Phagocytosis Of Low-density Lipoprotein Research Articles

Oxidized LDL phagocytosis during foam cell formation in atherosclerotic plaques relies on a PLD2-CD36 functional interdependence.

The uptake of cholesterol carried by low-density lipoprotein (LDL) is tightly controlled in the body. Macrophages are not well suited to counteract the cellular consequences of excess cholesterol leading to their transformation into "foam cells," an early step in vascular plaque formation. We have uncovered and characterized a novel mechanism involving phospholipase D (PLD) in foam cell formation. Utilizing bone marrow-derived macrophages from genetically PLD deficient mice, we demonstrate that PLD2 (but not PLD1)-null macrophages cannot fully phagocytose aggregated oxidized LDL (Agg-Ox-LDL), which was phenocopied with a PLD2-selective inhibitor. We also report a role for PLD2 in coupling Agg-oxLDL phagocytosis with WASP, Grb2, and Actin. Further, the clearance of LDL particles is mediated by both CD36 and PLD2, via mutual dependence on each other. In the absence of PLD2, CD36 does not engage in Agg-Ox-LDL removal and when CD36 is blocked, PLD2 cannot form protein-protein heterocomplexes with WASP or Actin. These results translated into humans using a GEO database of microarray expression data from atheroma plaques versus normal adjacent carotid tissue and observed higher values for NFkB, PLD2 (but not PLD1), WASP, and Grb2 in the atheroma plaques. Human atherectomy specimens confirmed high presence of PLD2 (mRNA and protein) as well as phospho-WASP in diseased arteries. Thus, PLD2 interacts in macrophages with Actin, Grb2, and WASP during phagocytosis of Agg-Ox-LDL in the presence of CD36 during their transformation into "foam cells." Thus, this study provides new molecular targets to counteract vascular plaque formation and atherogenesis.

Water extracts of cinnamon and clove exhibits potent inhibition of protein glycation and anti-atherosclerotic activity in vitro and in vivo hypolipidemic activity in zebrafish

Advanced glycation end products contribute to the pathogenesis of diabetic complications and atherosclerosis. Aqueous extracts of ground pepper, cinnamon, rosemary, ginger, and clove were analyzed and tested for anti-atherosclerotic activity in vitro and in vivo using hypercholesterolemic zebrafish. Cinnamon and clove extracts (at final 10μg/mL) had the strongest anti-glycation and antioxidant activity in this study. Cinnamon and clove had the strongest inhibition of activity against copper-mediated low-density lipoprotein (LDL) oxidation and LDL phagocytosis by macrophages. Cinnamon or clove extracts had potent cholesteryl ester transfer protein (CETP) inhibitory activity in a concentration-dependent manner. They exhibited hypolipidemic activity in a hypercholesterolemic zebrafish model; the clove extract-treated group had a 68% and 80% decrease in serum cholesterol and TG levels, respectively. The clove extract-fed group had the smallest increase in body weight and height and the strongest antioxidant activity following a 5-week high cholesterol diet.Hydrophilic ingredients of cinnamon and clove showed potent activities to suppress the incidence of atherosclerosis and diabetes via strong antioxidant potential, prevention of apoA-I glycation and LDL-phagocytosis, inhibition of CETP, and hypolipidemic activity. These results suggest the potential to develop a new functional dietary agent to treat chronic metabolic diseases, such as hyperlipidemia and diabetes.

Turmeric and Laurel Aqueous Extracts ExhibitIn VitroAnti-Atherosclerotic Activity andIn VivoHypolipidemic Effects in a Zebrafish Model

