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


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.
Laboratories of Vascular Pathology and Regeneration, School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom.
Andrea
A
Caporali
Marco
M
Meloni
Ashley M
AM
Miller
Klemens
K
Vierlinger
Alessandro
A
Cardinali
Gaia
G
Spinetti
Audrey
A
Nailor
Ezio
E
Faglia
Sergio
S
Losa
Ambra
A
Gotti
Orazio
O
Fortunato
Tijana
T
Mitic
Manuela
M
Hofner
Christa
C
Noehammer
Paolo
P
Madeddu
Costanza
C
Emanueli
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D048909:Diabetes Complications / Q000150:complications; D003920:Diabetes Mellitus / Q000378:metabolism / Q000401:mortality* / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D007511:Ischemia / Q000209:etiology / Q000503:physiopathology*; D035002:Lower Extremity / Q000098:blood supply*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000494:pharmacology / Q000502:physiology*; D011237:Predictive Value of Tests; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013311:Streptozocin / Q000009:adverse effects; D014945:Wound Healing / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D015415:Biomarkers; C079241:IL1RL1 protein, human; C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; D013311:Streptozocin; D048051:p38 Mitogen-Activated Protein Kinases