Abstract 488: Acute Fluvastatin Pleiotropy Is Mevalonate Independent
Objectives Thrombospondin 1 (TSP1) is a matricellular glycoprotein present in injured arteries, and acts as a chemoattractant for vascular smooth muscle cells (VSMC). Migration of VSMCs to an area of injury plays a role in the development of intimal hyperplasia. We have recently shown that acute treatment of VSMCs with statins leads to a decrease in TSP1-induced VSMC chemotaxis. The purpose of this study was to determine whether the acute statin effect is dependent on the mevalonate pathway or is a pleiotropic effect.
Methods Quiescent VSMCs were treated for 20 hours (standard time) or 20 minutes (acute treatment) with 100μM mevalonolactone, 0.5 μM fluvastatin, or mevalonolactone and fluvastatin combined. Migration of VSMCs towards 20 μg/ml TSP1 was assessed using a modified Boyden microchemotaxis chamber. Data was recorded as cells migrated per 5 high power fields and converted to percent positive control. Extracellular signal-regulated kinase 1/2 (ERK 1/2) activation was determined by Western blot. Densitometry is presented as percent positive control.
Results TSP1 induced VSMC migration compared to SFM, 100% + 7.6 vs. 35.3% + 4.5. Treatment with fluvastatin for 20 hours (34.3% + 6.9) or 20 minutes (38.4% + 9) inhibited TSP1-induced VSMC migration. 20 hour mevalonate treatment together with fluvastatin restored the migratory effect of TSP1, 81% +9.9, p=0.11. Addition of mevalonate to acute fluvastatin treatment, did not reverse the anti-migratory effect of fluvastatin compared to TSP1 alone, 35.6% + 9.9, p<0.0001. TSP1 significantly activated ERK 1/2 compared to basal medium, p42: 100% + 0 vs. 62.3% + 12.6; p44: 100% + 0 vs. 56.9% + 8.7. Acute fluvastatin did not inhibit ERK1/2 activation compared to TSP1, p42: 86.7% + 12.7; p44: 81.7% + 9.9.
Conclusion These data indicate long-term fluvastatin inhibition of TSP1 stimulated migration is at least partially dependent on the mevalonate pathway. In contrast, acute fluvastatin inhibition of TSP1-induced chemotaxis involves an alternate pathway resulting in pleiotropic statin effects. Previous studies found that standard treatment time with statins inhibited ERK 1/2 activation. Our current study found that acute fluvastatin inhibition of TSP1-induced chemotaxis does not appear to be ERK1/2 dependent.
- © 2012 by American Heart Association, Inc.