Small Dense LDL Particles in Relation to LDL Oxidation in Normolipidemic CAD Patients

HL (hepatic lipase) is a glycoprotein that is synthesized and secreted by the liver, and which binds to heparan sulphate proteoglycans on the surface of sinusoidal endothelial cells and on the external surface of parenchymal cells in the space of Disse. HL catalyses the hydrolysis of triacylglycerols and phospholipids in different lipoproteins, contributing to the remodelling of VLDL (very-low-density lipoprotein) remnants, as well as IDL, LDL and HDL (intermediate-, low- and high-density lipoprotein respectively). HL deficiency in humans is associated with diminished conversion of VLDL remnants into IDL and a near-complete absence of IDL-to-LDL conversion. Remnant lipoproteins and IDL are major determinants of coronary artery disease risk, and accumulation of these lipoproteins in the presence of low HL activity might lead to increased atherosclerosis. In addition to and independently of its lipolytic activity, HL participates as a ligand in promoting the hepatic uptake of remnants and IDL particles, and the latter may represent an additional mechanism linking low HL levels to plasma accumulation of these atherogenic lipoproteins. On the other hand, high HL activity may also result in an increased atherosclerotic risk by promoting the formation of atherogenic small, dense LDL particles. Finally, HL is also synthesized by human macrophages, suggesting that, at the arterial wall site, HL may also contribute locally to promote atherosclerosis by enhancing the formation and retention in the subendothelial space of the arterial wall of VLDL remnants, IDL and small, dense LDL. In conclusion, by interfering with the metabolism of apolipoprotein B100-containing lipoproteins, HL may have pro- as well as anti-atherogenic effects. The anti- or pro-atherogenic role of HL is likely to be modulated by the concurrent presence of other lipid abnormalities (i.e. LDL-cholesterol levels), as well as by the genetic regulation of other enzymes involved in lipoprotein metabolism.

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Growing Cardiovascular and Metabolic Diseases in the Developing Countries: Is there a Role for Small Dense LDL Particles as an Inclusion Criteria for Individuals at Risk for the Metabolic Syndrome?

Journal of Community Medicine & Health Education ◽

10.4172/2161-0711.1000243 ◽

2013 ◽

Vol 03 (06) ◽

Author(s):

Anjali Arora Qamar A Khan

Keyword(s):

Metabolic Syndrome ◽

At Risk ◽

Developing Countries ◽

Metabolic Diseases ◽

Inclusion Criteria ◽

Small Dense Ldl ◽

The Metabolic Syndrome ◽

Ldl Particles

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Hemopexin Is Protective Against Intravascular Hemolysis–Induced Vascular Damage

Blood ◽

10.1182/blood.v116.21.3207.3207 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3207-3207 ◽

Cited By ~ 1

Author(s):

Elena A Sher ◽

Keren Hemi ◽

Shai Efrati ◽

Joshua Weissgarten ◽

Matityahu Shaklai ◽

...

Keyword(s):

