ATORVASTATIN ATTENUATES ATHEROSCLEROSIS IN THE VALVES AND FEMURS FROM HYPERCHOLESTEROLEMIC LDLR-/- MICE AS=OP


Nalini M. Rajamannan, M.D., Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Atherosclerosis and osteoporosis 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 under investigation. This study proposes to test in an experimental hypercholesterolemia model is atherosclerosis develops in the valve and osteoporosis develops in the femurs, and to determine if statins play a protective role. LDLR-/- mice (n=60) were treated with Group I (n=20) normal diet, Group II (n=20) 1.25% chol diet (w/w), and Group III (n=20) 1.25% (w/w) chol diet+atorv to determine the development of calcification in the hearts and osteoporosis in the bones. The aortic valve and aortas (AVA) was examined for myofibroblast cell proliferation, calcification, and bone matrix markers by immunohistochemistry and RTPCR. Bone formation was assessed by micro Computed Tomography (microCT), calcein injection, osteocalcin, cbfa-1 and osteopontin expression. The cholesterol diet induced complex bone formations by microCT in the calcified AVA with an increase in cellular proliferation, osteopontin, osteocalcin and cbfa-1 expression. Atorvastatin reduced bone formation, cellular proliferation and cbfa-1 levels and calcification in the AVA. Ex vivo analysis of calcein label demonstrated an increase in calcein label (4+) in the hypercholesterolemia AVA and the periosteal femoral bone surface with attenuation of the calcein label (1+) with atorvastatin therapy in the AVA and the femoral bones. (Calcein Scale =1-4, 4+=severe label, 1+=minimal label). Hypercholesterolemic AV calcification and bone turnover is attenuated by atorvastatin and is mediated in part by an osteoblast pathway. This model may have future implications in the treatment of cardiovascular calcification and osteoporosis with statin therapy.