NF-κB Activation is Essential for Angiotensin II-dependent Proliferation and Migration of Vascular Smooth Muscle Cells

P. Zahradka, J. P. Werner, S. Buhay, B. Litchie, G. Helwer and S. Thomas. NF-κB Activation is Essential for Angiotensin II-dependent Proliferation and Migration of Vascular Smooth Muscle Cells. Journal of Molecular and Cellular Cardiology (2002) 34, 1609–1621. Angiotensin II (AngII) functions as a stress hormone under conditions of stretch, pressure and injury to stimulate smooth muscle cell migration and proliferation. Since the cellular response to stress is mediated in part by the transcription factor NF-κB, the relationship between AngII and NF-κB was investigated. Our study revealed that AngII promoted a dose-dependent and transient phosphorylation of the regulatory IκBα protein in smooth muscle cells from porcine coronary artery, with concomitant nuclear translocation of NF-κB and increased binding to a κB promoter element. Both nuclear translocation and κB-element binding were prevented by the AT1 receptor antagonist losartan. The role of NF-κB in AngII-dependent smooth muscle cell migration and proliferation was then assessed. Inhibitors of NF-κB nuclear translocation (phenethyl caffeiate) and IκB phosphorylation (Bay 11-7085) effectively arrested both AngII-dependent DNA synthesis and migration. These results were confirmed with SN50, a highly selective peptide inhibitor of NF-κB activation. Phenethyl caffeiate also prevented the phosphorylation of cdk2 and Rb, indicating NF-κB was required for G1/S transition. The target of NF-κB inhibition was identified as cyclin E, since induction of this gene, but not cyclin D1, was suppressed by phenethyl caffeiate. We subsequently examined the relationship between NF-κB and neointimal formation in response to angioplasty-induced injury, a process susceptible to inhibition by losartan. Both phenethyl caffeiate and Bay 11-7085 blocked neointimal hyperplasia in organ culture following balloon angioplasty. These data indicate NF-κB is an important mediator of intracellular signalling by AngII under normal physiological conditions, and following vascular injury.