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(Stroke. 2009;40:241.)
© 2009 American Heart Association, Inc.

Original Contributions

Dysregulated RANK Ligand/RANK Axis in Hyperhomocysteinemic Subjects

Effect of Treatment With B-Vitamins

Marit S. Nenseter, PhD; Thor Ueland, PhD; Kjetil Retterstøl, MD, PhD; Ellen Strøm, MS; Lars Mørkrid, MD, PhD; Sverre Landaas, MD, PhD; Leiv Ose, MD, PhD; Pål Aukrust, MD, PhD Kirsten B. Holven, PhD

From Lipid Clinic (M.S.N., K.R., E.S., L.O., K.B.H.), Research Institute for Internal Medicine (M.S.N., T.U., P.A., K.B.H.), Section of Clinical Immunology and Infectious Diseases (P.A.), and Department of Medical Biochemistry (L.M.), Rikshospitalet University Hospital, Oslo, Norway; Institute of Clinical Biochemistry, Faculty of Medicine (L.M.), Institute for Basic Medical Sciences, Department of Nutrition (K.B.H.), University of Oslo, Oslo, Norway; Department of Clinical Chemistry (S.L.), Ullevål University Hospital, Oslo, Norway.

Correspondence to Marit S. Nenseter, Research Institute for Internal Medicine, Rikshospitalet University Hospital, University of Oslo, 0027 Oslo, Norway. E-mail marit.s.nenseter{at}rr-research.no

Background and Purpose— Homocysteine has been linked to increased risk of ischemic stroke and other cardiovascular events. Matrix degradation and inflammation play an important role in these disorders, and we have demonstrated increased levels of matrix-degrading enzymes and inflammatory cytokines in hyperhomocysteinemic individuals. Recent studies suggest that RANK ligand (RANKL) through interaction with its receptor RANK can modulate matrix degradation and inflammation. The present study aimed to examine the role of the RANKL/RANK axis in hyperhomocystinemia.

Methods— RANKL/RANK was measured on protein or mRNA level before and after B-vitamin supplementation in hyperhomocysteinemic individuals. We also examined the in vitro effects of soluble RANKL in peripheral blood mononuclear cells from hyperhomocysteinemic individuals.

Results— Our main findings were: (1) compared to peripheral blood mononuclear cells from controls, cells from hyperhomocysteinemic individuals had significantly higher gene expression of RANKL and RANK; (2) folic acid treatment for 6 weeks in an open, uncontrolled study significantly reduced gene expression of RANKL/RANK in peripheral blood mononuclear cells from these individuals; (3) compared to placebo, treatment with folic acid, vitamin B₁₂, and vitamin B₆ for 3 months in a randomized, double-blind trial significantly lowered serum levels of soluble RANKL in hyperhomocysteinemic individuals; and (4) in vitro, soluble RANKL markedly increased the release of matrix metalloproteinase-9 and inflammatory cytokines from peripheral blood mononuclear cells in hyperhomocysteinemic subjects.

Conclusions— Our findings suggest a dysregulated RANKL/RANK axis in hyperhomocysteinemic subjects. Based on their role in atherogenesis, this enhanced expression of RANKL and RANK could contribute to the increased risk of cardiovascular disease in hyperhomocystinemia. Moreover, treatment with B-vitamins may have beneficial implications for plaque stability in these individuals.

Key Words: B-vitamins • homocysteine • inflammation • RANK • RANKL