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Correction of HDL dysfunction in individuals with diabetes and the haptoglobin 2-2 genotype.

Asleh R, Blum S, Kalet-Litman S, Alshiek J, Miller-Lotan R, Asaf R, Rock W, Aviram M, Milman U, Shapira C, Abassi Z, Levy AP - Diabetes (2008)

Bottom Line: RESULTS-Hb and lipid peroxides associated with HDL were increased and HDL function was impaired in Hp 2-2 diabetic individuals and mice.Vitamin E decreased oxidative modification of HDL and improved HDL function in Hp 2-2 diabetes but had no effect in Hp 1-1 diabetes.Vitamin E significantly improves the quality of HDL in Hp 2-2 diabetic individuals.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

ABSTRACT

Objective: Pharmacogenomics is a key component of personalized medicine. The Israel Cardiovascular Events Reduction with Vitamin E Study, a prospective placebo-controlled study, recently demonstrated that vitamin E could dramatically reduce CVD in individuals with diabetes and the haptoglobin (Hp) 2-2 genotype (40% of diabetic individuals). However, because of the large number of clinical trials that failed to demonstrate benefit from vitamin E coupled with the lack of a mechanistic explanation for why vitamin E should be beneficial only in diabetic individuals with the Hp 2-2 genotype, enthusiasm for this pharmacogenomic paradigm has been limited. In this study, we sought to provide such a mechanistic explanation based on the hypothesis that the Hp 2-2 genotype and diabetes interact to promote HDL oxidative modification and dysfunction.

Research design and methods: Hb and lipid peroxides were assessed in HDL isolated from diabetic individuals or mice with the Hp 1-1 or Hp 2-2 genotypes. HDL function was assessed based on its ability to promote cholesterol efflux from macrophages. A crossover placebo-controlled study in Hp 2-2 diabetic humans and in Hp 1-1 and Hp 2-2 diabetic mice assessed the ability of vitamin E to favorably modify these structural and functional parameters. RESULTS-Hb and lipid peroxides associated with HDL were increased and HDL function was impaired in Hp 2-2 diabetic individuals and mice. Vitamin E decreased oxidative modification of HDL and improved HDL function in Hp 2-2 diabetes but had no effect in Hp 1-1 diabetes.

Conclusions: Vitamin E significantly improves the quality of HDL in Hp 2-2 diabetic individuals.

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Related in: MedlinePlus

Hb released intravascularly from erythrocytes (RBC) is rapidly bound by Hp protein to form an Hp-Hb complex. In Hp 2-2 diabetic individuals, the complex is cleared more slowly than in Hp 1-1 diabetic individuals by the scavenger receptor CD163. The Hp-Hb complex can bind to Apo A1 in HDL, with increased binding of Hp 2-2–Hb occurring due its increased avidity for HDL and its increased plasma concentration. The Hp 2-2–Hb complex, but not the Hp 1-1–Hb complex, when bound to HDL can produce reactive oxygen species that can oxidize protein (i.e., ApoA1, glutathione peroxidase [GPx], and LCAT) and lipid components (cholesterol) of HDL and render the HDL dysfunctional (because of decreased reversed cholesterol transport [RCT] and antioxidant activity), proatherogenic, and prothrombotic.
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f7: Hb released intravascularly from erythrocytes (RBC) is rapidly bound by Hp protein to form an Hp-Hb complex. In Hp 2-2 diabetic individuals, the complex is cleared more slowly than in Hp 1-1 diabetic individuals by the scavenger receptor CD163. The Hp-Hb complex can bind to Apo A1 in HDL, with increased binding of Hp 2-2–Hb occurring due its increased avidity for HDL and its increased plasma concentration. The Hp 2-2–Hb complex, but not the Hp 1-1–Hb complex, when bound to HDL can produce reactive oxygen species that can oxidize protein (i.e., ApoA1, glutathione peroxidase [GPx], and LCAT) and lipid components (cholesterol) of HDL and render the HDL dysfunctional (because of decreased reversed cholesterol transport [RCT] and antioxidant activity), proatherogenic, and prothrombotic.

Mentions: In this translational study, we have provided a pathophysiological and pharmacogenomic rationale as to why vitamin E may provide cardiovascular benefit to individuals with the Hp 2-2 genotype and diabetes (Fig. 7). The main reason why Hp 2-2 diabetic individuals appear to uniquely derive benefit from vitamin E is that there is substantially more Hb associated with the HDL of Hp 2-2 diabetic individuals. This key structural difference between HDL in Hp 1-1 and Hp 2-2 diabetic individuals is the result of an impairment in the CD163-mediated clearance of Hp-Hb in Hp 2-2 diabetes (23,31).


