Glyoxalase 1 overexpression does not affect atherosclerotic lesion size and severity in ApoE-/- mice with or without diabetes

Nordin M J Hanssen, Olaf Brouwers, Marion J Gijbels, Kristiaan Wouters, Erwin Wijnands, Jack P M Cleutjens, Jo G De Mey, Toshio Miyata, Erik A Biessen, Coen D A Stehouwer, Casper G Schalkwijk

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

AIMS: Advanced glycation end-products (AGEs) and their precursors have been associated with the development of atherosclerosis. We recently discovered that glyoxalase 1 (GLO1), the major detoxifying enzyme for AGE precursors, is decreased in ruptured human plaques, and that levels of AGEs are higher in rupture-prone plaques. We here investigated whether overexpression of human GLO1 in ApoE(-/-) mice could reduce the development of atherosclerosis.

METHODS AND RESULTS: We crossed C57BL/6 ApoE(-/-) mice with C57BL/6 GLO1 overexpressing mice (huGLO1(+/-)) to generate ApoE(-/-) (n = 16) and ApoE(-/-) huGLO1(+/-) (n = 20) mice. To induce diabetes, we injected a subset with streptozotocin (STZ) to generate diabetic ApoE(-/-) (n = 8) and ApoE(-/-) huGLO1(+/-) (n = 13) mice. All mice were fed chow and sacrificed at 25 weeks of age. The GLO1 activity was three-fold increased in huGLO1(+/-) aorta, but aortic root lesion size and phenotype did not differ between mice with and without huGLO1(+/-) overexpression. We detected no differences in gene expression in aortic arches, in AGE levels and cytokines, in circulating cells, and endothelial function between ApoE(-/-) mice with and without huGLO1(+/-) overexpression. Although diabetic mice showed decreased GLO1 expression (P < 0.05) and increased lesion size (P < 0.05) in comparison with non-diabetic mice, GLO1 overexpression also did not affect the aortic root lesion size or inflammation in diabetic mice.

CONCLUSION: In ApoE(-/-) mice with or without diabetes, GLO1 overexpression did not lead to decreased atherosclerotic lesion size or systemic inflammation. Increasing GLO1 levels does not seem to be an effective strategy to reduce glycation in atherosclerotic lesions, likely due to increased AGE formation through GLO1-independent mechanisms.

OriginalsprogEngelsk
TidsskriftCardiovascular Research
Vol/bind104
Udgave nummer1
Sider (fra-til)160-70
Antal sider11
ISSN0008-6363
DOI
StatusUdgivet - 1. okt. 2014

