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Biochemical, Molecular, and Genetic Mechanisms

The Antiatherogenic Function of HDL Is Impaired in Hyperhomocysteinemic Subjects^1,2

³ Institute for Basic Medical Sciences, Department of Nutrition, University of Oslo, Blindern, 0316 Oslo, Norway; and ⁴ The Lipid Clinic, ⁵ Research Institute for Internal Medicine, and ⁶ Section of Clinical Immunology and Infection Diseases, Medical Department, Rikshospitalet University Hospital, 0027 Oslo, Norway

^* To whom correspondence should be addressed. E-mail: kirsten.holven{at}medisin.uio.no.

High plasma homocysteine concentrations have been associated with increased risk of cardiovascular disease, whereas plasma HDL concentration is inversely correlated to such disorders. We hypothesized that hyperhomocysteinemic subjects may have dysfunctional HDL. We therefore investigated the ability of serum from hyperhomocysteinemic male and female subjects (n = 10) and control subjects (n = 10) to induce cholesterol efflux and to inhibit release of inflammatory mediators from human umbilical vein endothelial cell. We found that serum from hyperhomocysteinemic subjects had impaired ability to induce cholesterol efflux from lipid-loaded macrophages compared with healthy controls. HDL from those with markedly raised homocysteine concentrations had a reduced antiinflammatory effect in tumor necrosis factor-–activated endothelial cells with an attenuated suppressive effect on interleukin-6 growth-related oncogene- release. Also, the activity of paraoxonase in serum, a multifunctional enzyme with antioxidative effects in relation to the function of HDL, was significantly reduced in hyperhomocysteinemic subjects, in particular those with markedly raised homocysteine concentration. Our findings suggest that hyperhomocysteinemic individuals have dysfunctional HDL particles with attenuated antiatherogenic activity and may represent a novel explanation for the increased risk of cardiovascular events in these individuals.