Liposomal Delivery of Purified Inhibitory-kBa Inhibits Tumor Necrosis Factor-a–Induced Human Vascular Smooth Muscle Proliferation

Vessel injury results in the elaboration of various cytokines, including tumor necrosis factor-a (TNF-a), which may influence vascular smooth muscle cell (VSMC) function and contribute to atherogenesis. We tested the hypothesis that TNF-a–induced VSMC proliferation requires activation of the transcription factor nuclear factor-kB (NF-kB), which could be prevented by delivery of the NF-kB inhibitory peptide, IkBa. TNF-a induced concentration-dependent human VSMC proliferation, and neutralizing antibody to interleukin-6 reduced TNF-a–induced VSMC proliferation by 65%. In TNF-a–stimulated VSMCs, there was a 3-fold increase in NF-kB–dependent luciferase reporter activity that was associated with degradation of IkBa. To determine an essential role for NF-kB in TNF-a–induced VSMC proliferation, recombinant IkBa was introduced into VSMCs via liposomal delivery. Under these conditions, TNF-a–induced NF-kB nuclear translocation and DNA binding were inhibited, NF-kB–dependent luciferase activity was reduced by 50%, there was no degradation of native IkBa detected, interleukin-6 production was reduced by 54%, and VSMC proliferation was decreased by 60%. In conclusion, the mitogenic effect of TNF-a on human arterial VSMCs is dependent on NF-kB activation and may be prevented by exogenously delivered IkBa. Furthermore, liposomal delivery of endogenous inhibitory proteins may represent a novel, therapeutically accessible method for selective transcriptional suppression in the response to vascular injury. (Circ Res. 1999;84:867-875.)