Meta-iodobenzylguanidine, an inhibitor of arginine-dependent mono(ADP-ribosyl)ation, prevents neointimal hyperplasia.

The association of ADP-ribosylation with cell proliferation and ischemia-reperfusion injury suggests that it may be a suitable target for therapeutic control of revascularization-induced injury. The purpose of this study was to investigate the inhibitory actions of ADP-ribosylation inhibitors on restenosis. In organ culture, the poly(ADP-ribose) polymerase (PARP) inhibitor 3,4-dihydro-5-methylisoquinolinone (PD128763) was unable to prevent neointimal hyperplasia, whereas the arginine-dependent mono(ADP-ribosyl)transferase (ART) inhibitor meta-iodobenzylguanidine (MIBG) was highly effective (EC(50) 21 microM).

Activation of MMP-2 in response to vascular injury is mediated by phosphatidylinositol 3-kinase-dependent expression of MT1-MMP.

Phosphatidylinositol 3-kinase (PI3K) is required for smooth muscle cell (SMC) proliferation. This study reports that inhibitors of PI3K also prevent SMC migration and block neointimal hyperplasia in an organ culture model of restenosis. Inhibition of neointimal formation by LY-294002 was concentration and time dependent, with 10 muM yielding the maximal effect.

NF-kappaB activation is essential for angiotensin II-dependent proliferation and migration of vascular smooth muscle cells.

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-kappaB, the relationship between AngII and NF-kappaB was investigated. Our study revealed that AngII promoted a dose-dependent and transient phosphorylation of the regulatory IkappaBalpha protein in smooth muscle cells from porcine coronary artery, with concomitant nuclear translocation of NF-kappaB and increased binding to a kappaB promoter element.