Soluble ST2 is regulated by p75 neurotrophin receptor and predicts mortality in diabetic patients with critical limb ischemia

Caporali, A. et al. (2012) Soluble ST2 is regulated by p75 neurotrophin receptor and predicts mortality in diabetic patients with critical limb ischemia. Arteriosclerosis, Thrombosis, and Vascular Biology, 32(12), e149-e160. (doi: 10.1161/ATVBAHA.112.300497) (PMID:23065828) (PMCID:PMC3616363)

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Abstract

<b>Objective—</b><p></p> The p75 neurotrophin receptor (p75<sup>NTR</sup>) contributes to diabetes mellitus−induced defective postischemic neovascularization. The interleukin-33 receptor ST2 is expressed as transmembrane (ST2L) and soluble (sST2) isoforms. Here, we studied the following: (1) the impact of p75<sup>NTR</sup> in the healing of ischemic and diabetic calf wounds; (2) the link between p75<sup>NTR</sup> and ST2; and (3) circulating sST2 levels in critical limb ischemia (CLI) patients. <p></p> <b>Methods and Results—</b><p></p> Diabetes mellitus was induced in p75<sup>NTR</sup> knockout (p75KO) mice and wild-type (WT) littermates by streptozotocin. Diabetic and nondiabetic p75KO and WT mice received left limb ischemia induction and a full-thickness wound on the ipsilateral calf. Diabetes mellitus impaired wound closure and angiogenesis and increased ST2 expression in WT, but not in p75KO wounds. In cultured endothelial cells, p75<sup>NTR</sup> promoted ST2 (both isoforms) expression through p38<sup>MAPK</sup>/activating transcription factor 2 pathway activation. Next, sST2 was measured in the serum of patients with CLI undergoing either revascularization or limb amputation and in the 2 nondiabetic groups (with CLI or nonischemic individuals). Serum sST2 increased in diabetic patients with CLI and was directly associated with higher mortality at 1 year from revascularization. <p></p> <b>Conclusion—</b><p></p> p75<sup>NTR</sup> inhibits the healing of ischemic lower limb wounds in diabetes mellitus and promotes ST2 expression. Circulating sST2 predicts mortality in diabetic CLI patients. <p></p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Miller, Dr Ashley and Meloni, Dr Marco
Authors: Caporali, A., Meloni, M., Miller, A. M., Vierlinger, K., Cardinali, A. C., Spinetti, G., Nailor, A., Faglia, E., Losa, S., Gotti, A., Fortunato, O., Mitić, T., Hofner, M., Noehammer, C., Madeddu, P., and Emanueli, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher:American Heart Association
ISSN:1079-5642
ISSN (Online):1524-4636
Published Online:11 October 2012

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