-217). Examines the effects of estrogens and phytoestrogens on plasma lipoprotein levels and other risk factors for cardiovascular disease, including the oxidisability of low density lipoprotein

Includes bibliographical references (leaves 172-217).
viii, 217 leaves : ill. ; 30 cm.
Examines the effects of estrogens and phytoestrogens on plasma lipoprotein levels and other risk factors for cardiovascular disease, including the oxidisability of low density lipoprotein
Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 1999

Ng Chi Ho.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2005.
Includes bibliographical references (leaves 147-160).
Abstracts in English and Chinese.
ACKNOWLEDGMENTS --- p.I
ABSTRACT --- p.II
LIST OF ABBREVIATIONS --- p.VII
TABLE OF CONTENTS --- p.IX
Chapter CHAPTER 1 --- GENERAL INTRODUCTION
Chapter 1.1 --- Introduction of Low-density lipoprotein --- p.1
Chapter 1.1.1 --- What are lipids? --- p.1
Chapter 1.1.2 --- Function and structure of cholesterol --- p.1
Chapter 1.1.3 --- Function and classification of lipoprotein --- p.1
Chapter 1.2 --- Functions of low-density lipoprotein --- p.2
Chapter 1.3 --- Basic structure of low-density lipoprotein --- p.4
Chapter 1.4 --- Principle on isolation and purification of low-density lipoprotein --- p.4
Chapter 1.5 --- Cholesterol transport system --- p.7
Chapter 1.5.1 --- Exogenous pathway of cholesterol metabolism --- p.7
Chapter 1.5.2 --- Endogenous pathway of cholesterol metabolism --- p.7
Chapter 1.5.3 --- Reverse transport of Cholesterol --- p.8
Chapter 1.6 --- Oxidation of LDL --- p.10
Chapter 1.6.1 --- Agents that causes oxidation --- p.10
Chapter 1.6.1.1 --- Lipoxygenases --- p.10
Chapter 1.6.1.2 --- Myeloperoxidase --- p.10
Chapter 1.6.1.3 --- Reactive nitrogen species --- p.11
Chapter 1.6.1.4 --- Reactive oxygen species --- p.11
Chapter 1.6.2 --- Factors that affect the susceptibility of LDL oxidation --- p.13
Chapter 1.7 --- Hyperlipidaemia 一 chance to increase LDL oxidation --- p.13
Chapter 1.7.1 --- Definition of hyperlipidemia and hypercholesterolemia --- p.13
Chapter 1.7.2 --- Risk factors of hyperlipidaemia --- p.13
Chapter 1.7.2.1 --- High fat low fibre diets: --- p.13
Chapter 1.7.2.2 --- Obesity --- p.14
Chapter 1.7.2.3 --- Type II diabetes --- p.14
Chapter 1.7.2.4 --- Genetic factors (Familial hyperlipidemias) --- p.14
Chapter 1.8 --- Diseases related to oxidized LDL --- p.15
Chapter 1.8.1 --- Cardiovascular diseases --- p.15
Chapter 1.8.1.1 --- Atherosclerosis and ischemic heart attack --- p.15
Chapter 1.8.1.2 --- Factors that affect incidence of atherosclerosis --- p.16
Chapter 1.8.1.2.1 --- Triglyceride-rich lipoprotein --- p.16
Chapter 1.8.1.2.2 --- Small and dense LDL --- p.16
Chapter 1.8.1.3 --- Stroke --- p.17
Chapter 1.8.2 --- Common ways to reduce plasma cholesterol level --- p.17
Chapter 1.8.2.1 --- Diet control --- p.17
Chapter 1.8.2.2 --- Physical activity --- p.17
Chapter 1.8.2.3 --- Drug therapy --- p.18
Chapter CHAPTER 2 --- IMPAIRMENT OF OXIDIZED LDL ON ENDOTHELIUM-DEPENDENT RELAXATION
Chapter 2.1 --- Introduction --- p.19
Chapter 2.1.1 --- Properties and function of phenylephrine hydrochloride --- p.22
Chapter 2.1.2 --- Properties and function of acetylcholine --- p.22
Chapter 2.2 --- Objectives --- p.23
Chapter 2.3 --- Materials and methods --- p.24
Chapter 2.3.1 --- Preparation of drugs --- p.24
Chapter 2.3.2 --- Preparation of human native LDL --- p.25
Chapter 2.3.3 --- Preparation of oxidized LDL --- p.27
Chapter 2.3.4 --- Preparation of aorta --- p.27
Chapter 2.3.5 --- Measurement of Isometric Force in vitro --- p.30
