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

Arterioscler Thromb Vasc Biol. 2012 Dec;32(12):e149-60. doi: 10.1161/ATVBAHA.112.300497. Epub 2012 Oct 11.

Abstract

Objective: The p75 neurotrophin receptor (p75(NTR)) 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(NTR) in the healing of ischemic and diabetic calf wounds; (2) the link between p75(NTR) and ST2; and (3) circulating sST2 levels in critical limb ischemia (CLI) patients.

Methods and results: Diabetes mellitus was induced in p75(NTR) 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(NTR) promoted ST2 (both isoforms) expression through p38(MAPK)/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.

Conclusions: p75(NTR) inhibits the healing of ischemic lower limb wounds in diabetes mellitus and promotes ST2 expression. Circulating sST2 predicts mortality in diabetic CLI patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 2 / metabolism
  • Aged
  • Aged, 80 and over
  • Animals
  • Biomarkers / metabolism
  • Cells, Cultured
  • Diabetes Complications / complications
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / mortality*
  • Diabetes Mellitus / physiopathology
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / physiopathology*
  • Disease Models, Animal
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Female
  • Humans
  • Interleukin-1 Receptor-Like 1 Protein
  • Ischemia / etiology
  • Ischemia / physiopathology*
  • Lower Extremity / blood supply*
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Nerve Tissue Proteins / pharmacology
  • Nerve Tissue Proteins / physiology*
  • Predictive Value of Tests
  • Receptors, Cell Surface / metabolism*
  • Receptors, Interleukin / metabolism*
  • Receptors, Nerve Growth Factor / deficiency
  • Receptors, Nerve Growth Factor / genetics
  • Receptors, Nerve Growth Factor / physiology*
  • Streptozocin / adverse effects
  • Wound Healing / physiology
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • ATF2 protein, human
  • Activating Transcription Factor 2
  • Biomarkers
  • IL1RL1 protein, human
  • Il1rl1 protein, mouse
  • Interleukin-1 Receptor-Like 1 Protein
  • NGFR protein, human
  • Nerve Tissue Proteins
  • Receptors, Cell Surface
  • Receptors, Interleukin
  • Receptors, Nerve Growth Factor
  • Ngfr protein, mouse
  • Streptozocin
  • p38 Mitogen-Activated Protein Kinases