Efficacy of simvastatin treatment of valvular interstitial cells varies with the extracellular environment.
OBJECTIVE
The lack of therapies that inhibit valvular calcification and the conflicting outcomes of clinical studies regarding the impact of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors on valve disease highlight the need for controlled investigations to characterize the interactions between HMG-CoA reductase inhibitors and valve tissue. Thus, we applied multiple in vitro disease stimuli to valvular interstitial cell (VIC) cultures and examined the impact of simvastatin treatment on VIC function.


RESULTS
VICs were cultured on 3 different substrates that supported various levels of nodule formation. Transforming growth factor (TGF)-beta1 was also applied as a disease stimulus to VICs on 2-D surfaces or encapsulated in 3-D collagen gels and combined with different temporal applications of simvastatin. Simvastatin inhibited calcific nodule formation in a dose-dependent manner on all materials, although the level of statin efficacy was highly substrate-dependent. Simvastatin treatment significantly altered nodule morphology, resulting in dramatic nodule dissipation over time, also in a substrate-dependent manner. These effects were mimicked in 3-D cultures, wherein simvastatin reversed TGF-beta1-induced contraction. Decreases in nodule formation were not achieved via the HMG-CoA reductase pathway, but were correlated with decreases in ROCK activity.


CONCLUSIONS
These studies represent a significant contribution to understanding how simvastatin may impact heart valve calcification.
Monzack
Elyssa L
EL
Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA.
Gu
Xiaoxiao
X
Masters
Kristyn S
KS
D000818:Animals; D001021:Aortic Valve / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002114:Calcinosis / Q000378:metabolism* / Q000473:pathology; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism*; D005337:Fibrin / Q000378:metabolism; D005782:Gels; D006349:Heart Valve Diseases / Q000378:metabolism* / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007797:Laminin / Q000378:metabolism; D008798:Mevalonic Acid / Q000494:pharmacology; D011137:Polystyrenes / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013552:Swine; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism
D005782:Gels; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007797:Laminin; D011137:Polystyrenes; D053773:Transforming Growth Factor beta1; D005337:Fibrin; D003094:Collagen; D019821:Simvastatin; D054460:rho-Associated Kinases; D008798:Mevalonic Acid