Correction of HDL dysfunction in individuals with diabetes and the haptoglobin 2-2 genotype.

Asleh R, Blum S, Kalet-Litman S, Alshiek J, Miller-Lotan R, Asaf R, Rock W, Aviram M, Milman U, Shapira C, Abassi Z, Levy AP - Diabetes (2008)

Hb released intravascularly from erythrocytes (RBC) is rapidly bound by Hp protein to form an Hp-Hb complex. In Hp 2-2 diabetic individuals, the complex is cleared more slowly than in Hp 1-1 diabetic individuals by the scavenger receptor CD163. The Hp-Hb complex can bind to Apo A1 in HDL, with increased binding of Hp 2-2–Hb occurring due its increased avidity for HDL and its increased plasma concentration. The Hp 2-2–Hb complex, but not the Hp 1-1–Hb complex, when bound to HDL can produce reactive oxygen species that can oxidize protein (i.e., ApoA1, glutathione peroxidase [GPx], and LCAT) and lipid components (cholesterol) of HDL and render the HDL dysfunctional (because of decreased reversed cholesterol transport [RCT] and antioxidant activity), proatherogenic, and prothrombotic.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2551691&req=5

f7: Hb released intravascularly from erythrocytes (RBC) is rapidly bound by Hp protein to form an Hp-Hb complex. In Hp 2-2 diabetic individuals, the complex is cleared more slowly than in Hp 1-1 diabetic individuals by the scavenger receptor CD163. The Hp-Hb complex can bind to Apo A1 in HDL, with increased binding of Hp 2-2–Hb occurring due its increased avidity for HDL and its increased plasma concentration. The Hp 2-2–Hb complex, but not the Hp 1-1–Hb complex, when bound to HDL can produce reactive oxygen species that can oxidize protein (i.e., ApoA1, glutathione peroxidase [GPx], and LCAT) and lipid components (cholesterol) of HDL and render the HDL dysfunctional (because of decreased reversed cholesterol transport [RCT] and antioxidant activity), proatherogenic, and prothrombotic.
Mentions: In this translational study, we have provided a pathophysiological and pharmacogenomic rationale as to why vitamin E may provide cardiovascular benefit to individuals with the Hp 2-2 genotype and diabetes (Fig. 7). The main reason why Hp 2-2 diabetic individuals appear to uniquely derive benefit from vitamin E is that there is substantially more Hb associated with the HDL of Hp 2-2 diabetic individuals. This key structural difference between HDL in Hp 1-1 and Hp 2-2 diabetic individuals is the result of an impairment in the CD163-mediated clearance of Hp-Hb in Hp 2-2 diabetes (23,31).

Bottom Line: RESULTS-Hb and lipid peroxides associated with HDL were increased and HDL function was impaired in Hp 2-2 diabetic individuals and mice.Vitamin E decreased oxidative modification of HDL and improved HDL function in Hp 2-2 diabetes but had no effect in Hp 1-1 diabetes.Vitamin E significantly improves the quality of HDL in Hp 2-2 diabetic individuals.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

ABSTRACT

Objective: Pharmacogenomics is a key component of personalized medicine. The Israel Cardiovascular Events Reduction with Vitamin E Study, a prospective placebo-controlled study, recently demonstrated that vitamin E could dramatically reduce CVD in individuals with diabetes and the haptoglobin (Hp) 2-2 genotype (40% of diabetic individuals). However, because of the large number of clinical trials that failed to demonstrate benefit from vitamin E coupled with the lack of a mechanistic explanation for why vitamin E should be beneficial only in diabetic individuals with the Hp 2-2 genotype, enthusiasm for this pharmacogenomic paradigm has been limited. In this study, we sought to provide such a mechanistic explanation based on the hypothesis that the Hp 2-2 genotype and diabetes interact to promote HDL oxidative modification and dysfunction.

Research design and methods: Hb and lipid peroxides were assessed in HDL isolated from diabetic individuals or mice with the Hp 1-1 or Hp 2-2 genotypes. HDL function was assessed based on its ability to promote cholesterol efflux from macrophages. A crossover placebo-controlled study in Hp 2-2 diabetic humans and in Hp 1-1 and Hp 2-2 diabetic mice assessed the ability of vitamin E to favorably modify these structural and functional parameters. RESULTS-Hb and lipid peroxides associated with HDL were increased and HDL function was impaired in Hp 2-2 diabetic individuals and mice. Vitamin E decreased oxidative modification of HDL and improved HDL function in Hp 2-2 diabetes but had no effect in Hp 1-1 diabetes.

Conclusions: Vitamin E significantly improves the quality of HDL in Hp 2-2 diabetic individuals.

Show MeSH
Related in: MedlinePlus