The redox state of transglutaminase 2 controls arterial remodeling

Jeroen van den Akker, Ed VanBavel, Remon van Geel, Hanke L Matlung, Bilge Guvenc Tuna, George M C Janssen, Peter A van Veelen, Wilbert C Boelens, Jo G R De Mey, Erik N T P Bakker

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

While inward remodeling of small arteries in response to low blood flow, hypertension, and chronic vasoconstriction depends on type 2 transglutaminase (TG2), the mechanisms of action have remained unresolved. We studied the regulation of TG2 activity, its (sub) cellular localization, substrates, and its specific mode of action during small artery inward remodeling. We found that inward remodeling of isolated mouse mesenteric arteries by exogenous TG2 required the presence of a reducing agent. The effect of TG2 depended on its cross-linking activity, as indicated by the lack of effect of mutant TG2. The cell-permeable reducing agent DTT, but not the cell-impermeable reducing agent TCEP, induced translocation of endogenous TG2 and high membrane-bound transglutaminase activity. This coincided with inward remodeling, characterized by a stiffening of the artery. The remodeling could be inhibited by a TG2 inhibitor and by the nitric oxide donor, SNAP. Using a pull-down assay and mass spectrometry, 21 proteins were identified as TG2 cross-linking substrates, including fibronectin, collagen and nidogen. Inward remodeling induced by low blood flow was associated with the upregulation of several anti-oxidant proteins, notably glutathione-S-transferase, and selenoprotein P. In conclusion, these results show that a reduced state induces smooth muscle membrane-bound TG2 activity. Inward remodeling results from the cross-linking of vicinal matrix proteins, causing a stiffening of the arterial wall.

OriginalsprogEngelsk
Artikelnummere23067
TidsskriftPLOS ONE
Vol/bind6
Udgave nummer8
Antal sider10
ISSN1932-6203
DOI
StatusUdgivet - 2011
Udgivet eksterntJa

Fingeraftryk

reducing agents
protein-glutamine gamma-glutamyltransferase
Reducing Agents
crosslinking
arteries
blood flow
mechanism of action
Selenoprotein P
Blood
selenoproteins
Membranes
mesenteric arteries
Proteins
vasoconstriction
Transglutaminases
Nitric Oxide Donors
proteins
fibronectins
Substrates
Vasoconstriction

Citer dette

van den Akker, J., VanBavel, E., van Geel, R., Matlung, H. L., Guvenc Tuna, B., Janssen, G. M. C., ... Bakker, E. N. T. P. (2011). The redox state of transglutaminase 2 controls arterial remodeling. PLOS ONE, 6(8), [e23067]. https://doi.org/10.1371/journal.pone.0023067
van den Akker, Jeroen ; VanBavel, Ed ; van Geel, Remon ; Matlung, Hanke L ; Guvenc Tuna, Bilge ; Janssen, George M C ; van Veelen, Peter A ; Boelens, Wilbert C ; De Mey, Jo G R ; Bakker, Erik N T P. / The redox state of transglutaminase 2 controls arterial remodeling. I: PLOS ONE. 2011 ; Bind 6, Nr. 8.
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title = "The redox state of transglutaminase 2 controls arterial remodeling",
abstract = "While inward remodeling of small arteries in response to low blood flow, hypertension, and chronic vasoconstriction depends on type 2 transglutaminase (TG2), the mechanisms of action have remained unresolved. We studied the regulation of TG2 activity, its (sub) cellular localization, substrates, and its specific mode of action during small artery inward remodeling. We found that inward remodeling of isolated mouse mesenteric arteries by exogenous TG2 required the presence of a reducing agent. The effect of TG2 depended on its cross-linking activity, as indicated by the lack of effect of mutant TG2. The cell-permeable reducing agent DTT, but not the cell-impermeable reducing agent TCEP, induced translocation of endogenous TG2 and high membrane-bound transglutaminase activity. This coincided with inward remodeling, characterized by a stiffening of the artery. The remodeling could be inhibited by a TG2 inhibitor and by the nitric oxide donor, SNAP. Using a pull-down assay and mass spectrometry, 21 proteins were identified as TG2 cross-linking substrates, including fibronectin, collagen and nidogen. Inward remodeling induced by low blood flow was associated with the upregulation of several anti-oxidant proteins, notably glutathione-S-transferase, and selenoprotein P. In conclusion, these results show that a reduced state induces smooth muscle membrane-bound TG2 activity. Inward remodeling results from the cross-linking of vicinal matrix proteins, causing a stiffening of the arterial wall.",
keywords = "Animals, Arteries, Calcimycin, Calcium Ionophores, Cell Line, Enzyme Activation, GTP-Binding Proteins, Male, Mice, Mice, Inbred C57BL, Myocytes, Smooth Muscle, Recombinant Proteins, Reducing Agents, Transglutaminases",
author = "{van den Akker}, Jeroen and Ed VanBavel and {van Geel}, Remon and Matlung, {Hanke L} and {Guvenc Tuna}, Bilge and Janssen, {George M C} and {van Veelen}, {Peter A} and Boelens, {Wilbert C} and {De Mey}, {Jo G R} and Bakker, {Erik N T P}",
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van den Akker, J, VanBavel, E, van Geel, R, Matlung, HL, Guvenc Tuna, B, Janssen, GMC, van Veelen, PA, Boelens, WC, De Mey, JGR & Bakker, ENTP 2011, 'The redox state of transglutaminase 2 controls arterial remodeling', PLOS ONE, bind 6, nr. 8, e23067. https://doi.org/10.1371/journal.pone.0023067

