Objective— Animal and clinical studies have suggested that polyphenols in fruits, red wine, and tea may delay the development of atherosclerosis through their antioxidant and anti-inflammatory properties. We investigated whether individual dietary polyphenols representing different polyphenolic classes, namely quercetin (flavonol), (−)-epicatechin (flavan-3-ol), theaflavin (dimeric catechin), sesamin (lignan), or chlorogenic acid (phenolic acid), reduce atherosclerotic lesion formation in the apolipoprotein E (ApoE) −/− gene–knockout mouse. Methods and Results— Quercetin and theaflavin (64-mg/kg body mass daily) significantly attenuated atherosclerotic lesion size in the aortic sinus and thoracic aorta ( P <0.05 versus ApoE −/− control mice). Quercetin significantly reduced aortic F 2 -isoprostane, vascular superoxide, vascular leukotriene B 4 , and plasma-sP-selectin concentrations; and augmented vascular endothelial NO synthase activity, heme oxygenase-1 protein, and urinary nitrate excretion ( P <0.05 versus control ApoE −/− mice). Theaflavin showed similar, although less extensive, significant effects. Although (−)-epicatechin significantly reduced F 2 -isoprostane, superoxide, and endothelin-1 production ( P <0.05 versus control ApoE −/− mice), it had no significant effect on lesion size. Sesamin and chlorogenic acid treatments exerted no significant effects. Quercetin, but not (−)-epicatechin, significantly increased the expression of heme oxygenase-1 protein in lesions versus ApoE −/− controls. Conclusion— Specific dietary polyphenols, in particular quercetin and theaflavin, may attenuate atherosclerosis in ApoE −/− gene–knockout mice by alleviating inflammation, improving NO bioavailability, and inducing heme oxygenase-1. These data suggest that the cardiovascular protection associated with diets rich in fruits, vegetables, and some beverages may in part be the result of flavonoids, such as quercetin.

Abstract-An initial step in reverse cholesterol transport is the movement of unesterified cholesterol from peripheral cells to high-density lipoproteins (HDLs). This transfer usually occurs in extracellular spaces, such as the subendothelial space of a vessel wall, and is promoted by the interaction of lipid-free or lipid-poor apolipoprotein (apo)AI with ATP binding cassette A1 cellular transporters on macrophages (M⌽). Because HDL does not interact with M⌽ ATP binding cassette A1 and apoAI is not synthesized by macrophages, this apoAI must be generated from spherical HDL. In this brief review, we propose that spherical apoAI is derived from HDL by remodeling events that are accomplished by proteins secreted by cholesteryl ester-loaded foam cells, including the lipid transfer proteins, phospholipid transfer protein, and cholesteryl ester transfer protein, and the triglyceride hydrolases hepatic lipase and lipoprotein lipase. T o remove cholesterol from the body, it must be dissolved into or converted to bile acids in the liver. This biliary excretion pathway is fed by the transport of cholesterol from peripheral tissues and is referred to as reverse cholesterol transport (RCT). An early step in RCT is the transfer of peripheral-cell unesterified cholesterol to plasma highdensity lipoproteins (HDLs). The HDLs serve as transport vehicles for excess cellular cholesterol through the plasma compartment to the liver. Importantly, the transfer of cellular cholesterol to HDL does not occur in plasma. It occurs in extracellular spaces, like the subendothelial space or intima of a vessel within an atherosclerotic lesion. We do not yet fully understand how apolipoprotein AI (apoAI) promotes the efficient transfer of excess cholesterol from peripheral cells [ie, intimal macrophage (M⌽) foam cells] to HDL. Convincing data have been published that in vivo apoAI participates in efficient free-cholesterol efflux from peripheral tissues, including atherosclerotic lesions. 1,2 There is no documented unique specificity for apoAI in mediating cellular cholesterol efflux in vitro, because many other exchangeable amphipathic alpha helical apoproteins can substitute for apoAI. Why is there specificity for apoAI in vivo in mediating efficient M⌽ cholesterol efflux from lesions? In this review, we wish to speculate that the in vivo efficiency of apoAI is a direct function of its ability to dissociate from spherical HDL and to form stable, lipid-poor apoAI, which can be rapidly lipidated with cellular M⌽ ATP binding cassette A1 (ABCA1)-transported free cholesterol and phospholipids. Multiple locally produced M⌽ liver X receptor (LXR)-regulated proteins probably participate in this interstitial remodeling of HDL to produce lipid-poor apoAI. Phospholipid transfer protein (PLTP) and cholesteryl ester (CE) transfer protein (CETP) are expressed by M⌽, can generate lipid-poor apoAI from spherical HDL, are present in lesions, and are induced by ligation of LXR. Thus, M⌽-expressed PLTP and CETP could promote M⌽ cholesterol efflux by generating ...

