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(Circulation. 1999;99:1230-1235.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Homocysteine Increases Nitric Oxide Synthesis in Cytokine-Stimulated Vascular Smooth Muscle Cells

Uichi Ikeda, MD, PhD; Michiyo Ikeda, MD, PhD; Seiji Minota, MD, PhD; Kazuyuki Shimada, MD, PhD

From the Departments of Cardiology (U.I., K.S.) and Clinical Immunology (M.I., S.M.), Jichi Medical School, Minamikawachi, Tochigi, Japan.

Correspondence to Uichi Ikeda, MD, PhD, Department of Cardiology, Jichi Medical School, Minamikawachi-Machi, Tochigi 329-04, Japan. E-mail uikeda{at}jichi.ac.jp

Background—Elevated plasma homocysteine levels have been reported to be an independent risk factor for vascular disease. However, there have been no reports concerning the effects of homocysteine on the production of nitric oxide (NO), another modulator of vascular function and proliferation, by the vascular smooth muscle.

Methods and Results—We investigated the effects of homocysteine on NO synthesis by measuring the production of nitrite, a stable metabolite of NO, in cultured rat vascular smooth muscle cells (VSMCs). Incubation of cultures with interleukin (IL)-1ß 10 ng/mL for 24 hours caused a significant increase in nitrite generation. The IL-1ß–induced nitrite production by VSMCs was significantly increased by homocysteine in a dose-dependent manner. This effect of homocysteine was significantly inhibited in the presence of N^G-monomethyl-L-arginine or actinomycin D. The homocysteine-induced nitrite production was accompanied by increased inducible NO synthase mRNA and protein accumulation. Cysteine, glutathione, or hydrogen peroxide also increased nitrite accumulation in IL-1ß–stimulated VSMCs. Coincubation with the radical scavenger catalase or superoxide dismutase markedly reduced homocysteine-induced nitrite accumulation.

Conclusions—Homocysteine enhances NO synthesis in IL-1ß–stimulated VSMCs, and oxidative products are involved in the effect of homocysteine.

Key Words: homocysteine • interleukins • nitric oxide • muscle, smooth • free radicals

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