There is evidence that inflammation contributes at each stage in the development of clinically significant Atherosclerosis. Importantly, patients with elevated levels of circulating inflammatory markers such as C-reactive protein and ICAM-1 are at increased risk of cardiovascular events. This is especially true for the growing numbers of Type 2 diabetics and patients with the metabolic syndrome. The major hypothesis of this PPG proposal is that specific pro-inflammatory events in endothelial cells and vascular smooth muscle cells modulate the severity of atherosclerosis. Our approach is to identify and characterize signal transduction mechanisms that promote vascular inflammation. We are using combined analyses of regulation by transcription, post-transcriptional, and post-translational modifications. The candidate signal pathways include flow-mediated regulation of thioredoxin, PPAR-gamma, MCP-1, and cyclic nucleotide phosphodiesterases. Our goals are to prove that these candidate mechanisms modulate the development and progression of atherosclerosis in the LDL receptor deficient mouse. We believe that the PPG mechanism will facilitate these goals by fostering a vibrant and highly focused environment that will advance our understanding of signal transduction mechanisms in blood vessels. In addition, by creating histopathology and imaging cores the expertise necessary for the analysis of transgenic and knockout mouse models will be readily available. We anticipate that the interactions among investigators in the present proposal will provide new insights into the pathogenic roles of inflammation in atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL077789-03
Application #
7270475
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Srinivas, Pothur R
Project Start
2005-08-01
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
3
Fiscal Year
2007
Total Cost
$1,965,413
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Heo, Kyung-Sun; Le, Nhat-Tu; Cushman, Hannah J et al. (2015) Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function. J Clin Invest 125:1299-310
Heo, Kyung-Sun; Fujiwara, Keigi; Abe, Jun-ichi (2014) Shear stress and atherosclerosis. Mol Cells 37:435-40
Le, Nhat-Tu; Heo, Kyung-Sun; Takei, Yuichiro et al. (2013) A crucial role for p90RSK-mediated reduction of ERK5 transcriptional activity in endothelial dysfunction and atherosclerosis. Circulation 127:486-99
Heo, Kyung-Sun; Chang, Eugene; Takei, Yuichiro et al. (2013) Phosphorylation of protein inhibitor of activated STAT1 (PIAS1) by MAPK-activated protein kinase-2 inhibits endothelial inflammation via increasing both PIAS1 transrepression and SUMO E3 ligase activity. Arterioscler Thromb Vasc Biol 33:321-9
Knight, W E; Yan, C (2012) Cardiac cyclic nucleotide phosphodiesterases: function, regulation, and therapeutic prospects. Horm Metab Res 44:766-75
Wang, Xiao-Qun; Nigro, Patrizia; World, Cameron et al. (2012) Thioredoxin interacting protein promotes endothelial cell inflammation in response to disturbed flow by increasing leukocyte adhesion and repressing Kruppel-like factor 2. Circ Res 110:560-8
Dhawan, Latika; Liu, Bin; Pytlak, Allison et al. (2012) Y-box binding protein 1 and RNase UK114 mediate monocyte chemoattractant protein 1 mRNA stability in vascular smooth muscle cells. Mol Cell Biol 32:3768-75
Lim, Jae Hyang; Jono, Hirofumi; Komatsu, Kensei et al. (2012) CYLD negatively regulates transforming growth factor-?-signalling via deubiquitinating Akt. Nat Commun 3:771
Cai, Yujun; Knight, Walter E; Guo, Shujie et al. (2012) Vinpocetine suppresses pathological vascular remodeling by inhibiting vascular smooth muscle cell proliferation and migration. J Pharmacol Exp Ther 343:479-88
Le, Nhat-Tu; Takei, Yuichiro; Shishido, Tetsuro et al. (2012) p90RSK targets the ERK5-CHIP ubiquitin E3 ligase activity in diabetic hearts and promotes cardiac apoptosis and dysfunction. Circ Res 110:536-50

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