Showing papers in "Current Opinion in Lipidology in 2003"
TL;DR: This review will provide the reader with an update on the understanding of the adverse effects of fatty acid accumulation in non-adipose tissues, a phenomenon known as lipotoxicity.
Abstract: Purpose of reviewThis review will provide the reader with an update on our understanding of the adverse effects of fatty acid accumulation in non-adipose tissues, a phenomenon known as lipotoxicity Recent studies will be reviewed Cellular mechanisms involved in the lipotoxic response will be discu
813 citations
TL;DR: Adiponectin is an endogenous biologically relevant modulator of vascular remodeling linking obesity and vascular disease, and acts as an anti-inflammatory and anti-atherogenic plasma protein.
Abstract: Purpose of review Obesity is the most common risk factor for cardiovascular diseases in industrial countries. It is now clear that adipose tissue secretes various bioactive substances, conceptualized as adipocytokines, and that dysregulation of adipocytokines directly contributes to obesity-related diseases. Chronic inflammatory processes contribute to the development of atherosclerosis. In this review, the authors focus on the relationship between adiponectin, a recently discovered anti-atherogenic adipocytokine, and vascular inflammation. Recent findings Plasma concentrations of adiponectin, an adipocyte-specific protein, are reduced in obese subjects and in patients with type 2 diabetes and coronary artery disease. Adiponectin inhibits the expression of tumor necrosis factor-alpha-induced endothelial adhesion molecules, macrophage-to-foam cell transformation, tumor necrosis factor-alpha expression in macrophages and adipose tissues, and smooth muscle cell proliferation. In addition, adenovirus-expressed adiponectin reduces atherosclerotic lesions in a mouse model of atherosclerosis, and adiponectin-deficient mice exhibit an excessive vascular remodeling response to injury. Clinically, hypoadiponectinemia is closely associated with increased levels of inflammatory markers such as C-reactive protein and interleukin-6. Summary Adiponectin acts as an anti-inflammatory and anti-atherogenic plasma protein. Adiponectin is an endogenous biologically relevant modulator of vascular remodeling linking obesity and vascular disease.
732 citations
TL;DR: During inflammatory processes biologically active lipid oxidation products accumulate that modulate the inflammatory process and may determine the fate and outcome of the body's reaction in acute inflammation during host defense.
Abstract: Purpose of reviewThis review will summarize recent evidence demonstrating that biologically active phospholipid oxidation products modulate inflammatory reactions.Recent findingsStructural identification of new biologically active oxidized phospholipids and the finding that they can also be formed a
296 citations
TL;DR: In a public health perspective these results underline the importance of fat quality in the diet for the development of a number of prevalent diseases and give strong support to present dietary guidelines.
Abstract: Purpose of reviewThe metabolic syndrome, a cluster of disorders often including abdominal obesity, is associated with a high risk of cardiovascular disease and premature death. Insulin resistance is a key feature of the metabolic syndrome. Observational studies have indicated that the type of fat in
285 citations
TL;DR: SCD1 appears to be an important metabolic control point, and inhibition of its expression could be of benefit for the treatment of obesity, diabetes and other metabolic diseases.
Abstract: Purpose of reviewStearoyl-Coenzyme A (CoA) desaturase is a central lipogenic enzyme catalyzing the synthesis of monounsaturated fatty acids - mainly oleate (C18:1). Oleate is the most abundant monounsaturated fatty acid in dietary fat and is therefore readily available. Why, then, is stearoyl-CoA de
253 citations
TL;DR: The identification of which cell types undergo apoptosis within the atherosclerotic lesion, the extracellular factors that impinge on these cells, and the intracellular mechanisms that govern their demise have begun to be elucidated.
