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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:592.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Paradoxical Effects of Statins on Aortic Valve Myofibroblasts and Osteoblasts

Implications for End-Stage Valvular Heart Disease

Bing Wu; Sammy Elmariah; Frederick S. Kaplan; Guanjun Cheng; Emile R. Mohler, III

From the Cardiovascular Division, Department of Medicine (B.W., S.E., G.C., E.R.M.), and the Division of Orthopaedic Molecular Medicine, Department of Orthopaedic Surgery (F.S.K.), University of Pennsylvania School of Medicine, Philadelphia, Pa.

Correspondence to Emile R. Mohler III, MD, University of Pennsylvania School of Medicine, Room 432 PHI Bldg, 51 N 39th St, Philadelphia, PA 19104. E-mail mohlere{at}uphs.upenn.edu

Objectives— We evaluated the effects of statins on aortic valve myofibroblasts (AVMFs) and osteoblast calcification in vitro.

Methods and 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.

We evaluated the effects of statins on AVMF and osteoblast calcification in vitro. Statins were found to inhibit cardiac valve calcification in AVMFs but to stimulate bone cell calcification. Consequently, statins may differentially regulate calcification within a valve, limiting dystrophic calcification but promoting ossification of formed bone.

Key Words: calcification • aortic valve • myofibroblasts • protein prenylation • HMG-CoA reductase

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