Shear Stress ◽

Vitamin E ◽

Oxidative Damage ◽

Ldl Oxidation ◽

Synthesis Rate ◽

Heme Oxygenase 1 ◽

Intravascular Hemolysis ◽

Fresh Blood ◽

Ldl Particles

Abstract Abstract 3207 Background: Intravascular hemolysis renders hemoglobin (Hb), usually protected by the red blood cell environment, susceptible to oxidation to its ferric (metHb) form. Haptoglobin (Hp) provides first aid to protect the vasculature from acellular metHb havoc. However, once Hp is consumed, ferrous Hb readily undergoes oxidation to metHb, in which the globin to heme affinity is reduced. MetHb releases the loosely bound heme allowing it to execute its oxidative activity. While nucleated cells, like endothelial cells, are equipped with the heme oxygenase-1 defence system, the nucleus lacking red blood cells (RBC) and low density lipoproteins (LDL) particles have no defence from heme-induced oxidation. Therefore the sole defence from heme oxidative damage remains the plasma protein hemopexin (Hx), which binds hemin with high affinity comparable to that of globin. Following hemin binding, Hx undergoes conformational changes rendering the heme inaccessible thereby inactive. Aim: The current study is focused on the ability of plasma Hx to defend the vasculature from acellular Hb induced damage. Results: Hx defence from metHb damage was studied in the following projects: a) preventing in vitro LDL oxidation by metHb, b) decreasing in vitro lysis of red cells created by hypotonic and mechanical stress. (c) Exploring consumption of Hx in hemodialysis (HD) treated patients by measuring their Hx levels. (a) Methemoglobin iron is a central cause of LDL oxidation. This process initiates formation of blood vessel plaques and atherosclerosis development. This part of the study examined the effect of apoHx (lacking heme) on LDL oxidation by metHb. Incubation of isolated native LDL (nLDL) or vitamin E depleted (dLDL) with low concentration of metHb range (1-10μM) resulted in covalent apoB inter-particle crosslinking in both LDL types, dLDL being more sensitive than nLDL to the oxidative crosslinking. Addition of apoHx abolished metHb-induced oxidation even in the dLDL. This Hx activity (comparable to that of haptoglobin) was confirmed by both SDS-PAGE and fluorescent assay of bityrosines formation. The fact that Hx protects LDL, especially vitamin E depleted particles, shed light on the controversial antioxidant vitamin E properties by indicating its efficacy in defence against acellular Hb induced LDL oxidation. (b) Like LDL the red cell membrane is exposed to metHb-induced oxidative damage. Acellular Hb was formed by hypotonic shock or mechanical shear stress to fresh whole blood of healthy donors. The effect of Hx on acellular Hb levels was measured spectrophotometrically. Reduction of osmotic pressure in fresh blood to 40% of its normal value resulted in formation of ∼300 μM acellular Hb. Supplementation of exogenous apoHx (20μM) to blood before exposure to hypotonicity reduced acellular Hb formation by half. The specificity of Hx was proved by addition of up to 80μM albumin, which had no effect on acellular Hb concentration. Acellular Hb was formed also by applying shear stress on circulating fresh blood in narrow channels using a peristaltic pump. Within 4 hours acellular Hb reached ∼500μM. However, in presence of 20μM apoHx hemolysis was significantly reduced (up to 50%). This reduction may be attributed to Hx's ability to block the hemolysis amplifying effect of metHb on the RBC membrane. (c) In HD treated patients RBCs are exposed to the effects of recurrent mechanical shear stress. The last part of the research was dedicated to quantisation of apoHx levels (by titration with hemin) in sera of HD patients (n=60) prior to and immediately after a single dialysis procedure versus normal controls (n=20). Sera apoHx levels in HD patients prior to a dialysis session were lower compared to healthy controls (10.91±3.19 μM vs. 14.95±2.63 μM, p<0.05) and were even lower (7.49±3.8 μM) immediately after the treatment. These findings indicate that in the plasma of HD treated patients Hx consumption rate exceeds synthesis rate leading to a chronically low level of Hx. Moreover, reduction of Hx was even more prominent in patients on long term HD treatment of above five years. Conclusion: Hx is specifically effective in attenuation of acellular Hb damage to the vasculature. These results point to the option that treating HD patients with exogenous Hx may slow down the rate of atherosclerotic cardiovascular disease development, the major cause of morbidity and mortality in these patients. Disclosures: No relevant conflicts of interest to declare.

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Combined effects of a dietary portfolio of plant sterols, vegetable protein, viscous fibre and almonds on LDL particle size

British Journal Of Nutrition ◽

10.1079/bjn20041241 ◽

2004 ◽

Vol 92 (4) ◽

pp. 657-663 ◽

Cited By ~ 44

Author(s):

Benoît Lamarche ◽

Sophie Desroches ◽

David J. A. Jenkins ◽

Cyril W. C. Kendall ◽

Augustine Marchie ◽

...

Keyword(s):

Particle Size ◽

Blood Lipids ◽

Saturated Fat ◽

Plant Sterols ◽

Ldl Particle Size ◽

Small Dense Ldl ◽

Ldl Particles ◽

Dietary Components ◽

Dietary Portfolio ◽

Combined Impact

Studies conducted in the last 20 years have led to the identification of small dense LDL as an important risk factor for CVD. Consumption of plant sterols, soyabean proteins, viscous fibre and nuts are known to modulate the risk of CVD favourably through their cholesterol (Chol)-lowering properties, both independently and more recently in combination. Nevertheless, their combined impact on the LDL particle size phenotype has never been tested. In the present study, we assessed the effect of incorporating concurrently plant sterols (1 g/4·2 MJ), soyabean protein (23 g/4·2 MJ), viscous fibre (9 g/4·2 MJ) and almonds (15 g/4·2 MJ) into a diet very low in saturated fat in twelve patients with mildly elevated plasma LDL-Chol levels. Fasting blood lipids were obtained at the start of the study and at 2-week intervals during the 4-week study. The diet-induced reduction in plasma LDL-Chol of 30·0 (SE 3·0) % (P<0·0001) was attributed to concurrent reductions in the serum Chol concentrations of large (>26.0 nm−30 (SE 8) %,P<0·001), medium (25·5–26·0 nm−29 (SE 3) %,P<0·001) and small (<25·5 nm − 21 (SD 6) %,P<0·01) LDL particles, with near maximal reductions seen by week 2. These results indicate that foods and dietary components advocated for their potential to reduce the risk of CVD are effective in reducing serum concentrations of all LDL fractions including small dense LDL, thus potentially further contributing to an overall lower risk of CVD.

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