Abstract: PURPOSE OF REVIEW Apoptosis is a critical regulator of homeostasis in many tissues, including the vasculature. Apoptosis in atherosclerotic lesions is triggered by inflammatory processes, both via cell-cell contact and by cytokines and oxidized lipids. Apoptosis of vascular smooth muscle cells, endothelial cells and macrophages may promote plaque growth and pro-coagulation and may induce rupture, the major consequence of atherosclerosis in humans. RECENT FINDINGS Studies over the past year have clearly demonstrated the significance of cell death in atherosclerosis. Some of the key cellular, cytokine and molecular regulators that contribute to the apoptosis of cells within the atherosclerotic lesion have been identified and their mechanism of action elucidated. Other studies have shed some light on the identity of cells whose loss by apoptosis contributes to plaque instability. SUMMARY The identification of which cell types undergo apoptosis within the atherosclerotic lesion, the extracellular factors that impinge on these cells, and the intracellular mechanisms that govern their demise have begun to be elucidated. This information is critical in the design of further in-vivo experiments such as the exploitation of animal models, and ultimately, in applying this knowledge to clinical practice.
197 citations
TL;DR: Recent findings suggest that oxidized forms of LDL interact with innate immune receptors, and the role of these interactions in inflammation and atherosclerosis is identified.
Abstract: Purpose of reviewAtherosclerosis is now recognized as a chronic inflammatory disease. This review discusses recent literature reporting that innate immune receptors bind oxidatively modified LDL and its many oxidized moieties and consequently modulate the atherogenic process. These innate pattern re
195 citations
TL;DR: Knowledge of these properties provides a framework for understanding transport and metabolism of cholesterol and fatty acids and how their putative membrane and intracellular transporters might function.
Abstract: Purpose of review The rates by which unesterified fatty acids and cholesterol move through and desorb from membranes have been difficult to measure, in part because of the simple structures of these lipids but also because methods have generally not clearly distinguished the two steps of membrane transport. Lack of definitive knowledge has given rise to speculation about the mechanism(s) of membrane 'transport' proteins for fatty acids and cholesterol. Recent findings New biophysical and biochemical approaches have provided evidence that fatty acids and cholesterol exhibit rapid diffusion (flip-flop), as fast as milliseconds, across both protein-free phospholipid bilayers and cell membranes. In contrast, desorption of the cholesterol molecule from a membrane surface (hours) is much slower than that of common dietary fatty acids (milliseconds to seconds). Summary Knowledge of these properties provides a framework for understanding transport and metabolism of cholesterol and fatty acids and how their putative membrane and intracellular transporters might function.
167 citations
TL;DR: The inflammatory protein myeloperoxidase is present, active and mechanistically poised to participate in the initiation and progression of cardiovascular disease, and this leukocyte protein may have clinical utility in risk stratification for cardiovascular disease status and outcomes.
Abstract: PURPOSE OF REVIEW Myeloperoxidase, an abundant leukocyte protein that generates reactive oxidant species, is present and catalytically active within atherosclerotic lesions. Numerous lines of evidence suggest mechanistic links between myeloperoxidase, inflammation and both acute and chronic manifestations of cardiovascular disease. RECENT FINDINGS Myeloperoxidase generates reactive oxidant species as part of its function in innate host defense mechanisms. The reactive species formed, however, may also damage normal tissues, contributing to inflammatory injury. Recent studies suggest that MPO-generated oxidants participate in multiple processes relevant to cardiovascular disease development and outcomes, including induction of foam cell formation, endothelial dysfunction, development of vulnerable plaque, and ventricular remodeling following acute myocardial infarction. Of note, measurements of myeloperoxidase mass and activity may be useful in cardiac risk stratification, both for chronic disease assessment, as well as in identification of patients at risk in the acute setting. SUMMARY The inflammatory protein myeloperoxidase is present, active and mechanistically poised to participate in the initiation and progression of cardiovascular disease. The many links between myeloperoxidase, oxidation and cardiovascular disease suggest this leukocyte protein may have clinical utility in risk stratification for cardiovascular disease status and outcomes.
160 citations
TL;DR: Intestinal cholesterol absorption represents a major route for the entry of cholesterol into the body's miscible pools and therefore can potentially impact the plasma LDL-cholesterol concentration.
