Low-density Lipoprotein Oxidation In Patients Research Articles

Hemodialysis reduces inhibitory effect of plasma ultrafiltrate on LDL oxidation and subsequent endothelial reactions

Oxidative modification of low-density lipoprotein (LDL) and its deleterious effect on endothelium is implicated in the pathogenesis of atherosclerosis. Endothelium responds to such an insult by upregulating the synthesis of heme oxygenase-1 (HO-1) and ferritin. Endothelial cell damage and dysfunction have been observed in patients with chronic kidney disease (CKD) on maintenance hemodialysis (HD). We studied the effect of low-molecular-weight components of uremic plasma on LDL oxidation and LDL-oxidation-provoked endothelial cell reactions, such as the induction of cytotoxicity and the upregulation of cell-protective HO-1 and ferritin. Plasma ultrafiltrate (molecular weight<5000 Da) from CKD patients on HD or when treated conservatively exhibited a pronounced inhibition on heme-mediated oxidative modification of LDL. Endothelial cell cytotoxicity provoked by LDL oxidation was also attenuated by plasma ultrafiltrate from CKD patients. During HD treatment, a dramatic drop occurred in the retardation of oxidative reactions, and a loss of endothelial cytoprotection exerted by plasma ultrafiltrate was noted. The upregulation of HO-1 and ferritin in response to oxidative stress of LDL was blunted by uremic plasma ultrafiltrate that was released by the end of HD. The decreased antioxidant capacity of ultrafiltrate after HD occurred as a consequence of the intradialytic removal of L-ascorbic acid, uric acid, bilirubin, 3-indoxyl sulfate, indoxyl-beta-D-glucuronide, p-cresol, and phenol. Intradialytic removal of L-ascorbic acid, uric acid, bilirubin, 3-indoxyl sulfate, indoxyl-beta-D-glucuronide, p-cresol, and phenol increases the risk of LDL oxidation and subsequent endothelial cell damage, which underlines the importance of activation of cytoprotective HO-1 and ferritin in endothelium.

L-arginine improves endothelial function and reduces LDL oxidation in patients with stable coronary artery disease

We investigated the effects of oral L-arginine on endothelial function, intravascular oxidative stress, and circulating inflammatory markers in patients with stable coronary artery disease (CAD). Thirty-one stable CAD patients were randomly assigned to oral L-arginine (10 g) or vitamin C (500 mg, an antioxidant, as active control) daily for 4 weeks, with crossover to the alternate therapy after 2 weeks off therapy, in this study. Brachial artery endothelial function studies were performed and serum concentrations of lipids and inflammatory markers were measured at baseline, at the end of each 4-week treatment period and at the 2-week wash-out period. Susceptibility of low-density lipoprotein (LDL) particles to oxidation, a marker of oxidative stress, was determined in 11 patients at random before and after 4-week treatment of oral L-arginine. We demonstrates that consumption of either L-arginine or vitamin C significantly increased brachial artery flow-mediated dilatation (mean diameter change from baseline of 4.87%, P<0.0001 and of 3.17%, P=0.0003, respectively). Neither oral L-arginine nor vitamin C affected lipid profiles and circulating levels of inflammatory markers. However, in the 11 patients whose LDL susceptibility to oxidation was determined, lag time significantly increased by 27.1% (P=0.045) after consumption of L-arginine for 4 weeks. Oral L-arginine supplement improved endothelial function and reduced LDL oxidation in stable CAD patients.

Increased Levels of Low-Density Lipoprotein Oxidation in Patients with Familial Hypercholesterolemia and in End-Stage Renal Disease Patients on Hemodialysis

