Paradoxical effects of statins on aortic valve myofibroblasts and osteoblasts: implications for end-stage valvular heart disease.
OBJECTIVE
We evaluated the effects of statins on aortic valve myofibroblasts (AVMFs) and osteoblast calcification in vitro.


RESULTS
Cultured porcine AVMFs and M2-10B4 cells were treated with simvastatin and pravastatin. Mevalonate, a 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase metabolite, was added in parallel experiments. Manumycin A, which inhibits protein prenylation, was added to cultures in the absence of statins. Calcification was assessed by counting the number of calcific nodules formed and measuring alkaline phosphatase activity (APA). Statins inhibited calcific nodule formation (P<0.01) and APA (P<0.01) in AVMFs. Mevalonate reversed the statin effect on nodule formation (P<0.05) and APA (P<0.01). Manumycin A had no effect on either parameter. M2-10B4 cells treated with simvastatin formed more calcific nodules compared with controls (P<0.01), although pravastatin had no effect. Both statins, however, resulted in increased APA in M2-10B4 cells (P<0.01). Mevalonate had no impact on nodule numbers or APA in M2-10B4 cells.


CONCLUSIONS
Statins inhibit calcification in AVMFs by inhibiting the cholesterol biosynthetic pathway, independent of protein prenylation, but paradoxically stimulate bone cell calcification. Because 15% of patients with end-stage valvular heart disease exhibit mature bone in their aortic valves, statins may differentially regulate calcification within a valve, limiting dystrophic calcification but promoting ossification of formed bone.
Wu
Bing
B
Cardiovascular Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa 19104, USA.
Elmariah
Sammy
S
Kaplan
Frederick S
FS
Cheng
Guanjun
G
Mohler
Emile R
ER
D000818:Animals; D001021:Aortic Valve / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002114:Calcinosis / Q000188:drug therapy* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006349:Heart Valve Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017035:Pravastatin / Q000494:pharmacology; D017368:Protein Prenylation; D019821:Simvastatin / Q000494:pharmacology*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013552:Swine
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D019821:Simvastatin; D017035:Pravastatin; D008798:Mevalonic Acid