Mutsuko Sarukawa

An anti-ulcer drug, geranylgeranylacetone, suppresses inducible nitric oxide synthase in cultured vascular smooth muscle cells.

Objective Geranylgeranylacetone (GGA) is commonly used as an anti-ulcer drug. If GGA affects inducible nitric oxide synthase (iNOS) in the vascular tissue, it could influence disease progression in coronary arteries. We investigated the effects of the anti-ulcer drug GGA on iNOS activity in vascular smooth muscle cells. Methods We measured the production of nitrite, a stable metabolite of nitric oxide, in cultured rat vascular smooth muscle cells with the Griess reagent. iNOS protein and mRNA expressions were assayed by western blotting and northern blotting, respectively. The levels of nuclear factor (NF)-κB proteins in nuclear extracts were analyzed by gel retardation assay. Heat shock protein 70, a cytoprotective molecule, was evaluated by western blotting. Results Incubation of cultures with interleukin-1β for 24 h caused a significant increase in nitrite generation. Interleukin-1β-induced nitrite production by vascular smooth muscle cells was significantly suppressed by GGA in a dose-dependent manner. GGA-suppressed nitrite production was accompanied by decreased iNOS mRNA and protein accumulations. GGA by itself did not modulate the basal level of nitrite production. Interleukin-1β induced NF-κB activation in vascular smooth muscle cells, and the addition of GGA further inhibited this NF-κB activation. GGA itself induced heat shock protein 70 expression in a dose-dependent manner. Conclusion These findings demonstrated that GGA suppresses iNOS expression in cytokine-stimulated cultured vascular smooth muscle cells partially through the suppression of NF-κB activation, suggesting that GGA may modulate the pathophysiology of cardiovascular diseases including atherosclerosis. In addition, this effect may be associated with heat shock protein 70 production by GGA.

616. Protection of Monocrotaline-Induced Pulmonary Hypertension by Adeno-Associated Virus Vector-Mediated Interleukin-10 Expression

Background: Inflammation in the pulmonary vasculature plays a pivotal role in the pathogenesis of primary pulmonary hypertension (PH). Interleukin (IL)-10, an antiinflammatory cytokine, exerts pleiotropic vasculoprotective effects by attenuating inflammatory responses, endothelial dysfunction, and smooth muscle cell proliferation. Adeno-associated virus (AAV) vectors can achieve sustained gene expression with minimal inflammatory and immune responses. We examined whether AAV-mediated IL-10 expression could prevent the monocrotaline (MCT)-induced PH progression in rats.