Patients with familial hypercholesterolemia (FH) and patients with end-stage renal disease (ESRD) undergoing dialysis suffer from accelerated atherosclerosis. Oxidation of low-density lipoprotein (LDL) cholesterol is crucial in atherogenesis. In the present study, we determined the LDL oxidation level and oxidizability of isolated LDL of 11 male patients with FH, 15 male ESRD patients on hemodialysis, and 15 age-matched male normolipidemic healthy controls. FH patients were without lipid-lowering medication for at least 4 weeks and were reassessed after 2 years of cholesterol-lowering therapy (statins). LDL oxidation level was measured by ELISA using monoclonal antibody 4E6 to oxidized LDL (oxLDL) as the capture antibody and anti-human apoB antibody for detection; results were expressed as percentage oxLDL. In FH patients and in ESRD patients on hemodialysis, both groups having a higher percentage of cardiovascular disease, mean plasma LDL oxidation levels were significantly elevated compared with controls (4.9 ± 1.3; 3.7 ± 2.0; 1.7 ± 0.6%, respectively). Within each group of subjects, LDL oxidation level was not associated with history of cardiovascular disease. Furthermore, in neither group was a significant correlation found between plasma concentration of LDL cholesterol and LDL oxidation level. After cholesterol-lowering therapy, LDL oxidation level in FH patients had not changed significantly and remained elevated compared with controls, despite a reduction of LDL cholesterol by 55% on average. Also, absolute plasma oxLDL concentrations, obtained by multiplying LDL oxidation level with plasma LDL cholesterol concentration, were significantly higher in FH patients before and after cholesterol-lowering therapy and in ESRD patients on hemodialysis than in controls (489 ± 145; 189 ± 122; 100 ± 65; and 59 ± 27 μmoles/L, respectively). No correlation was found between plasma oxLDL concentration and parameters of LDL oxidizability, LDL fatty acids, and LDL alpha-tocopherol content. We conclude that cholesterol-lowering therapy does not normalize elevated LDL oxidation levels in FH patients and elevated LDL oxidation level in FH and in ESRD might mirror atherosclerosis.

Increased levels of low-density lipoprotein oxidation in patients with familial hypercholesterolemia and in end-stage renal disease patients on hemodialysis

Increased levels of low-density lipoprotein oxidation in patients with familial hypercholesterolemia and in end-stage renal disease patients on hemodialysis

Losartan and lercanidipine attenuate low‐density lipoprotein oxidation in patients with hypertension and type 2 diabetes mellitus: A randomized, prospective crossover study

Lipoprotein oxidation, dyslipidemia, and hypertension are important underlying causes of accelerated atherosclerosis in patients with diabetes mellitus. The potential of antihypertensive medications to reduce lipid oxidation is, therefore, an important determinant in the choice of agents for patients with diabetes mellitus. The aim of this study was to compare the lowering effect of a new dihydropyridine calcium antagonist, lercanidipine, with that of the first angiotensin-receptor blocker, losartan, on low-density lipoprotein (LDL) oxidation. Forty patients in metabolically stable condition who had type 2 diabetes mellitus with hypertension were studied in this single-blind, randomized, prospective crossover study, comprising 2 treatment periods of 16 weeks each, separated by a 4-week washout period. LDL oxidation was evaluated by dialdehyde analysis by means of the thiobarbituric acid-reactive substances assay with and without cupric sulfate, as well as determination of conjugated dienes in the LDL lipid extract. Lercanidipine and losartan both significantly reduced the propensity of the serum to oxidize LDL (P =.001). With one method of estimation (conjugated dienes), the effect of lercanidipine was superior to that of losartan (P =.04). Losartan lowered urinary albumin excretion but lercanidipine did not. Both lercanidipine and losartan attenuate LDL oxidation in patients with type 2 diabetes mellitus and hypertension. This observation may offer insight into the mechanisms of the therapeutic effects of these agents in patients with diabetes mellitus.

Inhibition of Low-Density Lipoprotein Oxidation by Oral Herbal Mixtures Maharishi Amrit Kalash-4 and Maharishi Amrit Kalash-5 in Hyperlipidemic Patients

Low-density lipoprotein (LDL) oxidation is central to the pathogenesis of atherosclerosis. We have shown previously that the herbal mixtures Maharishi Amrit Kalash-4 (MAK-4) and Maharishi Amrit Kalash-5 (MAK-5) inhibit LDL oxidation induced by cupric ions (Cu+2) and endothelial cells in vitro and that MAK-4 reduces atherosclerosis in Watanabe heritable hyperlipidemic rabbits that were fed this herbal mixture. This study evaluates the antioxidant activity of MAK-4 and MAK-5 in vivo. Ten hyperlipidemic patients prescribed stable hypolipidemic therapy were treated with MAK-4 and MAK-5 for 18 weeks. Plasma lipoprotein, plasma lipid peroxide, and LDL oxidation studies were performed every 6 weeks. Apolipoprotein A, apolipoprotein B, and lipoprotein (a) levels were measured at baseline and 18 weeks. After 12 weeks of treatment with MAK-4 and MAK-5, a time-dependent increase in the lag phase and delay in the propagation phase of oxidation of LDL by Cu+2 and endothelial cells was seen. Lag phases at baseline and after 6, 12, and 18 weeks of MAK-4 and MAK-5 ingestion were 6.66 hours +/- 0.19 (mean +/- standard error of mean), 6.77 hours +/- 0.31, 7.22 hours +/- 0.24, and 18.00 hours +/- 0.73, respectively, for Cu(+2)-catalyzed LDL oxidation. Lag phases were 14.89 hours +/- 0.77, 13.33 hours +/- 0.50, 20.22 hours +/- 0.76, and 20.00 hours +/- 0.79, respectively, for endothelial cell-induced LDL oxidation. The levels of plasma lipid peroxide did not change significantly. No significant changes were seen in the plasma lipoproteins and the levels of apolipoprotein A, apolipoprotein B, and lipoprotein (a). The results show that MAK-4 and MAK-5 inhibit LDL oxidation in patients with hyperlipidemia. Therefore, MAK-4 and MAK-5 may be useful in the prevention and treatment of atherosclerosis.

