Westernized societies are experiencing an epidemic of type II diabetes (T2DM), related to life-style, obesity, and longevity. T2DM is a systemic vascular disorder;wide-spread low grade arterial inflammation, elevated TNF-alpha levels, &oxidative stresses disrupt macrovascular (e.g., heart, aorta) µvascular (e.g. retina, renal glomerulus) functions. A highly characteristic feature of T2DM is medial artery calcification (MAC). The negative consequences of reduced aortofemoral compliance of MAC have emerged;MAC perturbs normal Windkessel physiology, causing systolic &diastolic dysfunction that increases mortality &utation risk. The ability to prevent or treat MAC represents an unmet clinical need. A better understanding of how diabetes and kidney disease (CKD) promote MAC will provide insights useful for devising new strategies to reduce vascular calcium load, preserve aortic compliance, &improve vascular function. Recent data have identified activated aortic BMP2-Msx2-Wnt signaling in diabetic MAC--all inhibited by infliximab. The chief goal of this project is to assess how targeting these signals can improve aortic calcification, structure, &compliance.
Aim 1 : "To test whether inhibition of arterial BMP2- Wnt induction with theTNF-alpha antagonist infliximab or salicylate improves aortic compliance in diabetic vascular disease." By assessing aortic pressure- diameter relationships using ex vivo video plethysmography, we will establish the relationships between TNF-alpha &aortic calcium accumulation, Wnt signaling, and stiffness in a relevant T2DM model--the TOPGAL+;LDLR-/- mouse fed diabetogenic high fat diets (HFD). Comparison will be made with responses to the RANKL inhibitor, OPG.
Aim 2 : "To characterize the mechanisms whereby TNF- alpha signaling via NADPH oxidase promotes Msx2 gene transcription in aortic adventitial myofibroblasts." The NAPDH oxidase inhibitor, apocynin, inhibits Msx2 induction by TNF-alpha (transcriptionally mediated). By identifying the signaling cascades conveying Msx2 induction in response to TNF-alpha, novel strategies can be devised to inhibit vascular calcification.
Aim 3 : "To identify if NADPH oxidase signaling is required for induction of aortic BMP2-Msx-2-Wnt cascades in T2DM, using p47phox- /-;TOPGAL+;LDLR-/- mice as a model." By phenotyping p47phox-/-;TOPGAL+;LDLR-/- and p47phox+/-;TOPGAL+;LDLR-/- controls, we assess whether this TNF- regulated redox pathway contributes to aortic BMP2-Msx2-Wnt activation by HFD. Project Lay Narrative: Arterial hardening in diabetes &kidney disease increases the risk for heart attacks &foot amputation. This occurs in part via metabolic &inflammatory signals that induce bone- like calcification in large arteries. We test whether inhibiting these signals reduces arterial hardening.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088651-05
Application #
8217261
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Gao, Yunling
Project Start
2008-04-15
Project End
2013-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$376,200
Indirect Cost
$128,700
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Towler, Dwight A (2013) Molecular and cellular aspects of calcific aortic valve disease. Circ Res 113:198-208
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
Thompson, Bithika; Towler, Dwight A (2012) Arterial calcification and bone physiology: role of the bone-vascular axis. Nat Rev Endocrinol 8:529-43
Towler, Dwight A; Demer, Linda L (2011) Thematic series on the pathobiology of vascular calcification: an introduction. Circ Res 108:1378-80
Rajamannan, Nalini M; Evans, Frank J; Aikawa, Elena et al. (2011) Calcific aortic valve disease: not simply a degenerative process: A review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: Calcific aortic valve disease-2011 update. Circulation 124:1783-91
Bostrom, Kristina I; Rajamannan, Nalini M; Towler, Dwight A (2011) The regulation of valvular and vascular sclerosis by osteogenic morphogens. Circ Res 109:564-77
Shao, Jian-Su; Sierra, Oscar L; Cohen, Richard et al. (2011) Vascular calcification and aortic fibrosis: a bifunctional role for osteopontin in diabetic arteriosclerosis. Arterioscler Thromb Vasc Biol 31:1821-33
Towler, Dwight A (2011) Skeletal anabolism, PTH, and the bone-vascular axis. J Bone Miner Res 26:2579-82
Towler, Dwight A (2011) Vascular calcification: it's all the RAGE! Arterioscler Thromb Vasc Biol 31:237-9
Riek, Amy E; Towler, Dwight A (2011) The pharmacological management of osteoporosis. Mo Med 108:118-23

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