Abstract: Purpose of review Cholesterol absorption is a selective process in that plant sterols and other non-cholesterol sterols are absorbed poorly or not at all. Recent research on the sterol efflux pumps adenosine triphosphate-binding cassette transporter G5 and adenosine triphosphate-binding cassette transporter G8 has not only provided an explanation for this selectivity, but also, together with the discovery of a new class of cholesterol absorption inhibitor, has yielded new insights into the mechanisms that potentially regulate the flux of cholesterol across the enterocyte. This review discusses these recent developments and their importance to the regulation of whole body cholesterol homeostasis. Recent findings Adenosine triphosphate-binding cassette transporters G5/8 regulate plant sterol absorption and also the secretion into bile of cholesterol and non-cholesterol sterols. Loss of adenosine triphosphate-binding cassette transporter G5/8 function results in sitosterolemia. Ezetimibe, a novel, potent and selective inhibitor of cholesterol absorption which is effective in milligram doses, lowers plasma plant sterol concentrations in sitosterolemic subjects, thus suggesting that this drug might be inhibiting the activity of a putative sterol permease in the brush border membrane of the enterocyte that actively facilitates the uptake of cholesterol as well as other non-cholesterol sterols. Summary Intestinal cholesterol absorption represents a major route for the entry of cholesterol into the body's miscible pools and therefore can potentially impact the plasma LDL-cholesterol concentration. The combined use of agents that inhibit the absorption and synthesis of cholesterol provides a powerful new approach to the prevention and treatment of atherosclerosis.
156 citations
TL;DR: In humans there is extensive circumstantial evidence for a role of complement in Atherosclerosis, which is somewhat contradictory to recent modest or negative findings in atherosclerosis-prone genetically engineered hyperlipidemic mice.
Abstract: Purpose of reviewAtherosclerosis is characterized by a strong inflammatory component. One factor contributing to inflammation in the arterial intima is the complement system. Here we summarize recent progress in the field of complement research on atherogenesis.Recent findingsThe complement system i
TL;DR: In humans the weight of evidence suggests that Lp-PLA2 is a positive risk factor for coronary heart disease - an observation commensurate with its position in the direct pathological sequence leading from formation of oxidized LDL in the artery wall to cellular dysfunction and formation of lesions.
Abstract: Purpose of reviewPlasma lipoproteins carry a number of highly active enzymes in the circulation. One of these is lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase. This review addresses the molecular properties of Lp-PLA2, the controversy sur
TL;DR: Insights into the regulation of vitamin E transport and metabolism on the cellular level have made enormous advances, showing the complex interplay of influx, trafficking, efflux and metabolism of this crucial antioxidant.
Abstract: Purpose of reviewRecently, the intracellular transport as well as cellular uptake and excretion of α-tocopherol, the major representative of vitamin E, have been elucidated.Recent findingsAlpha-tocopherol transfer protein has been identified as the major intracellular transport protein for vitamin E
TL;DR: Understanding of how 5LO is involved in the atherosclerotic process will have important implications for diagnostic and therapeutic strategies in the future.
Abstract: Purpose of review5-Lipoxygenase (5LO) was recently identified as a gene that makes an important contribution to atherosclerosis in mice and humans, but the underlying mechanism(s) remains unknown.Recent findingsStudies of the 5LO pathway in other disease areas suggest that 5LO could contribute to at
TL;DR: Lp(a) both attenuates fibrinolysis, through inhibition of plasminogen activation, and promotes coagulation, through alleviation of extrinsic pathway inhibition.
Abstract: Purpose of reviewSince the homology between apolipoprotein(a) (apo(a)) and plasminogen was discovered in 1987, the role of lipoprotein(a) (Lp(a)) as an inhibitor of the normal fibrinolytic role of plasmin(ogen) has been a major research focus. In this review we summarize recent basic research aimed
TL;DR: Conincing evidence shows that hepatic lipase plays a key role in remnant lipoprotein catabolism as well as in remodeling of LDL and HDL particles, likely to be modulated by the concurrent presence of other lipid abnormalities.
