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.
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.
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|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|
|Towler, Dwight A (2015) Arteriosclerotic Calcification: A Serpi(n)ginous Path to Cardiovascular Health? Circ Res 117:744-6|
|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|
|Towler, Dwight A (2014) The platelet: sensing shear and the endocrine regulation of cardiovascular sclerosis. Arterioscler Thromb Vasc Biol 34:1803-5|
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|Cheng, Su-Li; Shao, Jian-Su; Behrmann, Abraham et al. (2013) Dkk1 and MSX2-Wnt7b signaling reciprocally regulate the endothelial-mesenchymal transition in aortic endothelial cells. Arterioscler Thromb Vasc Biol 33:1679-89|
|Towler, Dwight A (2013) Mitochondrial ROS deficiency and diabetic complications: AMP[K]-lifying the adaptation to hyperglycemia. J Clin Invest 123:4573-6|
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