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.
|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|
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|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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