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.

Public Health Relevance

Project Lay Narrative: Calcification of heart valves - particularly the aortic valve -- is relatively common, increased by aging, diabetes, and kidney failure. Valve calcification arises in part via metabolic &inflammatory signals that induce bone-like calcification in heart valves. We have identified a key protein, ?-catenin, that is activated with calcification and fibrosis of valves in diabetic mice. We discovered that the hormone PTH inhibits valve ss-catenin and vascular calcification while simultaneously increasing bone formation. We test if PTH signaling in heart valves and in bones is required for maintaining heart valve health, and determine whether treatment with PTH improves heart valve structure and function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL114806-01
Application #
8352879
Study Section
Special Emphasis Panel (ZHL1-CSR-N (M1))
Program Officer
Evans, Frank
Project Start
2012-08-23
Project End
2012-11-30
Budget Start
2012-08-23
Budget End
2012-11-30
Support Year
1
Fiscal Year
2012
Total Cost
$51,601
Indirect Cost
$17,653
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Ramachandran, Bindu; Stabley, John N; Cheng, Su-Li et al. (2018) A GTPase-activating protein-binding protein (G3BP1)/antiviral protein relay conveys arteriosclerotic Wnt signals in aortic smooth muscle cells. J Biol Chem 293:7942-7968
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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) Lipoprotein(a): A Taxi for Autotaxin Takes a Toll in Calcific Aortic Valve Disease. JACC Basic Transl Sci 2:241-243
Gay, Austin; Towler, Dwight A (2017) Wnt signaling in cardiovascular disease: opportunities and challenges. Curr Opin Lipidol 28:387-396
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
Towler, Dwight A (2017) Commonalities Between Vasculature and Bone: An Osseocentric View of Arteriosclerosis. Circulation 135:320-322
Zhao, Wei; Mazar, Joseph; Lee, Bongyong et al. (2016) The Long Noncoding RNA SPRIGHTLY Regulates Cell Proliferation in Primary Human Melanocytes. J Invest Dermatol 136:819-828
Towler, Dwight A (2016) AMPK?1: SUMO Wrestling Runx2 as a Strategy to Inhibit Arteriosclerotic Calcification. Circ Res 119:398-400
Towler, Dwight A (2015) Arteriosclerotic Calcification: A Serpi(n)ginous Path to Cardiovascular Health? Circ Res 117:744-6

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