Abstract: Purpose of review Hepatic lipase plays a key role in the metabolism of pro-atherogenic and anti-atherogenic lipoproteins affecting their plasma level as well as their physico-chemical properties. However, controversial evidence exists concerning whether hepatic lipase is pro or anti-atherogenic. The goal of this review is to summarize recent evidence that connects the enzyme to cardiovascular disease. The potential impact of genetic determinants of hepatic lipase activity in modulating both the development of coronary and carotid atherosclerosis will be discussed based on hepatic lipase proposed roles in lipoprotein metabolism. Recent findings Twenty to 30% of individual variation of hepatic lipase activity is accounted for by the presence of a common polymorphism in the promoter region (-514 C to T) of the hepatic lipase gene (LIPC). This polymorphism, via its impact on hepatic lipase synthesis and activity, appears to contribute to (1) individual susceptibility to cardiovascular disease: the presence of the T allele (low hepatic lipase activity) may carry a marginally increased risk of atherosclerosis; (2) carotid plaque composition and individual susceptibility to cerebrovascular events: the presence of the C allele (high hepatic lipase activity) is associated with increased carotid intima-media thickness and abundance of macrophages in the carotid plaque (unstable plaque); and (3) response of cardiovascular disease patients to lipid-lowering therapy: patients with the CC genotype have the greatest clinical benefit from intensive lipid-lowering therapy. Summary Convincing evidence shows that hepatic lipase plays a key role in remnant lipoprotein catabolism as well as in remodeling of LDL and HDL particles. The anti or pro-atherogenic role of hepatic lipase is likely to be modulated by the concurrent presence of other lipid abnormalities (i.e. increased LDL cholesterol levels) as well as by the genetic regulation of other enzymes involved in lipoprotein metabolism. Characterization of patients by their LIPC genotype will contribute to a better definition of individual risk of coronary and cerebrovascular events, specifically in patients with qualitative (small, atherogenic LDL and low HDL2 cholesterol) rather than quantitative lipid abnormalities for whom the routine lipid profile may underestimate the risk of coronary and cerebrovascular disease.
TL;DR: The available data suggest that ARH functions as an adaptor protein that couples LDLR to the endocytic machinery, and that conserved motifs in the C-terminal portion of the protein bind to clathrin and to the β2-adaptin subunit of AP-2.
Abstract: Purpose of review Autosomal recessive hypercholesterolemia (ARH) is a rare Mendelian dyslipidemia characterized by markedly elevated plasma LDL levels, xanthomatosis, and premature coronary artery disease. LDL receptor function is normal, or only moderately impaired in fibroblasts from ARH patients, but their cultured lymphocytes show increased cell-surface LDL binding, and impaired LDL degradation, consistent with a defect in LDL receptor internalization. Recently, the disorder was shown to be caused by mutations in a phosphotyrosine binding domain protein, ARH, which is required for internalization of low density lipoproteins in the liver. This review summarizes the findings of new investigations into the pathophysiology and molecular genetics of ARH. Recent findings All mutations that have been characterized to date preclude the synthesis of a full-length protein. GST-pulldown experiments indicate that the phosphotyrosine binding domain of ARH interacts with the internalization sequence (NPVY) in the cytoplasmic tail of LDLR, and that conserved motifs in the C-terminal portion of the protein bind to clathrin and to the β2-adaptin subunit of AP-2. Summary The available data suggest that ARH functions as an adaptor protein that couples LDLR to the endocytic machinery.
TL;DR: Significant progress has been made in the understanding of the molecular mechanisms controlling the folding of apolipoprotein A-I and its interaction with lipids and various other protein factors involved in HDL metabolism.
Abstract: Purpose of reviewApolipoprotein A-I is the major structural protein of HDL. Its physicochemical properties maintain a delicate balance between maintenance of stable lipoproteins and the ability to associate with and dissociate from the lipid transported. Here we review the progress made in the last
TL;DR: Evidence suggests that an increased intake of protein, particularly plant protein, may lower blood pressure and reduce the risk of cardiovascular disease, however, the data are not sufficiently compelling to advocate an increased consumption of protein.
