Atorvastatin inhibits hypercholesterolemia-induced calcification in the aortic valves via the Lrp5 receptor pathway.
BACKGROUND
Calcific aortic valve disease is the most common indication for surgical valve replacement in the United States. The cellular mechanisms of valve calcification are not well understood. We have previously shown that cellular proliferation and osteoblastogenesis are important in the development of valvular heart disease. Lrp5, a known low-density receptor-related protein, plays an essential role in cellular proliferation and osteoblastogenesis via the beta-catenin signaling pathway. We hypothesize that Lrp5 also plays a role in aortic valve (AV) calcification in experimental hypercholesterolemia.


RESULTS
We examined the effects of cholesterol and atorvastatin in Watanabe rabbits (n=54). Group I (n=18) received a normal diet, group II (n=18) a 0.25% cholesterol diet, and group III (n=18) a 0.25% (w/w) cholesterol diet with atorvastatin for the development of calcification. The AVs were examined for cellular proliferation, Lrp5/beta-catenin, and bone matrix markers. Bone formation was assessed by micro-computed tomography, calcein injection, and osteopontin expression. Low-density lipoprotein with and without atorvastatin was also tested in AV myofibroblasts for cellular proliferation and regulation of the Lrp5/beta-catenin pathway. Our results demonstrate that the cholesterol diet induced complex bone formations in the calcified AVs with an increase in the Lrp5 receptors, osteopontin, and p42/44 expression. Atorvastatin reduced bone formation, cellular proliferation, and Lrp5/beta-catenin protein levels in the AVs. In vitro analysis confirmed the Lrp5/beta-catenin expression in myofibroblast cell proliferation.


CONCLUSIONS
Hypercholesterolemic AV calcification is attenuated by atorvastatin and is mediated in part by the Lrp5/beta-catenin pathway. This developmental pathway may be important in the signaling pathway of this disease.
Rajamannan
Nalini M
NM
Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. n-rajamannan@northwestern.edu
Subramaniam
Malayannan
M
Caira
Frank
F
Stock
Stuart R
SR
Spelsberg
Thomas C
TC
D000818:Animals; D017849:Animals, Inbred Strains; D001024:Aortic Valve Stenosis / Q000209:etiology / Q000517:prevention & control*; D000069059:Atorvastatin; D002114:Calcinosis / Q000517:prevention & control*; D002455:Cell Division; D002478:Cells, Cultured / Q000187:drug effects; D002791:Cholesterol, Dietary / Q000633:toxicity; D004036:Diet, Atherogenic; D005347:Fibroblasts / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000150:complications* / Q000235:genetics; D026502:LDL-Receptor Related Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis / Q000235:genetics; D032383:Myocytes, Cardiac / Q000187:drug effects; D009999:Ossification, Heterotopic / Q000209:etiology / Q000517:prevention & control; D053495:Osteopontin; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics; D034421:Sus scrofa; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics
D002791:Cholesterol, Dietary; D006538:Heptanoic Acids; D026502:LDL-Receptor Related Proteins; D008077:Lipoproteins, LDL; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D011758:Pyrroles; D012795:Sialoglycoproteins; D051176:beta Catenin; D053495:Osteopontin; D000069059:Atorvastatin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3