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

Andrea Caporali, Marco Meloni, Ashley M. Miller, Klemens Vierlinger, Alessandro Cardinali, Gaia Spinetti, Audrey Nailor, Ezio Faglia, Sergio Losa, Ambra Gotti, Orazio Fortunato, Tijana Mitić, Manuela Hofner, Christa Noehammer, Paolo Madeddu, Costanza Emanueli

Research output: Contribution to journalArticle

Abstract

OBJECTIVE-: The p75 neurotrophin receptor (p75) 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 in the healing of ischemic and diabetic calf wounds; (2) the link between p75 and ST2; and (3) circulating sST2 levels in critical limb ischemia (CLI) patients. METHODS AND RESULTS-: Diabetes mellitus was induced in p75 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 promoted ST2 (both isoforms) expression through p38/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. CONCLUSION-: p75 inhibits the healing of ischemic lower limb wounds in diabetes mellitus and promotes ST2 expression. Circulating sST2 predicts mortality in diabetic CLI patients.

Original languageEnglish
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume32
Issue number12
DOIs
Publication statusPublished - Dec 2012

Keywords

  • diabetes mellitus
  • limb ischemia
  • p75 neurotrophin receptor
  • ST2
  • wound healing

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Caporali, A., Meloni, M., Miller, A. M., Vierlinger, K., Cardinali, A., Spinetti, G., Nailor, A., Faglia, E., Losa, S., Gotti, A., Fortunato, O., Mitić, T., Hofner, M., Noehammer, C., Madeddu, P., & Emanueli, C. (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). https://doi.org/10.1161/ATVBAHA.112.300497