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Vascular Biology

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 Mitic, Manuela Hofner, Christa Noehammer, Paolo Madeddu, Costanza Emanueli
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https://doi.org/10.1161/ATVBAHA.112.300497
Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;ATVBAHA.112.300497
Originally published October 11, 2012
Andrea Caporali
From the Laboratories of Vascular Pathology and Regeneration (A. Caporali, M.M., A.N., T.M., C.E.), Experimental Cardiovascular Medicine (P.M.), and Clinical Trial Unit (A. Cardinali), School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom (A.M.M.); AIT-Austrian Institute of Technology, Vienna, Austria (K.V.,M.H., C.N.); and IRCCS-MultiMedica, Milan, Italy (K.V., M.P.H.).
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Marco Meloni
From the Laboratories of Vascular Pathology and Regeneration (A. Caporali, M.M., A.N., T.M., C.E.), Experimental Cardiovascular Medicine (P.M.), and Clinical Trial Unit (A. Cardinali), School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom (A.M.M.); AIT-Austrian Institute of Technology, Vienna, Austria (K.V.,M.H., C.N.); and IRCCS-MultiMedica, Milan, Italy (K.V., M.P.H.).
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Ashley M. Miller
From the Laboratories of Vascular Pathology and Regeneration (A. Caporali, M.M., A.N., T.M., C.E.), Experimental Cardiovascular Medicine (P.M.), and Clinical Trial Unit (A. Cardinali), School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom (A.M.M.); AIT-Austrian Institute of Technology, Vienna, Austria (K.V.,M.H., C.N.); and IRCCS-MultiMedica, Milan, Italy (K.V., M.P.H.).
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Klemens Vierlinger
From the Laboratories of Vascular Pathology and Regeneration (A. Caporali, M.M., A.N., T.M., C.E.), Experimental Cardiovascular Medicine (P.M.), and Clinical Trial Unit (A. Cardinali), School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom (A.M.M.); AIT-Austrian Institute of Technology, Vienna, Austria (K.V.,M.H., C.N.); and IRCCS-MultiMedica, Milan, Italy (K.V., M.P.H.).
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Alessandro Cardinali
From the Laboratories of Vascular Pathology and Regeneration (A. Caporali, M.M., A.N., T.M., C.E.), Experimental Cardiovascular Medicine (P.M.), and Clinical Trial Unit (A. Cardinali), School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom (A.M.M.); AIT-Austrian Institute of Technology, Vienna, Austria (K.V.,M.H., C.N.); and IRCCS-MultiMedica, Milan, Italy (K.V., M.P.H.).
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Gaia Spinetti
From the Laboratories of Vascular Pathology and Regeneration (A. Caporali, M.M., A.N., T.M., C.E.), Experimental Cardiovascular Medicine (P.M.), and Clinical Trial Unit (A. Cardinali), School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom (A.M.M.); AIT-Austrian Institute of Technology, Vienna, Austria (K.V.,M.H., C.N.); and IRCCS-MultiMedica, Milan, Italy (K.V., M.P.H.).
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Audrey Nailor
From the Laboratories of Vascular Pathology and Regeneration (A. Caporali, M.M., A.N., T.M., C.E.), Experimental Cardiovascular Medicine (P.M.), and Clinical Trial Unit (A. Cardinali), School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom (A.M.M.); AIT-Austrian Institute of Technology, Vienna, Austria (K.V.,M.H., C.N.); and IRCCS-MultiMedica, Milan, Italy (K.V., M.P.H.).
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Ezio Faglia
From the Laboratories of Vascular Pathology and Regeneration (A. Caporali, M.M., A.N., T.M., C.E.), Experimental Cardiovascular Medicine (P.M.), and Clinical Trial Unit (A. Cardinali), School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom (A.M.M.); AIT-Austrian Institute of Technology, Vienna, Austria (K.V.,M.H., C.N.); and IRCCS-MultiMedica, Milan, Italy (K.V., M.P.H.).
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Sergio Losa
From the Laboratories of Vascular Pathology and Regeneration (A. Caporali, M.M., A.N., T.M., C.E.), Experimental Cardiovascular Medicine (P.M.), and Clinical Trial Unit (A. Cardinali), School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom (A.M.M.); AIT-Austrian Institute of Technology, Vienna, Austria (K.V.,M.H., C.N.); and IRCCS-MultiMedica, Milan, Italy (K.V., M.P.H.).
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Ambra Gotti
From the Laboratories of Vascular Pathology and Regeneration (A. Caporali, M.M., A.N., T.M., C.E.), Experimental Cardiovascular Medicine (P.M.), and Clinical Trial Unit (A. Cardinali), School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom (A.M.M.); AIT-Austrian Institute of Technology, Vienna, Austria (K.V.,M.H., C.N.); and IRCCS-MultiMedica, Milan, Italy (K.V., M.P.H.).
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Orazio Fortunato
From the Laboratories of Vascular Pathology and Regeneration (A. Caporali, M.M., A.N., T.M., C.E.), Experimental Cardiovascular Medicine (P.M.), and Clinical Trial Unit (A. Cardinali), School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom (A.M.M.); AIT-Austrian Institute of Technology, Vienna, Austria (K.V.,M.H., C.N.); and IRCCS-MultiMedica, Milan, Italy (K.V., M.P.H.).
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Tijana Mitic
From the Laboratories of Vascular Pathology and Regeneration (A. Caporali, M.M., A.N., T.M., C.E.), Experimental Cardiovascular Medicine (P.M.), and Clinical Trial Unit (A. Cardinali), School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom (A.M.M.); AIT-Austrian Institute of Technology, Vienna, Austria (K.V.,M.H., C.N.); and IRCCS-MultiMedica, Milan, Italy (K.V., M.P.H.).
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Manuela Hofner
From the Laboratories of Vascular Pathology and Regeneration (A. Caporali, M.M., A.N., T.M., C.E.), Experimental Cardiovascular Medicine (P.M.), and Clinical Trial Unit (A. Cardinali), School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom (A.M.M.); AIT-Austrian Institute of Technology, Vienna, Austria (K.V.,M.H., C.N.); and IRCCS-MultiMedica, Milan, Italy (K.V., M.P.H.).
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Christa Noehammer
From the Laboratories of Vascular Pathology and Regeneration (A. Caporali, M.M., A.N., T.M., C.E.), Experimental Cardiovascular Medicine (P.M.), and Clinical Trial Unit (A. Cardinali), School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom (A.M.M.); AIT-Austrian Institute of Technology, Vienna, Austria (K.V.,M.H., C.N.); and IRCCS-MultiMedica, Milan, Italy (K.V., M.P.H.).
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Paolo Madeddu
From the Laboratories of Vascular Pathology and Regeneration (A. Caporali, M.M., A.N., T.M., C.E.), Experimental Cardiovascular Medicine (P.M.), and Clinical Trial Unit (A. Cardinali), School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom (A.M.M.); AIT-Austrian Institute of Technology, Vienna, Austria (K.V.,M.H., C.N.); and IRCCS-MultiMedica, Milan, Italy (K.V., M.P.H.).
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Costanza Emanueli
From the Laboratories of Vascular Pathology and Regeneration (A. Caporali, M.M., A.N., T.M., C.E.), Experimental Cardiovascular Medicine (P.M.), and Clinical Trial Unit (A. Cardinali), School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom (A.M.M.); AIT-Austrian Institute of Technology, Vienna, Austria (K.V.,M.H., C.N.); and IRCCS-MultiMedica, Milan, Italy (K.V., M.P.H.).
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Abstract

