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.
((c)2001 Elsevier Science.)