The alpha arrestin family includes the best studied member, Txnip, and five other proteins with unknown functions. Txnip was originally considered a regulator of vascular redox state. Because Txnip is induced by hyperglycemia, and Txnip can inhibit thioredoxin, many investigators have proposed that hyperglycemia Induces oxidative stress through Txnip-mediated inhibition of thioredoxin. However, compelling evidence has now emerged that Txnip is a critical regulator of diverse signaling events relevant to vascular disease. Because Txnip can form a mixed disulfide complex with reduced thioredoxin (but not oxidized thioredoxin),Txnip may function as a redox-sensitive signaling regulator rather than simply as an inhibitor of thioredoxin. Our preliminary data show that Txnip is an important mediator of glucose and lipid metabolism, insulin sensitivity, adipogenesis, and energy balance. Here we present data supporting the central hypothesis that Txnip is a critical intracellular signaling regulator, and that Txnip's functions are unlikely to be solely due to inhibition of thioredoxin. We propose three Alms that will define the role of Txnip in endothelial cells:
AIM 1. To define the role of the interaction of Txnip and thioredoxin in the inflammatory response of endothelial cells. Here we will test the hypothesis that the role of Txnip In the regulation of the vascular inflammatory response is dependent on the specific molecular interaction with thioredoxin through an Intermolecular disulfide bond.
AIM 2. To define structure-function relations of Txnip. We present preliminary data that specific domains of Txnip regulate glucose metabolism;using the known structure of beta arrestins, we will define specific regions of Txnip as well as other alpha arrestins that regulate glucose metabolism and the endothelial shear stress response.
AIM 3 :To test the hypothesis that Txnip regulates metabolism in vivo via a PPAR-gamma dependent mechanism in endothelial cells. We will determine whether Txnip's ihipact on PPAR-gamma function is dependent on thioredoxin and test the hypothesis that Txnip causally influences PPAR-gamma function in vivo. Finally, we will explore in vivo the concept that Txnip impacts PPAR-gamma function to mediate whole body metabolic regulation through endothelial cell expression.
Many cardiovascular diseases are characterized by vascular inflammation and by damage to the endothelial cells that line blood vessels, arising from the oxidation of critical proteins in these cells. This research project studies a protein called Txnip, which regulates protein oxidation in vascular cells and other tissues. Txnip is involved In the metabolism of glucose and undergoes regulation by pathways that are altered in diabetes.
|Steinhorn, Benjamin; Sorrentino, Andrea; Badole, Sachin et al. (2018) Chemogenetic generation of hydrogen peroxide in the heart induces severe cardiac dysfunction. Nat Commun 9:4044|
|Brown, Jonathan D; Feldman, Zachary B; Doherty, Sean P et al. (2018) BET bromodomain proteins regulate enhancer function during adipogenesis. Proc Natl Acad Sci U S A 115:2144-2149|
|Samokhin, Andriy O; Stephens, Thomas; Wertheim, Bradley M et al. (2018) NEDD9 targets COL3A1 to promote endothelial fibrosis and pulmonary arterial hypertension. Sci Transl Med 10:|
|Pang, Paul; Abbott, Molly; Abdi, Malyun et al. (2018) Pre-clinical model of severe glutathione peroxidase-3 deficiency and chronic kidney disease results in coronary artery thrombosis and depressed left ventricular function. Nephrol Dial Transplant 33:923-934|
|Steinhorn, Benjamin; Sartoretto, Juliano L; Sorrentino, Andrea et al. (2017) Insulin-dependent metabolic and inotropic responses in the heart are modulated by hydrogen peroxide from NADPH-oxidase isoforms NOX2 and NOX4. Free Radic Biol Med 113:16-25|
|Handy, Diane E; Loscalzo, Joseph (2017) Responses to reductive stress in the cardiovascular system. Free Radic Biol Med 109:114-124|
|Ghiassian, Susan Dina; Menche, Jörg; Chasman, Daniel I et al. (2016) Endophenotype Network Models: Common Core of Complex Diseases. Sci Rep 6:27414|
|Maron, Bradley A; Stephens, Thomas E; Farrell, Laurie A et al. (2016) Elevated pulmonary arterial and systemic plasma aldosterone levels associate with impaired cardiac reserve capacity during exercise in left ventricular systolic heart failure patients: A pilot study. J Heart Lung Transplant 35:342-351|
|Bertero, Thomas; Oldham, William M; Cottrill, Katherine A et al. (2016) Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. J Clin Invest 126:3313-35|
|Wang, Rui-Sheng; Loscalzo, Joseph (2016) Illuminating drug action by network integration of disease genes: a case study of myocardial infarction. Mol Biosyst 12:1653-66|
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