The effect of sphingomyelin (SPM) on the structure and function of discoidal and spherical reconstituted high density lipoproteins (rHDL) has been studied. Three preparations of discoidal rHDL with 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC)/SPM/unesterified cholesterol (UC)/apolipoprotein (apo)A-I molar ratios of 99.6/0.0/10.2/1.0, 86.0/13.6/10.8/1.0, and 72.5/26.3/11.4/1.0 were prepared by cholate dialysis. SPM did not affect discoidal rHDL size or surface charge. Esterification of cholesterol by lecithin:cholesterol acyltransferase (LCAT) was inhibited in the SPM-containing discoidal rHDL. When the discoidal rHDL of POPC/SPM/UC/ apoA-I molar ratio 99.6/0.0/10.2/1.0 were incubated with low density lipoproteins (LDL) and LCAT, SPM transferred spontaneously from the LDL to the rHDL (t1 ⁄2 ‫؍‬ 0.8 h) and spherical particles with a POPC/SPM/UC/CE/ apoA-I molar ratio of 24.6/4.9/3.6/24.9/1.0 were formed. Depleting the spherical rHDL of SPM head groups by incubation with sphingomyelinase increased the negative charge on the surface, but did not change their size. Cholesteryl ester transfer protein (CETP)-mediated transfers of cholesteryl esters and triglyceride between spherical rHDL and Intralipid were not affected by SPM head group depletion. The effect of SPM on rHDL structure was assessed spectroscopically. SPM increased POPC acyl chain and head group packing in the discoidal rHDL. When the spherical rHDL were depleted of SPM head groups, POPC acyl chain packing order decreased, but head group packing order was not affected. SPM inhibited the lipid-water interfacial hydration of discoidal rHDL. This parameter was not affected when the spherical rHDL were depleted of SPM head groups. The SPM molecule and the SPM head group, respectively, inhibited the unfolding of apoA-I in discoidal and spherical rHDL. It is concluded that (i) SPM influences the structure of discoidal and spherical rHDL, (ii) SPM inhibits the LCAT reaction in discoidal rHDL, and (iii) the SPM head group does not affect CETP-mediated lipid transfers into or out of spherical rHDL. Sphingomyelin (SPM)1 is a glycosphingolipid which is present in cell membranes and plasma lipoproteins. For many years SPM was thought only to maintain the structural integrity of membranes, but recent studies have shown that it is also involved in a wide range of metabolic events (1, 2). The SPM molecule comprises a phosphocholine head group and a ceramide backbone with a sphingosine base and an amide-linked acyl chain. The ceramide backbone of SPM plays a regulatory role in cell growth, differentiation, and apoptosis (1, 2). Ceramide also modulates protein phosphorylation and has been implicated as a tumor-suppressor lipid (3). The influence of SPM on lipoprotein metabolism is poorly understood. It has been reported that the concentration of SPM in the artery wall increases with aging and that it comprises 70 -80% of the phospholipids in atherosclerotic lesions (4). These observations suggest that SPM may be involved in the development of atherosclerosis. The addit...

This article briefly reviews evidence of health effects associated with exposure to particulate matter (PM) air pollution from five common outdoor emission sources: traffic, coal-fired power stations, diesel exhaust, domestic wood combustion heaters, and crustal dust. The principal purpose of this review is to compare the evidence of health effects associated with these different sources with a view to answering the question: Is exposure to PM from some emission sources associated with worse health outcomes than exposure to PM from other sources? Answering this question will help inform development of air pollution regulations and environmental policy that maximises health benefits. Understanding the health effects of exposure to components of PM and source-specific PM are active fields of investigation. However, the different methods that have been used in epidemiological studies, along with the differences in populations, emission sources, and ambient air pollution mixtures between studies, make the comparison of results between studies problematic. While there is some evidence that PM from traffic and coal-fired power station emissions may elicit greater health effects compared to PM from other sources, overall the evidence to date does not indicate a clear ‘hierarchy’ of harmfulness for PM from different emission sources. Further investigations of the health effects of source-specific PM with more advanced approaches to exposure modeling, measurement, and statistics, are required before changing the current public health protection approach of minimising exposure to total PM mass.