Calcific aortic stenosis (CAS) arises from arteriosclerotic processes and valve morphological variants that progressively impair valve function, ultimately increasing the risk for congestive heart failure, stroke, and sudden cardiac death. Therapeutic strategies focused solely on statin-based intervention have been ineffective in treating calcific aortic valve disease (CAVD). Type I diabetes (T2DM) and metabolic syndrome are major contributors to CAVD risk. Biochemically, osteochondrocytic gene expression programs are elaborated by the calcifying valves and vessels of diabetic patients, indicating that active osteogenic processes contribute to vascular calcium accrual. Our data indicate that parathyroid hormone (PTH) -- the prototypic bone anabolic hormone and master endocrine regulator of vertebrate calcium metabolism -- reciprocally regulates skeletal vs. vascular osteogenic processes, promoting the former but inhibiting the latter in a murine model of diet-induced T2DM afflicted with calcific vasculopathy and arterial fibrosis. A fundamental understanding of how PTH regulates aortic valve sclerosis will guide the development of new strategies to prevent and treat CAVD.
Specific Aims are:
Aim 1 : """"""""To establish the role of valve myofibroblast PTH/PTHrP receptor tone on the initiation and progression of aortic valve sclerosis, using diabetic SM22- Cre;PTH1R(fl/fl);LDLR-/- as a model for study."""""""" PTH and PTHrP both signal through the PTH/PTHrP receptor (PTH1R), a G-protein coupled receptor expressed in bone, vascular smooth muscle and valve myofibroblasts, kidney, and other tissues. We assess whether valve myofibroblast PTH1R signaling impacts valve calcification and fibrosis in LDLR-/- mice. We implement Cre-lox technology to remove PTH1R expression from aortic valve myofibroblasts, analyzing the SM22-Cre;PTH1R(fl/fl);LDLR-/- mice we've generated with our collaborator, Dr. Kronenberg.
Aim 2 : """"""""To examine the therapeutic potential of intermittent PTH(1-34) dosing as an endocrine strategy to limit calcific aortic stenosis in LDLR-/-;ApoB100/100 mice."""""""" We wil study the impact of PTH(1-34) pharmacotherapy on CAVD in this hemodynamically-significant murine model of CAS.
Aim 3 : """"""""To determine the contributions of skeletal osteoblast PTH1R in the initiation and progression of aortic valve and vascular sclerosis, using diabetic Osx- tTA,tetO-CreGFP;PTH1R(fl/fl);LDLR-/- mice."""""""" We hypothesize that circulating endocrine or cellular signals elicited by anabolic PTH actions in the skeleton may contribute to reductions in CAVD risk. We assess the role of skeletal PTH1R signaling in the emerging """"""""bone-vascular"""""""" endocrine axis by abrogating postnatal osteoblast PTH1R expression in LDLR-/- mice.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL114806-04
Application #
8697129
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Evans, Frank
Project Start
2012-08-23
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Stabley, John N; Towler, Dwight A (2017) Arterial Calcification in Diabetes Mellitus: Preclinical Models and Translational Implications. Arterioscler Thromb Vasc Biol 37:205-217
Towler, Dwight A (2017) ""Osteotropic"" Wnt/LRP Signals: High-Wire Artists in a Balancing Act Regulating Aortic Structure and Function. Arterioscler Thromb Vasc Biol 37:392-395
Gay, Austin; Towler, Dwight A (2017) Wnt signaling in cardiovascular disease: opportunities and challenges. Curr Opin Lipidol 28:387-396
Towler, Dwight A (2017) Commonalities Between Vasculature and Bone: An Osseocentric View of Arteriosclerosis. Circulation 135:320-322
Towler, Dwight A (2016) AMPK?1: SUMO Wrestling Runx2 as a Strategy to Inhibit Arteriosclerotic Calcification. Circ Res 119:398-400
Zhao, Wei; Mazar, Joseph; Lee, Bongyong et al. (2016) The Long Noncoding RNA SPRIGHTLY Regulates Cell Proliferation in Primary Human Melanocytes. J Invest Dermatol 136:819-28
Towler, Dwight A (2015) Arteriosclerotic Calcification: A Serpi(n)ginous Path to Cardiovascular Health? Circ Res 117:744-6
Towler, Dwight A (2015) Arteriosclerosis, bone biology, and calciotropic hormone signaling: learning the ABCs of disease in the bone-vascular axis. J Am Soc Nephrol 26:243-5
Cheng, Su-Li; Ramachandran, Bindu; Behrmann, Abraham et al. (2015) Vascular smooth muscle LRP6 limits arteriosclerotic calcification in diabetic LDLR-/- mice by restraining noncanonical Wnt signals. Circ Res 117:142-56
Cheng, Su-Li; Behrmann, Abraham; Shao, Jian-Su et al. (2014) Targeted reduction of vascular Msx1 and Msx2 mitigates arteriosclerotic calcification and aortic stiffness in LDLR-deficient mice fed diabetogenic diets. Diabetes 63:4326-37

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