The redox state of transglutaminase 2 controls arterial remodeling. / van den Akker, Jeroen; VanBavel, Ed; van Geel, Remon; Matlung, Hanke L; Guvenc Tuna, Bilge; Janssen, George M C; van Veelen, Peter A; Boelens, Wilbert C; De Mey, Jo G R; Bakker, Erik N T P.

I: PLOS ONE, Bind 6, Nr. 8, e23067, 2011.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - The redox state of transglutaminase 2 controls arterial remodeling

AU - van den Akker, Jeroen

AU - VanBavel, Ed

AU - van Geel, Remon

AU - Matlung, Hanke L

AU - Guvenc Tuna, Bilge

AU - Janssen, George M C

AU - van Veelen, Peter A

AU - Boelens, Wilbert C

AU - De Mey, Jo G R

AU - Bakker, Erik N T P

PY - 2011

Y1 - 2011

N2 - While inward remodeling of small arteries in response to low blood flow, hypertension, and chronic vasoconstriction depends on type 2 transglutaminase (TG2), the mechanisms of action have remained unresolved. We studied the regulation of TG2 activity, its (sub) cellular localization, substrates, and its specific mode of action during small artery inward remodeling. We found that inward remodeling of isolated mouse mesenteric arteries by exogenous TG2 required the presence of a reducing agent. The effect of TG2 depended on its cross-linking activity, as indicated by the lack of effect of mutant TG2. The cell-permeable reducing agent DTT, but not the cell-impermeable reducing agent TCEP, induced translocation of endogenous TG2 and high membrane-bound transglutaminase activity. This coincided with inward remodeling, characterized by a stiffening of the artery. The remodeling could be inhibited by a TG2 inhibitor and by the nitric oxide donor, SNAP. Using a pull-down assay and mass spectrometry, 21 proteins were identified as TG2 cross-linking substrates, including fibronectin, collagen and nidogen. Inward remodeling induced by low blood flow was associated with the upregulation of several anti-oxidant proteins, notably glutathione-S-transferase, and selenoprotein P. In conclusion, these results show that a reduced state induces smooth muscle membrane-bound TG2 activity. Inward remodeling results from the cross-linking of vicinal matrix proteins, causing a stiffening of the arterial wall.

AB - While inward remodeling of small arteries in response to low blood flow, hypertension, and chronic vasoconstriction depends on type 2 transglutaminase (TG2), the mechanisms of action have remained unresolved. We studied the regulation of TG2 activity, its (sub) cellular localization, substrates, and its specific mode of action during small artery inward remodeling. We found that inward remodeling of isolated mouse mesenteric arteries by exogenous TG2 required the presence of a reducing agent. The effect of TG2 depended on its cross-linking activity, as indicated by the lack of effect of mutant TG2. The cell-permeable reducing agent DTT, but not the cell-impermeable reducing agent TCEP, induced translocation of endogenous TG2 and high membrane-bound transglutaminase activity. This coincided with inward remodeling, characterized by a stiffening of the artery. The remodeling could be inhibited by a TG2 inhibitor and by the nitric oxide donor, SNAP. Using a pull-down assay and mass spectrometry, 21 proteins were identified as TG2 cross-linking substrates, including fibronectin, collagen and nidogen. Inward remodeling induced by low blood flow was associated with the upregulation of several anti-oxidant proteins, notably glutathione-S-transferase, and selenoprotein P. In conclusion, these results show that a reduced state induces smooth muscle membrane-bound TG2 activity. Inward remodeling results from the cross-linking of vicinal matrix proteins, causing a stiffening of the arterial wall.

KW - Animals

KW - Arteries

KW - Calcimycin

KW - Calcium Ionophores

KW - Cell Line

KW - Enzyme Activation

KW - GTP-Binding Proteins

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Myocytes, Smooth Muscle

KW - Recombinant Proteins

KW - Reducing Agents

KW - Transglutaminases

U2 - 10.1371/journal.pone.0023067

DO - 10.1371/journal.pone.0023067

M3 - Journal article

VL - 6

JO - P L o S One

JF - P L o S One

SN - 1932-6203

IS - 8

M1 - e23067

ER -

van den Akker J, VanBavel E, van Geel R, Matlung HL, Guvenc Tuna B, Janssen GMC et al. The redox state of transglutaminase 2 controls arterial remodeling. PLOS ONE. 2011;6(8). e23067. https://doi.org/10.1371/journal.pone.0023067