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 |
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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 > School of Infection & Immunity |
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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