Fingeraftryk

Advanced Glycosylation End Products
Rupture
Enzymes

Citer dette

Hanssen, N. M. J., Brouwers, O., Gijbels, M. J., Wouters, K., Wijnands, E., Cleutjens, J. P. M., ... Schalkwijk, C. G. (2014). Glyoxalase 1 overexpression does not affect atherosclerotic lesion size and severity in ApoE-/- mice with or without diabetes. Cardiovascular Research, 104(1), 160-70. https://doi.org/10.1093/cvr/cvu189
Hanssen, Nordin M J ; Brouwers, Olaf ; Gijbels, Marion J ; Wouters, Kristiaan ; Wijnands, Erwin ; Cleutjens, Jack P M ; De Mey, Jo G ; Miyata, Toshio ; Biessen, Erik A ; Stehouwer, Coen D A ; Schalkwijk, Casper G. / Glyoxalase 1 overexpression does not affect atherosclerotic lesion size and severity in ApoE-/- mice with or without diabetes. I: Cardiovascular Research. 2014 ; Bind 104, Nr. 1. s. 160-70.
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title = "Glyoxalase 1 overexpression does not affect atherosclerotic lesion size and severity in ApoE-/- mice with or without diabetes",
abstract = "AIMS: Advanced glycation end-products (AGEs) and their precursors have been associated with the development of atherosclerosis. We recently discovered that glyoxalase 1 (GLO1), the major detoxifying enzyme for AGE precursors, is decreased in ruptured human plaques, and that levels of AGEs are higher in rupture-prone plaques. We here investigated whether overexpression of human GLO1 in ApoE(-/-) mice could reduce the development of atherosclerosis.METHODS AND RESULTS: We crossed C57BL/6 ApoE(-/-) mice with C57BL/6 GLO1 overexpressing mice (huGLO1(+/-)) to generate ApoE(-/-) (n = 16) and ApoE(-/-) huGLO1(+/-) (n = 20) mice. To induce diabetes, we injected a subset with streptozotocin (STZ) to generate diabetic ApoE(-/-) (n = 8) and ApoE(-/-) huGLO1(+/-) (n = 13) mice. All mice were fed chow and sacrificed at 25 weeks of age. The GLO1 activity was three-fold increased in huGLO1(+/-) aorta, but aortic root lesion size and phenotype did not differ between mice with and without huGLO1(+/-) overexpression. We detected no differences in gene expression in aortic arches, in AGE levels and cytokines, in circulating cells, and endothelial function between ApoE(-/-) mice with and without huGLO1(+/-) overexpression. Although diabetic mice showed decreased GLO1 expression (P < 0.05) and increased lesion size (P < 0.05) in comparison with non-diabetic mice, GLO1 overexpression also did not affect the aortic root lesion size or inflammation in diabetic mice.CONCLUSION: In ApoE(-/-) mice with or without diabetes, GLO1 overexpression did not lead to decreased atherosclerotic lesion size or systemic inflammation. Increasing GLO1 levels does not seem to be an effective strategy to reduce glycation in atherosclerotic lesions, likely due to increased AGE formation through GLO1-independent mechanisms.",
author = "Hanssen, {Nordin M J} and Olaf Brouwers and Gijbels, {Marion J} and Kristiaan Wouters and Erwin Wijnands and Cleutjens, {Jack P M} and {De Mey}, {Jo G} and Toshio Miyata and Biessen, {Erik A} and Stehouwer, {Coen D A} and Schalkwijk, {Casper G}",
note = "Published on behalf of the European Society of Cardiology. All rights reserved. {\circledC} The Author 2014. For permissions please email: journals.permissions@oup.com.",
year = "2014",
month = "10",
day = "1",
doi = "10.1093/cvr/cvu189",
language = "English",
volume = "104",
pages = "160--70",
journal = "Cardiovascular Research",
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Hanssen, NMJ, Brouwers, O, Gijbels, MJ, Wouters, K, Wijnands, E, Cleutjens, JPM, De Mey, JG, Miyata, T, Biessen, EA, Stehouwer, CDA & Schalkwijk, CG 2014, 'Glyoxalase 1 overexpression does not affect atherosclerotic lesion size and severity in ApoE-/- mice with or without diabetes', Cardiovascular Research, bind 104, nr. 1, s. 160-70. https://doi.org/10.1093/cvr/cvu189

Glyoxalase 1 overexpression does not affect atherosclerotic lesion size and severity in ApoE-/- mice with or without diabetes. / Hanssen, Nordin M J; Brouwers, Olaf; Gijbels, Marion J; Wouters, Kristiaan; Wijnands, Erwin; Cleutjens, Jack P M; De Mey, Jo G; Miyata, Toshio; Biessen, Erik A; Stehouwer, Coen D A; Schalkwijk, Casper G.

I: Cardiovascular Research, Bind 104, Nr. 1, 01.10.2014, s. 160-70.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Glyoxalase 1 overexpression does not affect atherosclerotic lesion size and severity in ApoE-/- mice with or without diabetes

