The proteasome inhibitor lactacystin attenuates growth and migration of vascular smooth muscle cells and limits the response to arterial injury

Exp Clin Cardiol. 2007 Fall;12(3):119-24.


Background: There is emerging evidence that the ubiquitin-proteasome system plays a role in vascular proliferative disorders such as restenosis after percutaneous coronary interventions. The present study examined the effect of proteasome inhibition on cultured vascular smooth muscle cell (VSMC) growth and migration, as well as on vascular lesion formation, following balloon arterial injury in the rat.

Methods: The effect of the proteasome inhibitor clasto-lactacystin beta-lactone (lactacystin) on cultured VSMC proliferation was assessed using cell proliferation assays and immunohistochemical assessment of S-phase entry. To test the effect of proteasome inhibition on lesion formation and to confirm the role of p21(Cip1/Waf1) (p21) in this effect in vivo, carotid injury was performed on anesthetized male Sprague-Dawley rats, followed by local treatment with either lactacystin or vehicle.

Results: Treatment of VSMCs with the proteasome inhibitor lactacystin resulted in a 60% and 80% decrease in cell number versus controls at day 3 and day 5 after treatment, respectively. This effect was accompanied by an 86% decrease in S-phase entry and an increased level of the cyclin-dependent kinase inhibitor p21. Additionally, lactacystin significantly inhibited VSMC migration in a modified Boyden chamber assay. Lactacystin resulted in a 59% reduction of neointimal formation at 14 days following balloon injury. This effect was associated with an early increase in p21 protein in the arterial wall.

Conclusions: Inhibition of the ubiquitin-proteasome system resulted in the attenuation of VSMC growth both in cultured cells and in an animal model of vascular injury, possibly via a mechanism involving upregulation of the p21 cyclin-dependent kinase inhibitor. These data provide support for a role of the proteasome in the vascular response to injury, and suggest an important role for p21 and attenuation of cellular migration in the mechanism of this effect.

Keywords: Proteasome; Restenosis; Smooth muscle cells.