An IkappaB-alpha mutant inhibits cytokine gene expression and proliferation in human vascular smooth muscle cells.

BACKGROUND

Inflammatory reaction and intimal proliferation of smooth muscle cells are characteristics of vascular stenotic lesions. Nuclear factor kappaB (NF-kappaB) is involved in regulation of inflammation and cell survival in a variety of cell types. We tested a hypothesis that selective inhibition of NF-kappaB by expression of a mutated, nondegradable inhibitor of NF-kappaB, IkappaB-alphaM, would inhibit proinflammatory cytokine expression and proliferation in human vascular smooth muscle cell.

MATERIALS AND METHODS

Smooth muscle cells were cultured from internal mammary artery and infected with recombinant adenovirus vectors.

RESULTS

Adenoviral expression of IkappaB-alphaM inhibited diverse signal-triggered cellular IkappaB-alpha degradation, subsequent NF-kappaB activation, and transactivation of proinflammatory cytokine genes. Expression of IkappaB-alphaM in low-density VSMC led to a 60% reduction in serum-stimulated cell growth and a 10% increment in apoptotic incidence but was without effect in high-density cultures. Coexpression of NF-kappaB p65 attenuated apoptosis in low-density cells induced by IkappaB-alphaM. Therefore, the susceptibility to apoptosis induction in the low-density cells correlated with lower constitutive NF-kappaB activity. The induction of apoptosis by IkappaB-alphaM and the rescue by NF-kappaB p65 might be explained by mutual control of NF-kappaB p65 and IkappaB-alphaM access to the nucleus.

CONCLUSION

Our results suggest that expression of nondegradable IkappaB-alpha might have therapeutic potential in both vascular inflammatory reaction and smooth muscle cell proliferation.