Abstract: Purpose of reviewInvestigators, especially those from western countries, have commonly assumed that there is either no association or a direct association of protein intake with elevated blood pressure and atherosclerosis. In contrast, recent observational studies and clinical trials have suggested
TL;DR: The favourable effects of ingested or infused isoflavones on several parameters of arterial function suggest an alternative explanation for the apparent low prevalence of coronary disease in populations that eat legumes as a staple food.
Abstract: Purpose of review Isoflavones - plant polyphenols with oestrogenic activity - are becoming widely distributed in foods and sold as nutriceuticals. Their similarity to steroidal oestrogens has stimulated research into potential cardiovascular benefits. The two major areas, those of lipid lowering and of improved vascular function, are reviewed. Recent findings A major plasma cholesterol lowering effect has not been sustained in recent publications. Relatively minor reductions in LDL-cholesterol or non-HDL-cholesterol have generally been reported, but studies in which no reduction was found have also been reported. Fewer publications have dealt with effects on vasculature, but these have been more consistent. Arterial compliance, a parameter of the elasticity or distensibility of large arteries, is improved by as much as has been reported for estrogens. Vasodilatory effects on the microcirculation with isoflavones or their metabolites may provide opportunities for pharmacological intervention. The metabolism of isoflavones is reviewed briefly in order to highlight its complexity. Summary Although research has failed to demonstrate substantial cholesterol lowering with dietary isoflavones, consumption of legumes is generally to be encouraged as part of the overall strategy for lowering plasma lipids. The favourable effects of ingested or infused isoflavones on several parameters of arterial function suggest an alternative explanation for the apparent low prevalence of coronary disease in populations that eat legumes as a staple food. A better understanding of the pharmacokinetics and bioavailabilty of individual isoflavones is needed if definitive studies are to be designed.
TL;DR: Current evidence suggests that individuals with coronary artery disease may reduce their risk of sudden cardiac death by increasing their intake of long-chain omega-3 fatty acids by approximately 1 g per day.
Abstract: Purpose of review Of all known dietary factors, long-chain omega-3 fatty acids may be the most protective against death from coronary heart disease. New evidence has confirmed and refined the cardioprotective role of these fatty acids. Recent findings Omega-3 fatty acid supplementation reduces the risk of sudden cardiac death and death from any cause within 4 months in post-myocardial infarction patients. Evidence continues to accrue for benefits in the primary prevention of coronary heart disease and stroke, and an anti-arrhythmogenic mechanism is emerging as the most likely explanation. Summary Current evidence suggests that individuals with coronary artery disease may reduce their risk of sudden cardiac death by increasing their intake of long-chain omega-3 fatty acids by approximately 1 g per day.
TL;DR: Recombinant apolipoprotein A-I(Milano), formulated as synthetic HDL with phospholipids, appears to exert a direct removing effect on arterial cholesterol, well evident in experimental animals and, more recently, as indicated by a dramatic increase in HDL free cholesterol after the infusion of different doses of the agent.
Abstract: Purpose of review: Strategies to increase HDL are among the major targets of clinical research in atherosclerosis prevention. The mutant apolipoprotein A-I(Milano) has been associated with a reduced incidence of coronary disease in carriers. Furthermore, recombinant apolipoprotein A-I(Milano) has displayed remarkable atheroprotective activities and the possibility of directly reducing the burden of atherosclerosis in experimental models. This review is aimed at providing an update on the experimental studies in which apolipoprotein A-I(Milano), produced as a recombinant protein, has displayed important effects in the treatment of vascular diseases.
Recent findings: In the past year, two reports have appeared, indicating that a single-dose administration of recombinant apolipoprotein A-I(Milano) dimers formulated into liposomes can reduce atheromas in models such as the apolipoprotein E-deficient mice and a rabbit model of carotid focal lesion, in which a direct 90 min infusion of the product reduced atheroma up to 30%. This finding was associated with an increase in HDL free cholesterol and the permanence of the recombinant product in the lesion for over 72 h.
