The overall hypothesis of this application is that graft arteriosclerosis (GA), the major cause of late cardiac allograft failure, results from a chronic hot T cell response to allogeneic graft endothelial cells (ECs) that takes the form of delayed-type hypersensitivity DTH within the vessel wall, locally generating IFN-g which is responsible for driving vascular smooth muscle cell (VSMC) proliferation and intimal hyperplasia. The clinical correlations and evidence from other experimental systems have suggested that non-immune factors, especially peri-operative stress-induced alterations in the graft, are important contributors to GA pathogenesis. It is proposed and demonstrated experimentally that signals in the graft, primarily from ECs, generated as a result of peri-operative stress can produce mediators that influence T cell activation and differentiation. However, how the peri-operative stresses such as hypoxia couple intracellular signaling pathway to alter ECs alloimmunity and GA is not understood, and is the subject of this project. We have identified two major intracellular signaling proteins- cytosolic ASK1-interacting protein-1 (AIP1) and mitochondrial thioredoxin-2 (Trx2) in ECs that protect ECs from oxidative stress-induced injuries. Specifically, AIP1 in the cytoplasm via its inhibitory effect on the NADPH oxidase (Nox) while Trx2 in mitochondria via its anti-oxidant activity, prevent ischemia-reperfusion-elicited ROS and oxidative stress-induced inflammatory responses. In this proposal, we hypothesize that the responses to non-immune peri-operative injuries of graft endothelial cells (EC) are modulated by Trx2 in the mitochondria and AIP1 in the cytosol, altering the EC in a manner that affects T cell- mediated alloimmunity and GA. We propose to explore this hypothesis in the following specific aims: 1) Characterize AIP1-regulated cytosolic signaling pathways that mediate peri-operative stress-induced responses that alter EC immunogenicity and GA progression. 2) Characterize Trx2-regulated mitochondrial signaling pathways that mediate peri-operative stress-induced responses that alter EC immunogenicity and GA progression. If successful, this study will provide therapeutic strategies by modulating these two molecules in ECs to reduce GA incidence or delay GA progression.

Public Health Relevance

Heart transplantation can saves lives of patients with severe heart failure but its success is limited by a form of late rejection, called graft arteriosclerosis (GA), that involves progressive narrowing of the blood vessels supplying the graft and is worthend by peroperative stresses. This application focuses on two critical molecules AIP1 and Trx2 that suppresses the peroperative stresses. If successful, this study will provide therapeutic strategies by modulating these two molecules in grafts to reduce GA incidence or delay GA progression.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL109420-01A1
Application #
8292774
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Hasan, Ahmed AK
Project Start
2012-04-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$414,688
Indirect Cost
$164,688
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Chen, Xiaodong; Zhou, Huanjiao Jenny; Huang, Qunhua et al. (2014) Novel action and mechanism of auranofin in inhibition of vascular endothelial growth factor receptor-3-dependent lymphangiogenesis. Anticancer Agents Med Chem 14:946-54
Ji, Weidong; Yang, Mei; Praggastis, Alexandra et al. (2014) Carbamoylating activity associated with the activation of the antitumor agent laromustine inhibits angiogenesis by inducing ASK1-dependent endothelial cell death. PLoS One 9:e103224
Qin, Lingfeng; Huang, Qunhua; Zhang, Haifeng et al. (2014) SOCS1 prevents graft arteriosclerosis by preserving endothelial cell function. J Am Coll Cardiol 63:21-9
Zhou, Huanjiao Jenny; Chen, Xiaodong; Huang, Qunhua et al. (2014) AIP1 mediates vascular endothelial cell growth factor receptor-3-dependent angiogenic and lymphangiogenic responses. Arterioscler Thromb Vasc Biol 34:603-15
Wan, Ting; Xu, Zhe; Zhou, Huanjiao Jenny et al. (2013) Functional analyses of TNFR2 in physiological and pathological retina angiogenesis. Invest Ophthalmol Vis Sci 54:211-21
Zhang, Yong; Tang, Wenwen; Zhang, Haifeng et al. (2013) A network of interactions enables CCM3 and STK24 to coordinate UNC13D-driven vesicle exocytosis in neutrophils. Dev Cell 27:215-26
Qin, Lingfeng; Yu, Luyang; Min, Wang (2013) Mouse models for graft arteriosclerosis. J Vis Exp :e50290
Huang, Qunhua; Qin, Lingfeng; Dai, Shengchuan et al. (2013) AIP1 suppresses atherosclerosis by limiting hyperlipidemia-induced inflammation and vascular endothelial dysfunction. Arterioscler Thromb Vasc Biol 33:795-804