Chapter 2.3.5.1 --- Protocol 1- Dose effect of oxidized LDL on acetylcholine-induced vasorelaxation --- p.30
Chapter 2.3.5.2 --- Protocol 2 - Time effect of oxidized LDL on acetylcholine-induced vasorelaxation --- p.30
Chapter 2.3.5.3 --- Protocol 3 - Effect of co-incubation of LDL and copper(ll) sulphate on acetylcholine-induced vasorelaxation --- p.31
Chapter 2.3.5.4 --- Protocol 4 - Effect of oxidized LDL on selected vasodilators --- p.32
Chapter 2.3.5.5 --- Protocol 5 - Effect of pretreatment of L-arginine on oxidized LDL impaired -endothelium-induced relaxation --- p.32
Chapter 2.3.5.6 --- Protocol 6 - Effect of a -tocopherol on oxidized LDL-damaged acetylcholine- induced vasorelaxation --- p.33
Chapter 2.3.5.7 --- Protocol 7 - Effect of a -tocopherol on LDL and copper(ll) sulphate- induced endothelial dysfunction --- p.33
Chapter 2.3.6 --- Western blot analysis of endothelial nitric oxide synthase (eNOS) protein --- p.34
Chapter 2.3.7 --- Statistics --- p.35
Chapter 2.4 --- Results --- p.36
Chapter 2.4.1 --- Dose effect of oxidized LDL on acetylcholine-induced vasorelaxation --- p.36
Chapter 2.4.2 --- Time effect of oxidized LDL on acetylcholine-induced vasorelaxation --- p.36
Chapter 2.4.3 --- Effect of co-incubation of LDL and copper(II) sulphate on acetylcholine- induced vasorelaxation --- p.39
Chapter 2.4.4 --- Effect of oxidized LDL on selected vasodilators --- p.41
Chapter 2.4.5 --- Effect of pretreatment of L-arginine on oxidized LDL impaired- acetylcholine-induced relaxation --- p.41
Chapter 2.4.6 --- Effect of a-tocopherol on oxidized LDL-damaged acetylcholine- induced vasorelaxation --- p.48
Chapter 2.4.7 --- Effect of a-tocopherol on LDL and copper(II) sulphate-induced endothelial dysfunction --- p.50
Chapter 2.4.8 --- eNOS Protein expression --- p.50
Chapter 2.5 --- Discussion --- p.53
Chapter CHAPTER 3 --- EFFECTS OF LDL INJECTION ON THE ENDOTHELIAL FUNCTION OF RATS
Chapter 3.1 --- Introduction --- p.58
Chapter 3.2 --- Objective --- p.60
Chapter 3.3 --- Methods and Materials --- p.61
Chapter 3.3.1 --- Preparation of Drugs --- p.61
Chapter 3.3.2 --- Preparation of LDL --- p.61
Chapter 3.3.3 --- Animal Treatment --- p.61
Chapter 3.3.4 --- Serum lipid and lipoprotein determinations --- p.62
Chapter 3.3.5 --- Measurement of serum MDA level by TBARS assay --- p.62
Chapter 3.3.6 --- Preparation of aorta --- p.62
Chapter 3.3.7 --- Organ bath experiment --- p.63
Chapter 3.3.8 --- Statistics --- p.64
Chapter 3.4 --- Result --- p.65
Chapter 3.4.1 --- Growth and food intake --- p.65
Chapter 3.4.2 --- "Effect of LDL injection on serum TC, TG and HDL-C" --- p.65
Chapter 3.4.3 --- Effect of LDL injection on non-HDL-C and ratio of non-HDL-C to HDL-C --- p.65
Chapter 3.4.4 --- Serum MDA level --- p.68
Chapter 3.4.5 --- Phenylephrine-induced contraction --- p.70
Chapter 3.4.6 --- Endothelium-dependent and -independent relaxation --- p.75
Chapter 3.5 --- Discussion --- p.79
Chapter CHAPTER 4 --- EFFECTS OF INDIVIDUAL COMPONENT OF OXIDIZED LDL ON ENDOTHELIUM-DEPENDENT RELAXATION
Chapter 4.1 --- Introduction --- p.83
Chapter 4.2 --- Objectives --- p.85
Chapter 4.3 --- Materials and methods --- p.86
Chapter 4.3.1 --- Preparation of drugs --- p.86
Chapter 4.3.2 --- Preparation of human native LDL and oxidized LDL --- p.86
Chapter 4.3.3 --- GC analysis of fatty acid composition in LDL --- p.86
Chapter 4.3.4 --- TBARS assay analysis of MDA content in LDL --- p.87
Chapter 4.3.5 --- GC analysis of cholesterol oxidation products in LDL --- p.89
Chapter 4.3.6 --- Thin-layer chromatography analysis of LPC in LDL --- p.91
