Aortic Valve Stenosis is a common consequence of the traditional risk factors for vascular atherosclerosis including: hypertension, hypercholesterolemia, smoking, increased BMI, aging and diabetes. Once thought to be caused by a passive process involving calcium attaching to the valve leaflet;there is growing evidence to support that hypercholesterolemia can induce the valve myofibroblast cell to differentiate to an osteoblast-like phenotype. The ability to treat or slow the progression of aortic valve calcification (AVC) represents an unmet clinical need. Understanding of AVC initiation and progression is required for future therapies for this disease. A growing number of laboratories are demonstrating that osteogenic gene programs in calcifying cardiovascular tissue involve complex signaling pathways similar to bone biology. We hypothesize that lipids regulate the Lrp5/Wnt/b-catenin cascade in aortic valve myofibroblast cells to express the osteogenic gene program. Statin agents reverse this differentiation pathway via inhibition of Lrp5 in the myofibroblast cell. We have shown that statins inhibit calcification and Cbfal gene expression in the aortic valve. In this proposal we will study the role the role of Lrp5 receptor in the lipid regulation of the Lrp5/beta catenin-Cbfal signaling in AVC.
Aim 1, will test whether activation of Lrp5 signaling by lipids is sufficient to induce bone formation in aortic valve myofibroblasts.
Aim 2, will investigate whether statins and other candidate inhibitors of Lrp5 signaling can inhibit the osteoblastogenesis pathway in these cells.
Aim 3, will define the role of Lrp5/beta-catenin in the development of aortic valve calcification and osteoporosis by testing experimental hypercholesterolemia on the LRP5-null,LDLR-null and the double knock-out for the LDLR/Lrp5 receptors mice.
Aim 4, will use the TOPGAL+ and the LRP5-/-. TOPGAL + reporter mice (LacZ transgene under control of Wnt-responsive TCF/LEF element) to determine if lipids can activate diet-induced Cbfal-Wnt expression and induce bone formation in aortic valve myofibroblasts and inhibit bone formation in the osteoblasts from the bones. Our long term goal is to understand the role of Lrp5/beta-catenin in aortic valve calcification and how this information may be used to develop more effective therapies. The objectives of this proposal are to determine if the Lrp5 receptor is critical in activation of mineralization in aortic valve calcification.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085591-05
Application #
8133392
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Evans, Frank
Project Start
2007-09-30
Project End
2012-01-15
Budget Start
2011-07-01
Budget End
2012-01-15
Support Year
5
Fiscal Year
2011
Total Cost
$377,029
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Rajamannan, Nalini M (2015) Atorvastatin Attenuates Bone Loss and Aortic Valve Atheroma in LDLR Mice. Cardiology 132:11-5
Rajamannan, Nalini M (2014) Myxomatous mitral valve disease bench to bedside: LDL-density-pressure regulates Lrp5. Expert Rev Cardiovasc Ther 12:383-92
Rajamannan, Nalini M (2014) Embryonic cell origin defines functional role of Lrp5. Atherosclerosis 236:196-7
Sun, Ling; Rajamannan, Nalini M; Sucosky, Philippe (2013) Defining the role of fluid shear stress in the expression of early signaling markers for calcific aortic valve disease. PLoS One 8:e84433
Rajamannan, Nalini M (2013) The risk of infective endocarditis in the 21st century. Indian Heart J 65:452-3
Rajamannan, Nalini M (2013) Calcific Aortic Valve Disease: Osteoblast Differentiation in a Stem Cell Niche. J Clin Exp Cardiolog Suppl 11:9
Rajamannan, Nalini M (2012) Oxidative-mechanical stress signals stem cell niche mediated Lrp5 osteogenesis in eNOS(-/-) null mice. J Cell Biochem 113:1623-34
Boström, Kristina I; Rajamannan, Nalini M; Towler, Dwight A (2011) The regulation of valvular and vascular sclerosis by osteogenic morphogens. Circ Res 109:564-77
Shuvy, Mony; Nyska, Abraham; Beeri, Ronen et al. (2011) Histopathology and apoptosis in an animal model of reversible renal injury. Exp Toxicol Pathol 63:303-6
Rajamannan, Nalini M (2011) The role of Lrp5/6 in cardiac valve disease: experimental hypercholesterolemia in the ApoE-/- /Lrp5-/- mice. J Cell Biochem 112:2987-91

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