SOCS-1 and endothelial dysfunction in graft arteriosclerosis

Yale University, New Haven CT

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Abstract

Graft arteriosclerosis (GA), defined as progressive loss of lumen in allograft conduit arteries, is the major[unreadable] cause of chronic cardiac allograft failure. Several recent lines of evidence have implicated the cytokine IFN-y[unreadable] as a pro-arteriosclerotic factor and that a key functional effect of IFN-Y on endothelial cells (EC) is an early[unreadable] impairment of EC-dependent relaxation which occurs prior to and is causally linked to smooth muscle cell[unreadable] (SMC) accumulation. Specifically, my colleagues have reported IFN-y-dependent reduction in the[unreadable] function/expression of endothelial nitric oxide synthase (eNOS) in graft EC. Interestingly, IFN-y by itself does[unreadable] not affect eNOS. It acts in concert with INF, another proinflammatoy cytokine, to reduce eNOS expression[unreadable] and NO release by EC. However, the mechanism by which IFN-Y and TNF synergistically reduce NO[unreadable] production by EC is not known, and is the subject of this project. Our data suggest that SOCS1, a member of[unreadable] suppressor of cytokine signaling proteins, is a critical mediator in IFN-y and TNF-induced EC dysfunction.[unreadable] We propose the following hypotheses: 1). In resting (and IFN-y-exposed) EC, SOCS1 binds to inactive[unreadable] (tyrosine phosphorylated) ASK1 leading to mutual degradation of both SOCS1 and ASK1. 2). In response to[unreadable] TNF, ASK1 is dissociated from SOCS1 leading to activation of ASK1-JNK signaling which in turn[unreadable] phosphorylates and activates SOCS1. 3). Activated SOCS1 and ASK1-JNK independently and[unreadable] synergistically inhibit growth factors (e.g. VEGF and IGF-1 )-mediated NO release leading to EC dysfunction[unreadable] and GA progression. We propose the following specific aims to test our hypothesis: 1) Determine the[unreadable] mechanism(s) by which SOCS1 induces ASK1 degradation in EC and how IFN-y and TNF modify this[unreadable] response. 2) Determine the mechanism(s) by which SOCS1 impairs NO function. 3) Determine the role of[unreadable] SOCS1 in EC function in allograft and xenograft models. These studies should facilitate the development of[unreadable] new therapeutic approaches to control GA and graft failure as well as other vascular diseases such as[unreadable] atherosclerosis.