Chapter 4.3.7 --- Preparation of aorta --- p.92
Chapter 4.3.8 --- Measurement of Isometric Force in vitro --- p.92
Chapter 4.3.8.1 --- Protocol 1- effect of LPC on acetylcholine-induced vasorelaxation --- p.92
Chapter 4.3.8.2 --- Protocol 2- effect of cholesterol oxidation products on acetylcholine-induced vasorelaxation --- p.92
Chapter 4.3.8.3 --- Protocol 3- effect of oxidized fatty acids on acetylcholine-induced vasorelaxation --- p.93
Chapter 4.3.9 --- Statistics --- p.93
Chapter 4.4 --- Results --- p.94
Chapter 4.4.1 --- Compositional differences between native LDL and oxidized LDL.… --- p.94
Chapter 4.4.2 --- Effect of LPC on endothelium-dependent relaxation --- p.98
Chapter 4.4.3 --- Effect of COPs on endothelium-dependent relaxation --- p.98
Chapter 4.4.4 --- Effect of oxidized fatty acids on endothelium-dependent relaxation --- p.101
Chapter 4.5 --- Discussion --- p.103
Chapter CHAPTER 5 --- EFFECTS OF DIETARY OXIDIZED CHOLESTEROL ON BLOOD CHOLESTEROL LEVEL IN HAMSTERS
Chapter 5.1 --- Introduction --- p.107
Chapter 5.2 --- Objectives --- p.111
Chapter 5.3 --- Materials and Methods --- p.112
Chapter 5.3.1 --- Preparation of Oxidized Cholesterol --- p.112
Chapter 5.3.2 --- Diet preparation --- p.112
Chapter 5.3.3 --- Animals --- p.113
Chapter 5.3.4 --- Serum lipid and lipoprotein determinations --- p.116
Chapter 5.3.5 --- GC analysis of cholesterol and cholesterol oxidation products on organs --- p.116
Chapter 5.3.6 --- Extraction of neutral and acidic sterols from fecal samples --- p.117
Chapter 5.3.6.1 --- Determination of neutral sterols --- p.117
Chapter 5.3.6.2 --- Determination of acidic sterols --- p.117
Chapter 5.3.6.3 --- GLC analysis of neutral and acidic sterols --- p.118
Chapter 5.3.7 --- Organ bath experiment --- p.121
Chapter 5.3.7.1 --- Preparation of aorta --- p.121
Chapter 5.3.7.2 --- Aortic relaxation --- p.121
Chapter 5.3.8 --- Analysis of the total area of atherosclerotic plaque on aorta --- p.122
Chapter 5.3.9 --- Statistics --- p.122
Chapter 5.4 --- Results --- p.123
Chapter 5.4.1 --- GC of oxidized cholesterol --- p.123
Chapter 5.4.2 --- Growth and food intake --- p.123
Chapter 5.4.3 --- "Effect of non-oxidized and oxidized cholesterol on serum TC, TG and HDL-C" --- p.123
Chapter 5.4.4 --- Effect of non-oxidized and oxidized cholesterol on non-HDL-C and ratio of non-HDL-C to HDL-C --- p.124
Chapter 5.4.5 --- Effect ofnon-oxidized and oxidized cholesterol on concentration of hepatic cholesterol --- p.128
Chapter 5.4.6 --- Effect of non-oxidized and oxidized cholesterol on concentration of cholesterol oxidation products accumulated in liver --- p.128
Chapter 5.4.7 --- Effect of non-oxidized and oxidized cholesterol on concentration of brain and aortic cholesterol --- p.128
Chapter 5.4.8 --- Effect of non-oxidized and oxidized cholesterol on fecal neutral and acidic sterols --- p.129
Chapter 5.4.9 --- Effect of non-oxidized and oxidized cholesterol on aortic relaxation --- p.135
Chapter 5.4.10 --- Effect of non-oxidzied and oxidized cholesterol on area of atherosclerotic plaque --- p.137
Chapter 5.5 --- Discussion --- p.139
Chapter CHAPTER 6 --- CONCLUSION --- p.143
REFERENCES --- p.146

