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

doi:10.1161/atvbaha.112.300497

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^*

^*Corresponding author for this work

School of Engineering, Computing and Mathematics

Research output: Contribution to journal › Article › peer-review

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. Conclusion— 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.

Original language	English
Number of pages	0
Journal	Arteriosclerosis, Thrombosis, and Vascular Biology
Volume	32
Issue number	12
DOIs	https://doi.org/10.1161/atvbaha.112.300497
Publication status	Published - Dec 2012

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10.1161/atvbaha.112.300497

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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

@article{bb55c1e5384d4cc9b6b2fffbbdcb18f3,

title = "Soluble ST2 Is Regulated by p75 Neurotrophin Receptor and Predicts Mortality in Diabetic Patients With Critical Limb Ischemia",

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. Conclusion— 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. ",

author = "Andrea Caporali and Marco Meloni and Miller, {Ashley M.} and Klemens Vierlinger and Alessandro Cardinali and Gaia Spinetti and Audrey Nailor and Ezio Faglia and Sergio Losa and Ambra Gotti and Orazio Fortunato and Tijana Miti{\'c} and Manuela Hofner and Christa Noehammer and Paolo Madeddu and Costanza Emanueli",

year = "2012",

month = dec,

doi = "10.1161/atvbaha.112.300497",

language = "English",

volume = "32",

journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",

issn = "1079-5642",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "12",

}

Caporali, A, Meloni, M, Miller, AM, 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, vol. 32, no. 12. https://doi.org/10.1161/atvbaha.112.300497

TY - JOUR

T1 - Soluble ST2 Is Regulated by p75 Neurotrophin Receptor and Predicts Mortality in Diabetic Patients With Critical Limb Ischemia

AU - Caporali, Andrea

AU - Meloni, Marco

AU - Miller, Ashley M.

AU - Vierlinger, Klemens

AU - Cardinali, Alessandro

AU - Spinetti, Gaia

AU - Nailor, Audrey

AU - Faglia, Ezio

AU - Losa, Sergio

AU - Gotti, Ambra

AU - Fortunato, Orazio

AU - Mitić, Tijana

AU - Hofner, Manuela

AU - Noehammer, Christa

AU - Madeddu, Paolo

AU - Emanueli, Costanza

PY - 2012/12

Y1 - 2012/12

N2 - 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. Conclusion— 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.

AB - 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. Conclusion— 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.

U2 - 10.1161/atvbaha.112.300497

DO - 10.1161/atvbaha.112.300497

M3 - Article

SN - 1079-5642

VL - 32

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

IS - 12

ER -

Soluble ST2 Is Regulated by p75 Neurotrophin Receptor and Predicts Mortality in Diabetic Patients With Critical Limb Ischemia

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