Abstract 11967: Soluble St2 is Regulated By P75NTR and Predicts Mortality in Diabetic Patients With Critical Limb Ischemia
BACKGROUND: The neurotrophin p75NTR receptor contributes into diabetes mellitus (DM)-induced defective post-ischemic neovascularization. The interleukin-33 receptor ST2 (also known as IL-1RL1) is expressed as a transmembrane (ST2L) and a soluble (sST2) isoform. Here we studied: 1) the impact of p75NTR on the healing of ischemic wounds in normoglycemic and diabetic mice; 2) the regulation of ST2 expression by p75NTR in cultured endothelial cells (ECs); 3) circulating sST2 levels in patients with DM and critical limb ischemia (CLI).
METHODS and RESULTS: DM was induced in p75NTR knock-out (p75KO) and wild type littermates (WT) mice by streptozotocin. Diabetic and normoglycemic p75KO and WT mice received left limb ischemia induction and a full thickness wound on the ipsilateral calf. Non-diabetic p75KO and WT mice exhibited similar wound closure rate and wound capillary density. DM reduced wound closure and capillary density in WT mice (p < 0.05 and p < 0.01 vs. non-diabetic WT mice). Diabetic p75KO mice showed accelerate wound closure and increased angiogenesis (p < 0.05 for both comparisons vs. diabetic WT mice). DM increased sST2 expression in wounded skin of WT mice (p < 0.05 vs. non-DM), but not of p75KO mice (p=N.S, vs. non-diabetic p75KO mice). In cultured human umbilical vein ECs (HUVECs), p75NTR silencing prevented TNF-alpha or PMA-induced ST2 expression. Finally, we measured serum sST2 levels in patients with DM and CLI undergoing either revascularization or major amputation and healthy controls. Circulating sST2 was increased in diabetic patients with CLI undergoing revascularization (271.8 ± 138.7 vs. 142.8 ± 41.2 pg/ml in healthy controls, p < 0.05) and within this patient population, sST2 was directly associated with mortality within one year of follow-up (p=0.001 and after multivariate linear regression analysis). Circulating sST2 was further increased in DM patients in need of lower limb amputation for CLI (552.5 ± 118.7 pg/ml, P < 0.05 for comparisons vs. both controls and patients undergoing revascularization).
CONCLUSIONS: 1) p75NTR contributes into DM-induced impaired healing of calf ischemic wounds; 2) ST2 is regulated by p75NTR in ECs; 3) circulating sST2 predicts mortality in diabetic patients with CLI.
- © 2012 by American Heart Association, Inc.