Summary: Recombinant apolipoprotein A-I(Milano), formulated as synthetic HDL with phospholipids, appears to exert a direct removing effect on arterial cholesterol. This is well evident in experimental animals and, more recently in clinical findings, as indicated by a dramatic increase in HDL free cholesterol after the infusion of different doses of the agent. As the product appears to be well tolerated and non-immunogenic, ongoing phase II studies in patients are being awaited with interest to obtain a 'proof of principle' for 'HDL therapy'.
TL;DR: These findings identify the crucial roles of peroxisome proliferator-activated receptors in macrophages, improving the comprehension of the patho-physiological mechanisms of atherogenesis.
Abstract: Purpose of reviewThis review focuses on recent advances on the roles of peroxisome proliferator-activated receptors in the control of lipid metabolism, and the inflammatory response of macrophages and the potential participation of these actions in the modulation of atherogenesis.Recent findingsAlte
TL;DR: The ‘anti-atherosclerotic’ plasma lipoprotein profile and the fact that hormone-sensitive lipase deficient animals become lean identifies the inhibition of hormone- sensitive lipase as a potential target for the treatment of lipid disorders and obesity.
Abstract: Purpose of reviewDespite their pathophysiological importance, the molecular mechanisms and enzymatic components of lipid mobilization from intracellular storage compartments are insufficiently understood. The aim of this review is to evaluate the role of hormone-sensitive lipase in this process.Rece
TL;DR: Recombinant apolipoprotein A-IMilano, formulated as synthetic HDL with phospholipids, appears to exert a direct removing effect on arterial cholesterol as well evident in experimental animals and, more recently, in clinical findings.
Abstract: Purpose of reviewStrategies to increase HDL are among the major targets of clinical research in atherosclerosis prevention. The mutant apolipoprotein A-IMilano has been associated with a reduced incidence of coronary disease in carriers. Furthermore, recombinant apolipoprotein A-IMilano has displaye
TL;DR: Statins have biphasic potential either to promote or inhibit angiogenesis, and there is increasing evidence that statins improve endothelial function through molecular mechanisms that mediate an increase in endothelium-derived nitric oxide.
Abstract: Purpose of reviewClinical studies suggested that 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy has an additional cardiovascular protective activity that may function independently of the ability of statins to lower serum cholesterol. This paper reviews the available dat
TL;DR: Improved understanding of the pathogenesis, diagnosis and treatment of components of the metabolic syndrome in children, and potentially the risk profiles for cardiovascular disease as children make the transition toward adolescence and young adulthood are improved.
Abstract: Purpose of review The metabolic syndrome, a cluster of potent risk factors for atherosclerotic cardiovascular disease and type 2 diabetes mellitus in adults, is composed of insulin resistance, obesity, hypertension and hyperlipidemia. Of significant impact in the adult population, atherosclerotic cardiovascular disease and death are rarely seen in the young, but the pathologic processes and risk factors associated with its development have been shown to begin during childhood. The current review summarizes the work published during the past year in the following areas: childhood obesity, insulin resistance, dyslipidemia, hypertension and type 2 diabetes mellitus. Recent findings Recent studies have revealed the presence of components of the metabolic syndrome in children and adolescents. Obesity has a central role in the syndrome. There is an increasing amount of data to show that being overweight during childhood and adolescence is significantly associated with insulin resistance, abnormal lipids, and elevated blood pressure in young adulthood. Weight loss in these situations results in a decrease in insulin concentration and an increase in insulin sensitivity toward normalcy. With cardiovascular disease, obesity, and type 2 diabetes reaching epidemic proportions, it is of great importance to understand and control the risk factors at an early age. Summary The information obtained during the past year has improved our understanding of the pathogenesis, diagnosis and treatment of components of the metabolic syndrome in children, and potentially could improve the risk profiles for cardiovascular disease as children make the transition toward adolescence and young adulthood.
TL;DR: PC-hydrolyzing s PLA2 isozymes, particularly sPLA2-V and sPLA 2-X, are attractive candidates for proatherosclerotic factors that may act in place of sPLA1-IIA, however, their expression in human atherosclerosis lesions requires confirmation by specific methods that can distinguish between the different sPLA3 isoz enzymes.
