Basic and clinical studies on the role of inflammatory mechanisms in the pathogenesis ischemic heart disease

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1) Rho-kinase is substantially involved in the inflammatory mechanisms of arteriosclerosis. The expression of Rho-kinase in vascular smooth muscle cells is upregulated by inflammatory stimuli, such as angiotensin II and IL-1β with an involvement of Nf-_KB.2) Rho-kinase mediates hypoxia-induced downregulation of endothelial NO synthase (eNOS) in cultured human endothelial cells. Hydroxyfasudil, a specific Rho-kinase inhibitor, prevents the hypoxia-induced downregufayion of eNOS.3) Long-term inhibition of Rho-kinase suppresses in-stent restenosis in porcine coronary arteries, in which multiple mechanisms are involved, including enhancement of VSMC apoptosis, suppression of MCP-1 expression and inflammatory cell recruitment, and suppression of collagen synthesis through TGF-bl inhibition.4) Long-term inhibition of Rho-kinase suppresses angiotensin Il-induced formation of cardiovascular lesions by multiple mechanisms, including suppressions of NAD(P)H and TGF-β1 expression and of superoxide production.5) Long-term inhibition of Rho-kinase suppresses cardiac allograft vasculopathy, in which inhibition of the expression of macrophage migration inhibitory factor (MIF) is involved.