STRESS SIGNALING PATHWAYS LINKING ENDOTHELIAL INJURY TO GRAFT ARTERIOSCLEROSIS Abstract: The overall hypothesis of this application is that graft arteriosclerosis (GA), the major cause of late cardiac allograft failure, results from a chronic host 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-? 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. We have identified SENP1 is a critical mediator of peri-operative stresses. We hypothesize that SENP1 mediates the responses to non-immune peri-operative injuries of graft ECs, increasing T cell-mediated alloimmunity and GA. We propose to explore this hypothesis in the following specific aims: 1) Characterize SENP1-enhanced cytosolic NOX2 activity that mediates peri-operative stress- induced EC immunogenicity and GA progression. We will elucidate the mechanisms by which SENP1 activates NOX2-dependent ROS generation in ECs, define the role of SENP1-NOX2 axis in peri-operative stress-exacerbated GA progression in vivo using EC-specific SENP1 knockout mice and NOX2-deficient as graft donors, and determine how SENP1 couples NOX2 deSUMOylation to EC phenotypic changes. 2) Characterize SENP1-mediated deSUMOylation and disruption of mitochondrial Trx2 activity that augments peri-operative stress-induced EC immunogenicity and GA progression. We will elucidate the mechanisms by which SENP1 attenuates Trx2-dependent mitochondrial function in EC, define the role of mitochondrial SENP1-Trx2 axis in peri-operative stress-exacerbated GA progression in vivo using EC-specific Trx2- transgenic mice expressing WT, SUMO-defective KR mutant and Trx2-SUMO fusion forms as graft donors, and determine how SENP1 couples Trx2 deSUMOylation, mitochondrial dysfunction and ROS production to EC phenotypic changes that modulate T cell responses. 3) Characterize SENP1-ROS-ASK1 signaling pathway that mediates peri-operative stress-induced EC immunogenicity and GA progression. We will determine if cytosolic SENP1-NOX2 and mitochondrial SENP1-Trx2 converge on ASK1 in regulating EC function and GA progression, determine how SENP1-NOX2 and SENP1-Trx2 couple ASK1 to EC phenotypic changes that modulate T cell responses, and test if pharmacological inhibitors of SENP1, NOX2, TRX2 and SENP1 could prevent/ameliorate GA. If successful, this study will provide therapeutic strategies by modulating these two molecules in ECs to reduce GA incidence or delay GA progression.
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 how a post- translational modifying enzyme SENP1 (SUMO endopeptidase-1) which modifies several critical intracellular proteins that mediate 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.
|He, Li; Pierce, Richard W; Min, Wang (2018) Rare and Low-Frequency Variant of ARHGEF17 Is Associated With Intracranial Aneurysms. Circ Genom Precis Med 11:e002248|
|Zhang, Jiqin; Chen, Chaofei; Li, Li et al. (2018) Endothelial AIP1 Regulates Vascular Remodeling by Suppressing NADPH Oxidase-2. Front Physiol 9:396|
|Long, Lingli; Yin, Mingzhu; Min, Wang (2018) 3D Co-culture System of Tumor-associated Macrophages and Ovarian Cancer Cells. Bio Protoc 8:|
|Zhou, Huanjiao Jenny; Xu, Zhe; Wang, Zongren et al. (2018) SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis. Nat Commun 9:3303|
|Liu, Tingting; Zhou, Huanjiao Jenny; Min, Wang (2017) ASK family in cardiovascular biology and medicine. Adv Biol Regul 66:54-62|
|Tan, Shu; Feng, Boya; Yin, Mingzhu et al. (2017) Stromal Senp1 promotes mouse early folliculogenesis by regulating BMP4 expression. Cell Biosci 7:36|
|Yin, Mingzhu; Zhou, Huanjiao Jenny; Zhang, Jiqin et al. (2017) ASK1-dependent endothelial cell activation is critical in ovarian cancer growth and metastasis. JCI Insight 2:|
|Zhu, Xiaolong; Ding, Sha; Qiu, Cong et al. (2017) SUMOylation Negatively Regulates Angiogenesis by Targeting Endothelial NOTCH Signaling. Circ Res 121:636-649|
|Chen, Chaofei; Li, Li; Zhou, Huanjiao Jenny et al. (2017) The Role of NOX4 and TRX2 in Angiogenesis and Their Potential Cross-Talk. Antioxidants (Basel) 6:|
|Qiu, Cong; Wang, Yuewen; Zhao, Haige et al. (2017) The critical role of SENP1-mediated GATA2 deSUMOylation in promoting endothelial activation in graft arteriosclerosis. Nat Commun 8:15426|
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