Air pollution is a leading global risk factor for cardiovascular disease. Experimental animal models and short-term studies in humans are consistent with systemic effects of particulate matter smaller than 2.5 microns. Exposure to fine as well as ultrafine particles (<0.1 microns) have been shown to be consistently associated with a number of risk factors including hypertension, diabetes, and abnormalities in lipoproteins. The size of particles and the chemical composition are key determinants of propensity for systemic effects. While direct chemical translocation of smaller particles across the alveolar–capillary membrane is possible, oxidative modification of phospholipids in entities such as lipoproteins and other plasma proteins may represent additional mechanisms by which exposure may transduce systemic effects. Studies in susceptible disease models have been particularly informative as exposure to air pollution appears to aggravate a number of risk factors such as hypertension and diabetes. Collectively, these studies seem to suggest that chronic exposure to air pollution may potentiate the risk factors and may represent a convergent pathway through which air pollution may mediate susceptibility to cardiovascular disease. Air pollution exposure also exerts acute effects through mechanisms that include alterations in vascular tone, coagulation abnormalities, and changes in blood pressure. Collectively, these findings argue for the recognition of air pollution as an independent risk factor for the pathogenesis of cardiovascular disease.

Aspirin, considered the prototypic platelet antagonist, has been available for over a century and currently represents a mainstay both in the prevention and treatment of vascular events that include stroke, myocardial infarction, peripheral vascular occlusion, and sudden death. Aspirin irreversibly acetylates cyclooxygenase (COX), impairing prostaglandin metabolism and thromboxane A2 (TXA2) synthesis. As a result, platelet aggregation in response to collagen, adenosine diphosphate (ADP), and thrombin (in low concentrations) is attenuated (Roth and Majerus, 1975). Because aspirin more selectively inhibits COX-1 activity (found predominantly in platelets) than COX-2 activity (expressed in tissues following an inflammatory stimulus), its ability to prevent platelet aggregation is seen at relatively low doses, compared with the drug’s potential antiinflammatory effects, which require much higher doses (Patrono, 1994). Several alternative mechanisms of platelet inhibition by aspirin have been proposed, including: (1) inhibition of platelet activation by neutrophils and (2) enhanced nitric oxide production. In addition, aspirin may prevent the progression of atherosclerosis by protecting low-density lipoprotein (LDL) cholesterol from oxidation and scavenging hydroxyl radicals. Following oral ingestion, aspirin is promptly absorbed in the proximal gastrointestinal (GI) tract (stomach, duodenum), achieving peak serum levels within 15 to 20 minutes and platelet inhibition within 40 to 60 minutes. Enteric-coated preparations are less well absorbed, causing an observed delay in peak serum levels and platelet inhibition to 60 and 90 minutes, respectively. The antiplatelet effect occurs even before acetylsalicylic acid is detectable in peripheral blood, probably from platelet exposure in the portal circulation. The plasma concentration of aspirin decays rapidly with a circulating half-life of approximately 20 minutes. Despite the drug’s rapid clearance, platelet inhibition persists for the platelet’s life span (7 ± 2 days) due to aspirin’s irreversible inactivation of COX-1. Because 10% of circulating platelets are replaced every 24 hours, platelet activity (bleeding time, primary hemostasis) returns toward normal (≥50% activity) within 5 to 6 days of the last aspirin dose (O’Brien, 1968). A single dose of 100 mg of aspirin effectively reduces the production of TXA2 in many (but not all) individuals.