AU - Hanssen, Nordin M J

AU - Brouwers, Olaf

AU - Gijbels, Marion J

AU - Wouters, Kristiaan

AU - Wijnands, Erwin

AU - Cleutjens, Jack P M

AU - De Mey, Jo G

AU - Miyata, Toshio

AU - Biessen, Erik A

AU - Stehouwer, Coen D A

AU - Schalkwijk, Casper G

N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

PY - 2014/10/1

Y1 - 2014/10/1

N2 - AIMS: Advanced glycation end-products (AGEs) and their precursors have been associated with the development of atherosclerosis. We recently discovered that glyoxalase 1 (GLO1), the major detoxifying enzyme for AGE precursors, is decreased in ruptured human plaques, and that levels of AGEs are higher in rupture-prone plaques. We here investigated whether overexpression of human GLO1 in ApoE(-/-) mice could reduce the development of atherosclerosis.METHODS AND RESULTS: We crossed C57BL/6 ApoE(-/-) mice with C57BL/6 GLO1 overexpressing mice (huGLO1(+/-)) to generate ApoE(-/-) (n = 16) and ApoE(-/-) huGLO1(+/-) (n = 20) mice. To induce diabetes, we injected a subset with streptozotocin (STZ) to generate diabetic ApoE(-/-) (n = 8) and ApoE(-/-) huGLO1(+/-) (n = 13) mice. All mice were fed chow and sacrificed at 25 weeks of age. The GLO1 activity was three-fold increased in huGLO1(+/-) aorta, but aortic root lesion size and phenotype did not differ between mice with and without huGLO1(+/-) overexpression. We detected no differences in gene expression in aortic arches, in AGE levels and cytokines, in circulating cells, and endothelial function between ApoE(-/-) mice with and without huGLO1(+/-) overexpression. Although diabetic mice showed decreased GLO1 expression (P < 0.05) and increased lesion size (P < 0.05) in comparison with non-diabetic mice, GLO1 overexpression also did not affect the aortic root lesion size or inflammation in diabetic mice.CONCLUSION: In ApoE(-/-) mice with or without diabetes, GLO1 overexpression did not lead to decreased atherosclerotic lesion size or systemic inflammation. Increasing GLO1 levels does not seem to be an effective strategy to reduce glycation in atherosclerotic lesions, likely due to increased AGE formation through GLO1-independent mechanisms.

AB - AIMS: Advanced glycation end-products (AGEs) and their precursors have been associated with the development of atherosclerosis. We recently discovered that glyoxalase 1 (GLO1), the major detoxifying enzyme for AGE precursors, is decreased in ruptured human plaques, and that levels of AGEs are higher in rupture-prone plaques. We here investigated whether overexpression of human GLO1 in ApoE(-/-) mice could reduce the development of atherosclerosis.METHODS AND RESULTS: We crossed C57BL/6 ApoE(-/-) mice with C57BL/6 GLO1 overexpressing mice (huGLO1(+/-)) to generate ApoE(-/-) (n = 16) and ApoE(-/-) huGLO1(+/-) (n = 20) mice. To induce diabetes, we injected a subset with streptozotocin (STZ) to generate diabetic ApoE(-/-) (n = 8) and ApoE(-/-) huGLO1(+/-) (n = 13) mice. All mice were fed chow and sacrificed at 25 weeks of age. The GLO1 activity was three-fold increased in huGLO1(+/-) aorta, but aortic root lesion size and phenotype did not differ between mice with and without huGLO1(+/-) overexpression. We detected no differences in gene expression in aortic arches, in AGE levels and cytokines, in circulating cells, and endothelial function between ApoE(-/-) mice with and without huGLO1(+/-) overexpression. Although diabetic mice showed decreased GLO1 expression (P < 0.05) and increased lesion size (P < 0.05) in comparison with non-diabetic mice, GLO1 overexpression also did not affect the aortic root lesion size or inflammation in diabetic mice.CONCLUSION: In ApoE(-/-) mice with or without diabetes, GLO1 overexpression did not lead to decreased atherosclerotic lesion size or systemic inflammation. Increasing GLO1 levels does not seem to be an effective strategy to reduce glycation in atherosclerotic lesions, likely due to increased AGE formation through GLO1-independent mechanisms.

U2 - 10.1093/cvr/cvu189

DO - 10.1093/cvr/cvu189

M3 - Journal article

VL - 104

SP - 160

EP - 170

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 1

ER -