Abstract 667: Atorvastatin Attenuates Experimental Hypercholesterolemia Induced Aortic Valve Calcification and Osteoporosis via Paradoxical Regulation of Cbfa1
Atherosclerosis and osteoprorosis are the leading causes of morbidity and mortality in the aging population in the Unites States. Evidence indicates that hyperlipidemia plays a paradoxical role in these disease processes. However, the hyperlipidemic mechanisms of atherosclerotic calcification and decrease bone mass are not well understood. We propose to test this hypothesis in an experimental hypercholesterolemia model and further test if statins play a protective role in this process. LDLR−/− mice (n=60). Group I (n=20) normal diet, Group II (n=20) 0.2% chol diet (w/w), Group III (n=20) 0.2% (w/w) chol diet + atorvastatin for 8 weeks total and Group IV (n=20) chol diet for 4 weeks and then atorvastatin for 4 weeks for a total of 8 weeks. We tested for the development of calcification in the aortic valve and osteoporosis in the femurs. The aortic valve and aortas (AVA) was examined for proliferation, calcification, and bone matrix markers. Bone formation was assessed by micro Computed Tomography (microCT), calcein injection, cbfa-1 and osteocalcin expression.
Results: The cholesterol diet induced complex bone formations in the calcified AVA with an increase in cellular proliferation, osteocalcin and cbfa-1 expression (4-fold p<0.05). Atorvastatin reduced osteocalcin, cellular proliferation and cbfa-1 levels in the AVA (2-fold, p<0.05) in the primary prevention group (Group III). In the secondary prevention (Group IV), atorvastatin reduced the markers of proliferation and bone matrix synthesis (3-fold, p<0.05). The femurs from the mice demonstrated increase in bone resorption as measured by calcein incorporation and bone histomorphometry as measured by increase in osteoclasts and decrease in bone formation. Cbfa1 expression was completely inhibited with the cholesterol treatment which was resuced in the femurs with the atorvastatin treatment in both Group III and Group IV (2-fold, p<0.05).
Conclusion: Hypercholesterolemic AV calcification and bone turnover is attenuated by atorvastatin and is mediated in part by the transcription Cbfa1 osteoblast transcription pathway. This model may have future implications in the treatment of cardiovascular calcification and osteoporosis with statin therapy.