Objective—The p75 neurotrophin receptor (p75NTR) 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 p75NTR in the healing of ischemic and diabetic calf wounds; (2) the link between p75NTR and ST2; and (3) circulating sST2 levels in critical limb ischemia (CLI) patients.

Methods and Results—Diabetes mellitus was induced in p75NTR 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, p75NTR promoted ST2 (both isoforms) expression through p38MAPK/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—p75NTR inhibits the healing of ischemic lower limb wounds in diabetes mellitus and promotes ST2 expression. Circulating sST2 predicts mortality in diabetic CLI patients.

  • diabetes mellitus
  • limb ischemia
  • p75 neurotrophin receptor
  • ST2
  • wound healing
  • Received February 17, 2012.
  • Accepted September 28, 2012.
  • © 2012 American Heart Association, Inc.
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    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 Mitic, Manuela Hofner, Christa Noehammer, Paolo Madeddu and Costanza Emanueli
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;ATVBAHA.112.300497, originally published October 11, 2012
    https://doi.org/10.1161/ATVBAHA.112.300497

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    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 Mitic, Manuela Hofner, Christa Noehammer, Paolo Madeddu and Costanza Emanueli
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;ATVBAHA.112.300497, originally published October 11, 2012
    https://doi.org/10.1161/ATVBAHA.112.300497
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