Enhanced susceptibility of low-density lipoprotein to in vitro oxidation in type 1 and type 2 diabetic patients

Macrovascular disease represents a major cause of morbidity and mortality in patients with diabetes mellitus. Low-density lipoprotein (LDL) is involved in the pathogenesis of atherosclerotic lesions, through modifying processes such as oxidation. We examined the in vitro susceptibility to oxidation and the oxidizability of LDL isolated from the plasma of Type 1 and Type 2 diabetic patients. Two groups of diabetic patients (20 Type l, 20 Type 2) were compared with sex- and age-matched non-diabetic control groups. In vitro oxidation of the purified LDL preparations was assessed by determination of the kinetics for the formation of conjugated dienes (lag phase duration, maximal rate and maximal dienes concentration) and by measurement of thiobarbituric acid-reacting substances (TBARS) in the presence of copper ions. LDL from both Type 1 and Type 2 diabetic patients exhibited a shorter lag phase duration for conjugated dienes formation (94 ± 14 vs. 108 ± 20 and 97 ± 26 vs. 112 ± 18 min for Type 1 and Type 2 diabetic groups vs. respective control groups, P < 0.05). We also observed an increase in maximal rate of conjugated dienes formation (2.21 ± 0.55 vs. 1.52 ± 0.31 and 2.02 ± 0.55 vs. 1.52 ± 0.31 nmol/mg LDL/min, P < 0.01) and of maximal production of TBARS (77.9 ± 11.8 vs. 65.5 ± 10.4 and 76.7 ± 9.9 vs. 65.3 ± 9.4 nmol/mg LDL protein, P < 0.05) in diabetic groups. Our results demonstrate both a higher susceptibility to oxidation and a higher oxidizability of LDL from diabetic patients, as much for Type 1 as Type 2 diabetic subjects with or without pre-existent vascular complications. This enhanced propensity of LDL oxidation in patients with diabetes mellitus could at least partly be attributable to quantitative and qualitative alterations in the chemical composition of LDL and to the glycoxidation process occurring on these lipoproteins.

Predisposition to LDL oxidation in patients with and without angiographically established coronary artery disease

Oxidative modification of low density lipoprotein (LDL) may play an important role in the mechanism of atherosclerotic damage to blood vessels. In the present study the LDL isolated from the plasmas of 73 coronary artery disease (CAD) patients, 28 valvular heart disease (VHD) patients, 59 subjects affected by type IIa hyperlipoproteinemia and 71 controls was oxidatively modified by incubation with copper ions. In 15 CAD and 15 Type IIa patients and 15 controls the LDL chemical composition and polyunsaturated fatty acid (PUFA) content were also measured. Differences in the LDL susceptibilities to lipid peroxidation were studied by measuring the changes of fluorescence intensity. The lag phase in the CAD patients was found to be significantly lower than in the VHD and controls ( P < 0.001). The lag phase in the type IIa patients was significantly higher than in the CAD patients ( P < 0.01), and significantly lower than the VHD and controls ( P < 0.01). The LDL isolated from the type Ila patients had an increase in the relative content of free and esterified cholesterol ( P < 0.05), while the CAD patients had a decrease in the relative content of free cholesterol ( P < 0.05), and an increase in the relative content of protein ( P < 0.05). The lowest value of the LDL cholesterol to protein ratio and LDL size, was found in the CAD patients ( P < 0.05). When expressed in μg/mg LDL cholesterol, the concentration of the LDL PUFAs was significantly higher in the CAD group than in the others ( P < 0.05). The LDL α-tocopherol concentration was quite similar in the different groups. In conclusion the results show that the patients with established CAD and type IIa hyperlipoproteinemia have a greater predisposition to LDL oxidation in vitro than the subjects without CAD. The enhanced in vitro susceptibility for oxidation is probably the result of both a variation of LDL chemical composition and increase of PUFAs.