Inflammation contributes to development of atherosclerosis. Atherosclerosis is decreased in regions of steady flow associated with high shear stress (termed s-flow), compared to regions of disturbed and low flow (termed d-flow). This finding has yielded the concept that s-flow is atheroprotective and d-flow is atheropromoting, in part by causing endothelial cell (EC) dysfunction. Previously we showed that s-flow activated thioredoxin-1 (Trx1) in EC, decreased expression of the Trx1 interacting protein (Txnip), and inhibited tumor necrosis factor (TNF) signaling. Several findings indicate that Txnip-dependent signaling represents a unique atheropromoting mechanism. 1) Txnip expression is increased by d-flow and promotes the adhesive phenotype of EC, by stimulating VCAM-1 expression. 2) Txnip specifically inhibits Trx1 function and contributes to oxidative stress in EC. 3) Txnip is required for TNF- alpha mediated JNK and caspase-3 activation in EC. 4) Exciting preliminary data show that TNF causes Trx1 and Txnip to translocate to the plasma membrane and stimulate a tyrosine kinase receptor (TKR) signaling pathway that inhibits apoptosis via Akt activation (Fig. 1). Recently, SHP2, a protein tyrosine phosphatase (PTPase), was shown to stimulate the Apoptosis Signal-regulated Kinase (ASK1)-JNK-VCAM1 pathway. 5) Our data show that Txnip binding to SHP2 also activates this pathway (Fig. 1). Thus our major hypothesis is Txnip, like NF-kB, stimulates both pro-survival and pro-inflammatory pathways in EC. In the proposed aims we will identify mechanisms to separate the Txnip-Trx1-TKR-Akt survival pathway from the Txnip-SHP2-ASK1 inflammation pathway.
Aim 1 : Show that Trx-Txnip stimulates TKR activation and survival by assembling signal complexes and inhibiting PTPases.
Aim 2 : Show that Txnip regulates SHP2 activity and subcellular location modulating ASK1 activity.
Aim 3 : Show that d-flow alters Txnip expression and location inhibiting Trx1 activity and activating ASK1.
Aim 4 : Show that EC-specific Txnip knockout mice exhibit improved EC function and decreased atherosclerosis. These studies should provide insight into mechanisms by which flow inhibits inflammation and facilitate development of therapeutic approaches to limit atherosclerosis.
Strokes and heart attacks are the leading cause of death in the US. Interventions such as bypass surgery and angioplasty treat acute events, but there are limited therapies to prevent the underlying disease termed atherosclerosis. We have found that thioredoxin interacting protein is increased in blood vessels at sites where atherosclerosis develops. Here we will focus on novel approaches to inhibit the function of this protein. Elucidating the specific pathways by which thioredoxin interacting protein modulates vessel function will provide the basis to develop new therapies to prevent atherosclerosis.
|Abe, Jun-ichi; Berk, Bradford C (2014) Novel mechanisms of endothelial mechanotransduction. Arterioscler Thromb Vasc Biol 34:2378-86|
|Spindel, Oded N; Burke, Ryan M; Yan, Chen et al. (2014) Thioredoxin-interacting protein is a biomechanical regulator of Src activity: key role in endothelial cell stress fiber formation. Circ Res 114:1125-32|
|Abe, Jun-ichi; Berk, Bradford C (2013) Atheroprone flow activation of the sterol regulatory element binding protein 2 and nod-like receptor protein 3 inflammasome mediates focal atherosclerosis. Circulation 128:579-82|
|Park, Shin-Young; Shi, Xi; Pang, Jinjiang et al. (2013) Thioredoxin-interacting protein mediates sustained VEGFR2 signaling in endothelial cells required for angiogenesis. Arterioscler Thromb Vasc Biol 33:737-43|
|Spindel, Oded N; Berk, Bradford C (2012) Redox redux: protecting the ischemic myocardium. J Clin Invest 122:30-2|
|Spindel, Oded N; Yan, Chen; Berk, Bradford C (2012) Thioredoxin-interacting protein mediates nuclear-to-plasma membrane communication: role in vascular endothelial growth factor 2 signaling. Arterioscler Thromb Vasc Biol 32:1264-70|
|Spindel, Oded N; World, Cameron; Berk, Bradford C (2012) Thioredoxin interacting protein: redox dependent and independent regulatory mechanisms. Antioxid Redox Signal 16:587-96|
|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|
|World, Cameron; Spindel, Oded N; Berk, Bradford C (2011) Thioredoxin-interacting protein mediates TRX1 translocation to the plasma membrane in response to tumor necrosis factor-*: a key mechanism for vascular endothelial growth factor receptor-2 transactivation by reactive oxygen species. Arterioscler Thromb Vasc Biol 31:1890-7|