Haptoglobin Genotype Is a Determinant of Hemoglobin Adducts and Vitamin E Content in HDL.

Hagit Goldenstein,Tina Costacou,John Ward,Andrew P Levy,Nina S Levy

doi:10.1155/2018/6125420

Abstract

Haptoglobin (Hp) is an abundant hemoglobin- (Hb-) binding serum protein and a constituent of the HDL proteome. In man, there exists a common polymorphism at the Hp locus with two common alleles defined by the presence (Hp 2 allele) or absence (Hp 1 allele) of a 1.7 kb in-frame partial duplication of exons 3 and 4 of the Hp gene. Numerous studies have demonstrated that the Hp 2-2 genotype is associated with a 3–5-fold increase in vascular disease among individuals with diabetes mellitus (DM). Increased Hp-Hb complex has been shown to be associated with the HDL of Hp 2-2 DM individuals. Hb-associated HDL has been proposed to result in the oxidation of HDL and the consumption of antioxidants in HDL, such as vitamin E, rendering the HDL further susceptible to oxidation. In this study, we set out to identify proteins which become cross-linked to Hb in HDL and to measure vitamin E in HDL as a function of the Hp genotype. We report on the identification of a novel 72 kd Hb reactive species which is cross-linked to HDL and demonstrate that vitamin E in HDL is decreased in Hp 2-2 DM individuals.

Highlights

Haptoglobin (Hp) is a plasma protein which binds free hemoglobin (Hb) and prevents oxidative damage between the heme iron of Hb and proteins and lipids [1]
The Israel Cardiovascular Vitamin E study (ICARE) [3] and the Strong Heart Study [4] demonstrated that Hp 2-2 diabetes mellitus (DM) individuals were three to five times more likely to suffer from cardiovascular disease (CVD) than DM individuals with the Hp 1-1 or 2-1 genotypes
We have shown here that Hb can form protein cross-links with High-density lipoprotein (HDL) and that Hp 2-2 is inferior to Hp 1-1 in inhibiting the formation of these adducts with HDL

Summary

Introduction

Haptoglobin (Hp) is a plasma protein which binds free hemoglobin (Hb) and prevents oxidative damage between the heme iron of Hb and proteins and lipids [1]. The mechanism of increased vascular risk in Hp 2-2 individuals is likely due to the impaired ability of the Hp 2-2 protein to prevent Hb-driven oxidation as compared to the Hp 1-1 protein. This mechanism is supported by results from randomized placebo-controlled clinical trials that have demonstrated that vitamin E is effective in reducing vascular disease risk of DM Hp 2-2 individuals [5, 6]

Methods

Results

Conclusion