Divergent Effects ofα-Tocopherol and Vitamin C on the Generation of Dysfunctional HDL Associated with Diabetes and the Hp 2-2 Genotype

Abstract

The haptoglobin (Hp) 2-2 genotype is associated with increased risk of cardiovascular disease (CVD) in diabetes (DM). We recently proposed this increased risk arises from the tethering of redox active hemoglobin (Hb) to high density lipoprotein (HDL), thereby resulting in oxidative modification of HDL. Clinical trials have demonstrated that vitamin E (a-tocopherol) decreases while vitamin C increases CVD in Hp 2-2 DM individuals. We sought to test the hypothesis that the interaction of a-tocopherol or vitamin C on CVD in Hp 2-2 DM was due to their divergent effects on HDL oxidation and function. Vitamin C significantly increased while a-tocopherol completely blocked oxidation mediated by glycosylated Hb-Hp 2-2. Vitamin C had no benefit while a-tocopherol completely restored HDL function in Hp 2-2 DM mice. Co-administration of vitamin C mitigated the protective effects of a-tocopherol on HDL. There exists a pharmacogenomic interaction between vitamin C and a-tocopherol and the Hp 2-2 genotype on HDL function and structure. Choosing the correct antioxidant in the correct subset of patients may be critical in order to demonstrate benefit from antioxidant therapy. Antioxid. Redox Signal. 12, 209-218.

Haptoglobin genotype modifies the association between dietary vitamin C and serum ascorbic acid deficiency

“…Cross-sectional and longitudinal studies performed in different ethnic groups and geographic areas have consistently shown that the Hp1-1 homozygote genotype protects against the development of vascular complications of diabetes mellitus (46). However, the results of the present study and of other studies (44,47) do not imply that supplemental vitamin C is a suitable therapy for patients with diabetes at risk of cardiovascular disease who are not deficient in serum ascorbic acid.…”

“…In addition, whereas both Hp1-1 and Hp2-2 proteins are able to bind free hemoglobin, the Hp1-1 protein has been shown to be superior to the Hp2-2 protein in mediating the clearance of hemoglobin via the CD163 pathway, which is the only means of clearing hemoglobin in the extravascular compartment (42). The differences in the antioxidant capacity of the Hp1-1 and Hp2-2 proteins are enhanced markedly when the hemoglobin is glycosylated (43,44), which commonly occurs in individuals with diabetes mellitus. The glycosylated hemoglobin-Hp2-2 complex can become a proatherogenic, proinflammatory compound (45), oxidatively modifying the HDL of Hp2-2 individuals with diabetes and resulting in increased oxidative damage that increases the susceptibility to atherosclerosis.…”

Present trends in vitamin E research

“…Divergent effects of a-tocopherol and vitamin C on the generation of dysfunctional HDL, which is associated with diabetes and the haptoglobin 2-2 genotype have been described [117]. In this study, it has been concluded that ''choosing the correct antioxidant in the correct subset of patients may be critical to demonstrate benefit from antioxidant therapy''.…”

Vitamin E in the prevention of cardiovascular disease: the importance of proper patient selection

“…We have proposed that this apparent harmful effect of vitamin C in Hp 2-2 diabetic individuals on angiographic progression of atherosclerosis was due to the ability of vitamin C to promote redox cycling of the increased nontransferrin bound iron (Hp 2-2-Hg complexes) found in Hp 2-2 diabetic individuals ( 74 ). Supporting this hypothesis, divergent effects of ␣ -tocopherol and vitamin C on HDL function have been demonstrated in vitro and in vivo in Hp 2-2 diabetic mice ( 75 ). It was shown that vitamin C could not block HDL oxidation by glycosylated Hp 2-2-Hb complexes in vitro (glycosylated Hb was prepared by a 3 day incubation with glycolaldehyde), nor could it restore the ability of serum from Hp 2-2 diabetic mice to mediate HDL-mediated cholesterol effl ux from macrophages, whereas ␣ -tocopherol could favorably affect both.…”