Anti-atherosclerotic factors induced by Smad signaling in vascular cells

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Aim: To investigate the molecular basis of TGF-beta signaling involved in its anti-atherosclerotic effect.Methods and Results: Double knockout mice for ApoE and Smad3, a major intracellular signaling molecule for TGF-beta, were generated, and subjected to in vivo and in vitro analyses. The double knockout mice developed significantly larger atheromatous lesions in the aorta compared with the control apoE knockout mice. The aortic lesions of double knockout mice were rich in macrophages, scarce in collagen deposition, and highly expressed monocyte chemoattractant protein-1 (MCP-1). Inhibitory effect of TGF-beta on MCP-1 gene expression was lost in the peritoneal macrophages derived from Smad3 knockout mice. The Smad3 knockout macrophages were also resistant to growth inhibitory effect of TGF beta.Conclusion: Our results suggest that endogenous Smad3 in macrophage has inhibitory effects on progression of atherosclerosis via modulation of inflammatory gene expression and cell growth.