The central theme of Project 3 is to investigate the biochemical, genetic, cell biological and integrated physiological basis of the predisposition to atherosclerotic cardiovascular disease in patients with type 2 diabetes. Within this larger context. Project 3 sets out to determine mechanisms of impaired insulin signaling in vascular endothelial cells-with a focus on the contribution of FoxO transcription factors to this process. We hypothesize that insulin signaling through isoforms of transcription factor FoxO plays an important role in endothelial cell function and that its alteration promotes endothelial dysfunction. To address this hypothesis, in AIM 1 we propose to characterize the susceptibility to atherosclerosis in mice with loss-of-function mutations of the three Foxo in endothelial cells. Preliminary data in triple Foxo knockout mice show a striking atheroprotective effect of FoxO ablation, associated with increased nitric oxide synthesis, reduced ROS generation, and reduced monocyte recruitment. We propose to characterize the mechanism of atherosclerosis protection and the vascular function phenotype in endothelial cell-specific triple Foxo knockouts. To understand how insulin resistance and hyperglycemia contribute to alter endothelial cell function, in AIM 2 we will generate two different FoxOI gain-of-function mutants in endothelial cells of transgenic mice. Insulin resistance results in FoxOI nuclear retention. We have shown in the past cycle that FoxOI nuclear retention is associated with increased ROS generation and monocyte recruitment. We will test the physiologic impact of these in vitro observations by developing models of FoxOI gain-of-function that mimic the effects of insulin resistance and hyperglycemia, respectively, on endothelial function. We envision that the following innovations will arise from this work: (i) Establishing FoxO proteins as the linchpin of cell biological processes that predispose to endothelial dysfunction in atherosclerosis, including inflammation, cell survival, NO generation, ROS production, and cell adhesion, (ii) Identifying effector genes and mechanisms of endothelial dysfunction in insulin resistance through the functional analysis of the triple Foxo knockout and Foxo gain-of-function models in vascular endothelial cells, (iii) Identification of a novel regulatory Foxo-Akt feed-forward loop, whereby Foxo function controls insulin sensitivity in endothelial cells, (iv) Development and analysis of mouse models to understand the effects of hyperglycemia on vascular function. Given the central role of endothelial dysfunction in diabetic atherosclerosis, the dearth of suitable reductionist experimental models, and the fact that atherosclerosis treatment must occur in the context of hyperglycemia, analyses of the targeted mouse mutants described in Aim 2 will provide unique mechanistic and treatment insight into the identification of biochemical and cell biological pathways that regulate the important interaction between hyperglycemia and endothelial dysfunction.

Public Health Relevance

The proposed studies will reveal new dimensions to the interaction between disordered insulin action, vascular cell biology and atherosclerosis, and expand the repertoire of currently available targets for atherosclerosis therapy in type 2 diabetes. Building on lessons of the past funding cycle, we will explore new mechanisms of vascular disease with the potential to provide actionable targets for therapy. The driving theme is to define pathways that can be enlisted in the clinic against atherosclerosis and insulin resistance.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL087123-06A1
Application #
8460254
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
6
Fiscal Year
2013
Total Cost
$540,059
Indirect Cost
$202,522
Name
Columbia University (N.Y.)
Department
Type
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Nagareddy, Prabhakara R; Kraakman, Michael; Masters, Seth L et al. (2014) Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab 19:821-35
Ozcan, Lale; Tabas, Ira (2014) CaMKII in cardiometabolic disease. Aging (Albany NY) 6:430-1
Fredman, Gabrielle; Ozcan, Lale; Tabas, Ira (2014) Common therapeutic targets in cardiometabolic disease. Sci Transl Med 6:239ps5
Ai, Ding; Jiang, Hongfeng; Westerterp, Marit et al. (2014) Disruption of mammalian target of rapamycin complex 1 in macrophages decreases chemokine gene expression and atherosclerosis. Circ Res 114:1576-84
Libby, Peter; Tabas, Ira; Fredman, Gabrielle et al. (2014) Inflammation and its resolution as determinants of acute coronary syndromes. Circ Res 114:1867-79
Richards, M Rachel; Black, Audrey S; Bonnet, David J et al. (2013) The LPS2 mutation in TRIF is atheroprotective in hyperlipidemic low density lipoprotein receptor knockout mice. Innate Immun 19:20-9
Ozcan, Lale; Cristina de Souza, Jane; Harari, Alp Avi et al. (2013) Activation of calcium/calmodulin-dependent protein kinase II in obesity mediates suppression of hepatic insulin signaling. Cell Metab 18:803-15
Nagareddy, Prabhakara R; Murphy, Andrew J; Stirzaker, Roslynn A et al. (2013) Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab 17:695-708
Murphy, Andrew J; Funt, Samuel; Gorman, Darren et al. (2013) Pegylation of high-density lipoprotein decreases plasma clearance and enhances antiatherogenic activity. Circ Res 113:e1-9
Tsuchiya, Kyoichiro; Accili, Domenico (2013) Liver sinusoidal endothelial cells link hyperinsulinemia to hepatic insulin resistance. Diabetes 62:1478-89

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