In vitro stimulation of HDL anti-inflammatory activity and inhibition of LDL pro-inflammatory activity in the plasma of patients with end-stage renal disease by an apoA-1 mimetic peptide

Abstract

Features of end-stage renal disease such as oxidative stress, inflammation, hypertension, and dyslipidemia are associated with accelerated atherosclerosis and increased risk of death from cardiovascular disease. By inhibiting the formation and increasing the disposal of oxidized lipids, HDL exerts potent antioxidant and anti-inflammatory actions. Given that apolipoproteinA-1 can limit atherosclerosis, we hypothesized that an apolipoproteinA-1 mimetic peptide, 4F, may reduce the proinflammatory properties of LDL and enhance the anti-inflammatory properties of HDL in uremic plasma. To test this, plasma from each of 12 stable hemodialysis patients and age-matched control subjects was incubated with 4F or vehicle. The isolated HDL and LDL fractions were added to cultured human aortic endothelial cells to quantify monocyte chemotactic activity, thus measuring their pro- or anti-inflammatory index. The LDL from the hemodialysis patients was more pro-inflammatory and their HDL was less anti-inflammatory than those of the control subjects. Pre-incubation of the plasma from the hemodialysis patients with 4F decreased LDL pro-inflammatory activity and enhanced HDL anti-inflammatory activity. Whether 4F or other apolipoproteinA-1 mimetic peptides will have any therapeutic benefit in end-stage renal disease will have to be examined directly in clinical studies.

Figure 1

High-density lipoprotein antioxidative capacity in the normal control and ESRD groups. Oxidized LDL (25 μl, 250 μg/ml) was incubated at room temperature for 2 h alone (Ox-LDL) or together with HDL from control individuals and ESRD patients. Fluorescence intensity was determined after 2 h of incubation at room temperature as described in the Materials and Methods section. *P<0.005 ESRD versus control HDL. CTL, control; ESRD, end-stage renal disease.

Figure 2

The inflammatory index determined after addition of LDL was significantly improved after treatment with apoA-I mimetic peptides. The values for the monocyte chemotactic activity obtained with the control LDL (diamonds) were normalized to 1.0 and used as the basis for expression of values obtained with the patients’ vehicle- (squares) or L-4F-treated (circles) LDL. P<0.005 ESRD versus control LDL.

Figure 3

HDL-inflammatory index (HII) was significantly improved after treatment with ApoA-I mimetic peptides. The values for the monocyte chemotactic activity obtained with the control LDL (diamonds) were normalized to 1.0 and used as the basis for expression of activity obtained with LDL plus the patients’ vehicle- (squares) or L-4F-treated (circles) HDL. P<0.005 ESRD versus control HDL.

Figure 4

L-4F improves the HDL-inflammatory index of normal plasma. Plasma was obtained from 10 normal healthy individuals aged 47.2±11.7 years (five male and five female individuals) and was sham-treated or treated with L-4F and the HDL-inflammatory index was determined as described in the Materials and Methods section.