Effects of Statin Treatment and Withdrawal on MAP Kinases in Vascular Smooth Muscle Cells.

Background. Abrupt discontinuation of 3-hydroxy-3--methylglutaryl-coenzyme-A-reductase inhibitors (statins) is associated with increased cardiovascular risk. Objectives. To investigate the molecular mechanisms determining the increased cardiovascular risk observed after statin withdrawal. Methods and Results. In this study we investigated the effects of statin treatment and withdrawal on angiotensin II (AII) actions in rat aortic vascular smooth muscle cells (VSMC) in culture. In VSMC, AII stimulated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), and of p38 mitogen-activated protein kinase (p38 MAPK), at an EC50% of 0.86 and 3 nM, respectively. Maximal stimulation was observed after 5-10 min of exposure to AII. Pretreatment with 1-3 μM simvastatin for 24 hours inhibited AII-mediated stimulation of ERK1/2 and p38 MAPK phosphorylation; without affecting the levels on non-phosphorylated MAPK. Washout of simvastatin produced a rebound increase above control levels of AII-mediated phosphorylation of ERK1/2 and p38 MAPK. As previously reported for other agonists, the rebound increase of AII effects was observed from 1 to 3 hours after statin withdrawal, and was lost at later times. The basal levels of phosphorylation and the amount of non-phosphorylated kinases were unaffected by statin withdrawal. Similar effects were observed with lovastatin. Conclusions. Our results suggest that statins may modulate AII- effects in VSMC, and that transient increases in AII effects mediated via the MAPK pathway may play a role in the vascular dysfunction associated with statin withdrawal.