Culinary herbs and spices have been widely used for their hypoglycemic, lipid-lowering, and anti-inflammatory activities. This study examined the physiologic activity of hydrophilic components using extracts of turmeric or laurel leaf powder. Aqueous extracts of turmeric and laurel showed potent inhibitory activity against fructose-mediated glycation with antioxidant ability against low-density lipoprotein (LDL) oxidation and radical scavenging activity. The turmeric and laurel extracts had potent cholesteryl ester transfer protein (CETP) inhibitory ability (up to 23% and 40% inhibition, respectively) at a final concentration of 10 μg/mL. The turmeric and laurel extracts inhibited the cellular uptake of oxidized LDL into macrophages, which is the initial step in atherogenesis. For in vivo testing, zebrafish consumed a high cholesterol diet (HCD) (final concentration, 4% [wt/wt]) with or without turmeric or laurel powder (final concentration, 10% [wt/wt]). The turmeric and laurel groups had a 14% and 12% decrease, respectively, in the weight and height ratios compared to the HCD group. The plasma total cholesterol level was significantly lower in the turmeric and laurel groups (48% and 28% less, respectively, than in the HCD group). Plasma triglycerides were more markedly reduced in the turmeric and laurel groups than in the HCD group (68% and 56% less, respectively, than the HCD group). In conclusion, the hydrophilic extracts of turmeric and laurel potently suppressed the incidence of atherosclerosis via a strong antioxidant potential, prevention of apolipoprotein A-I glycation and LDL phagocytosis, and inhibition of CETP. Consumption of turmeric and laurel extracts exhibited hypolipidemic and antioxidant activities in a hypercholesterolemic zebrafish model.

Effect of Glucose and Insulin on Oxidized Low-Density Lipoprotein Phagocytosis by Human Monocytes: A Pilot Study

We assessed the effect of glucose and insulin on human monocytes. Monocytes were isolated from 16 healthy obese and 10 lean healthy participants. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp. Obese participants were subdivided into 2 subgroups: insulin sensitive (IS) and insulin resistant (IR). Monocyte oxidized low-density lipoprotein (oxLDL) phagocytosis was assessed pre and poststimulation in vitro with glucose or insulin. Experiments were repeated after incubation with a Na(+)/H(+) exchanger-1 inhibitor ([NHE-1]; cariporide) or rosiglitazone. Glucose increased oxLDL phagocytosis in all groups studied (at 1 or 3 hours incubation; P = .037-.002). Insulin increased oxLDL phagocytosis in all groups studied after 1-hour incubation (P = .027-.015) but not at 3 hours. Incubation with cariporide attenuated oxLDL phagocytosis except in the obese IS group. Rosiglitazone eliminated glucose- and insulin-induced increase in oxLDL phagocytosis in all studied groups. Glucose and insulin induce oxLDL phagocytosis.

Effect of alterations of blood cholesterol levels on macrophages in the myocardium of New Zealand White rabbits.

We investigated the effect of alterations of blood cholesterol levels on macrophages (mphi) in the myocardium of New Zealand White (NZW) rabbits. Three groups of NZW rabbits were used: controls, rabbits fed a 0.5% cholesterol-enriched diet (CH-D) for 96 days, and rabbits fed a 0.5% CH-D for 96 days followed by normal chow for 4 months. Immunohistochemical analysis by mAbs directed against mphi (RAM-11) and Mn superoxide dismutase (MnSOD) were quantified by computer-assisted morphometry. Using cultured human and rabbit mphi, a cross-reaction of the human MnSOD mAbs was found as well as the predominant localization of MnSOD-immunoreactivity (IR) in mitochondria. In group 1, only a very few RAM-11-immunoreactive (ir) mphi occurred in the interstitial space of the myocardium. In group II blood cholesterol levels significantly increased in parallel with the numbers of mphi, which often contained lipid droplets (foam cells). Although blood cholesterol concentrations regressed about 10-fold in group III, mphi in the myocardium were found to be reduced only about 20%. Most mphi were also MnSOD-ir. In atherosclerotic coronary arteries RAM-11-IR was located in mphi and also extracellularly, whereas MnSOD-IR was found only in mphi. Drastically induced MnSOD in the mitochondria of mphi is suggested as an indicator of increased oxidative stress caused by in vitro conditions or by phagocytosis of low-density lipoprotein in vivo. Elevation of the cholesterol level leads to a long-term increase and its regression results in a delayed reduction of such mphi, which seem to play a key role in the atherogenesis of the coronary arteries as well.