Abstract: Purpose of review Inflammation is an integral feature of atherosclerosis, in which inflammatory processes contribute to the initiation, progression and rupture of lipid-rich atherosclerotic plaques. Recent studies have suggested the involvement of the proinflammatory secretory phospholipase A 2 (sPLA 2 )-IIA in the development of atherosclerosis. This enzyme has been proposed to hydrolyze phosphatidylcholine (PC) in lipoproteins to liberate lyso-PC and free fatty acids in the arterial wall, thereby facilitating the accumulation of bioactive lipids and modified lipoproteins in atherosclerotic foci. However, the recent discovery of several novel sPLA 2 isozymes has raised the question of which types of sPLA 2 truly contribute to the atherosclerotic process. Recent findings Amongst the 10 mammalian sPLA 2 isozymes, SPLA 2 -X, -V, -IIF and -III exhibit much more potent PC-hydrolyzing activity than do the others, and can release free fatty acids and lysophospholipids from the PC-rich outer leaflet of the cellular plasma membrane. In particular, sPLA 2 -X and sPLA 2 -V hydrolyze PC in lipoproteins far more efficiently than does SPLA a -IIA. Moreover, sPLA 2 -X' promotes foam cell formation in vitro and is expressed in the atherosclerotic arterial walls of apolipoprotein E deficient mice in vivo. PC-hydrolyzing sPLA 2 isozymes, particularly sPLA 2 -V and sPLA 2 -X, are attractive candidates for proatherosclerotic factors that may act in place of SPLA 2 -IIA. However, their expression in human atherosclerotic lesions requires confirmation by specific methods that can distinguish between the different sPLA 2 isozymes.
TL;DR: Understanding the genetic underpinnings associated with variant HDL and reverse cholesterol transport provides an exceptional opportunity to identify novel agents that may optimize this process and reduce vascular event rates beyond currently available LDL lowering therapies.
Abstract: PURPOSE OF REVIEW To review gene regulation of HDL-cholesterol and discuss molecular abnormalities in HDL candidate genes that may lead to human pathologic states. RECENT FINDINGS The inverse association between HDL-cholesterol and vascular disease, especially coronary heart disease, has long been recognized, but understanding gene regulation of HDL in humans gained considerable momentum following the identification of ABCA1 as playing a pivotal role in reverse cholesterol transport. Recent data suggest that potentially important targets for upregulating HDL in humans include upregulators of ABCA1 and APOA1 (e.g. peroxisome proliferator activated receptor and liver X receptor agonists) and downregulators of CETP (e.g. JTT-705). A host of other nuclear receptors under investigation in animal models may advance to human testing in the near future. SUMMARY Disorders affecting HDL metabolism are complex because monogenic disorders causing low HDL do not necessarily correlate with premature vascular disease. To date, pathologic phenotypes have only been deduced among several HDL candidate genes. Understanding the genetic underpinnings associated with variant HDL and reverse cholesterol transport provides an exceptional opportunity to identify novel agents that may optimize this process and reduce vascular event rates beyond currently available LDL lowering therapies.
TL;DR: Endothelium-derived nitric oxide bioactivity appears to be increased by supplementation with a number of phenols, and this may explain some of the favourable effects of high phenolic intake seen in epidemiological studies.
Abstract: PURPOSE OF REVIEW There continues to be considerable interest in the concept that antioxidant therapy may reduce cardiovascular risk. Phenols have antioxidant properties and may be important micronutrients. Epidemiological studies have demonstrated a strong link between phenolic intake and reduced cardiovascular risk, but the mechanism of benefit has not been determined. RECENT FINDINGS Recent evidence has emerged that a number of phenolic compounds, particularly flavonoids, reverse vascular endothelial dysfunction. The normal endothelium plays a critical role in regulating vascular function, and endothelial dysfunction is associated with increased cardiovascular risk. The present article reviews the links between phenolic intake, endothelial function and cardiovascular risk. SUMMARY Endothelium-derived nitric oxide bioactivity appears to be increased by supplementation with a number of phenols, and this may explain some of the favourable effects of high phenolic intake seen in epidemiological studies.