Abstract
Recently, atherosclerosis is thought to be a kind of inflammatory disease. Lymphocytes and macrophages, which migrate into vascular walls, play an important role in the development and progression of atherosclerosis. Cytokines are produced and secreted in a variety of cells and act on not only lymphocytes and macrophages but also endothelial and smooth muscle cells. Pro-inflammatory cytokines, such as interferon-γ (IFN-γ), tumor necrotic factor-a (TNF-α), interleukin (IL)-1, IL-6, IL-12 and IL-18 are expressed in the atherosclerotic lesions. Many investigations using knockout or antagonist of these cytokines demonstrated that pro-inflammatory cytokines could augment atherogenesis. Interestingly, pro-inflammatory cytokines can regulate lipid and glucose metabolism, which could also modulate atherogenesis. On the other hand, anti-inflammatory cytokines, such as IL-4, IL-10, and IL-11 are suggested to have an anti-atherogenic effect. An anti-inflammatory strategy could be a promising approach to prevent and treat atherosclerotic disease. We are investigating this approach using gene therapy. As atherogenesis is a chronic process, a long-term expression of anti-inflammatory cytokines is required to show its effect on the process of atherosclerotic disease. Therefore, we used adeno-associated virus (AAV) vectors to inhibit atherogenesis. We have tried AAV-mediated IL-10 gene transfer into apolipoprotein E knockout mice to prevent atherosclerosis. Serum IL-10 concentration of IL-10 transduced mice is maintained at least for three month. The atheromatous plaque area was significantly reduced in IL-10- transduced mice when compared with that in lacZ-transduced mice. These findings suggest that anti-inflammatory cytokine gene therapy is promising for the treatment of atherosclerosis.
Keywords: inflammation, cytokines, atherosclerosis, adeno-associated virus, gene therapy