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Lack of the antioxidant enzyme glutathione peroxidase-1 accelerates atherosclerosis in diabetic apolipoprotein E-deficient mice.
Circulation. 2007 Apr 24; 115(16):2178-87.Circ

Abstract

BACKGROUND

Recent clinical studies have suggested a major protective role for the antioxidant enzyme glutathione peroxidase-1 (GPx1) in diabetes-associated atherosclerosis. We induced diabetes in mice deficient for both GPx1 and apolipoprotein E (ApoE) to determine whether this is merely an association or whether GPx1 has a direct effect on diabetes-associated atherosclerosis.

METHODS AND RESULTS

ApoE-deficient (ApoE-/-) and ApoE/GPx1 double-knockout (ApoE-/- GPx1-/-) mice were made diabetic with streptozotocin and aortic lesion formation, and atherogenic pathways were assessed after 10 and 20 weeks of diabetes. Aortic proinflammatory and profibrotic markers were determined by both quantitative reverse-transcription polymerase chain reaction analysis after 10 weeks of diabetes and immunohistochemical analysis after 10 and 20 weeks of diabetes. Sham-injected nondiabetic counterparts served as controls. Atherosclerotic lesions within the aortic sinus region, as well as arch, thoracic, and abdominal lesions, were significantly increased in diabetic ApoE-/- GPx1-/- aortas compared with diabetic ApoE-/- aortas. This increase was accompanied by increased macrophages, alpha-smooth muscle actin, receptors for advanced glycation end products, and various proinflammatory (vascular cell adhesion molecule-1) and profibrotic (vascular endothelial growth factor and connective tissue growth factor) markers. Quantitative reverse-transcription polymerase chain reaction analysis showed increased expression of receptors for advanced glycation end products (RAGE), vascular cell adhesion molecule-1, vascular endothelial growth factor, and connective tissue growth factor. Nitrotyrosine levels were significantly increased in diabetic ApoE-/- GPx1-/- mouse aortas. These findings were observed despite upregulation of other antioxidants.

CONCLUSIONS

Lack of functional GPx1 accelerates diabetes-associated atherosclerosis via upregulation of proinflammatory and profibrotic pathways in ApoE-/- mice. Our study provides evidence of a protective role for GPx1 and establishes GPx1 as an important antiatherogenic therapeutic target in patients with or at risk of diabetic macrovascular disease.

Authors+Show Affiliations

Oxidative Stress Group, JDRF Diabetes and Metabolism Division, Baker Heart Research Institute, PO Box 6492, St Kilda Rd Central, Melbourne, VIC 8008, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17420349

Citation

Lewis, Paul, et al. "Lack of the Antioxidant Enzyme Glutathione Peroxidase-1 Accelerates Atherosclerosis in Diabetic Apolipoprotein E-deficient Mice." Circulation, vol. 115, no. 16, 2007, pp. 2178-87.
Lewis P, Stefanovic N, Pete J, et al. Lack of the antioxidant enzyme glutathione peroxidase-1 accelerates atherosclerosis in diabetic apolipoprotein E-deficient mice. Circulation. 2007;115(16):2178-87.
Lewis, P., Stefanovic, N., Pete, J., Calkin, A. C., Giunti, S., Thallas-Bonke, V., Jandeleit-Dahm, K. A., Allen, T. J., Kola, I., Cooper, M. E., & de Haan, J. B. (2007). Lack of the antioxidant enzyme glutathione peroxidase-1 accelerates atherosclerosis in diabetic apolipoprotein E-deficient mice. Circulation, 115(16), 2178-87.
Lewis P, et al. Lack of the Antioxidant Enzyme Glutathione Peroxidase-1 Accelerates Atherosclerosis in Diabetic Apolipoprotein E-deficient Mice. Circulation. 2007 Apr 24;115(16):2178-87. PubMed PMID: 17420349.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lack of the antioxidant enzyme glutathione peroxidase-1 accelerates atherosclerosis in diabetic apolipoprotein E-deficient mice. AU - Lewis,Paul, AU - Stefanovic,Nada, AU - Pete,Josefa, AU - Calkin,Anna C, AU - Giunti,Sara, AU - Thallas-Bonke,Vicki, AU - Jandeleit-Dahm,Karin A, AU - Allen,Terri J, AU - Kola,Ismail, AU - Cooper,Mark E, AU - de Haan,Judy B, Y1 - 2007/04/09/ PY - 2007/4/11/pubmed PY - 2007/6/1/medline PY - 2007/4/11/entrez SP - 2178 EP - 87 JF - Circulation JO - Circulation VL - 115 IS - 16 N2 - BACKGROUND: Recent clinical studies have suggested a major protective role for the antioxidant enzyme glutathione peroxidase-1 (GPx1) in diabetes-associated atherosclerosis. We induced diabetes in mice deficient for both GPx1 and apolipoprotein E (ApoE) to determine whether this is merely an association or whether GPx1 has a direct effect on diabetes-associated atherosclerosis. METHODS AND RESULTS: ApoE-deficient (ApoE-/-) and ApoE/GPx1 double-knockout (ApoE-/- GPx1-/-) mice were made diabetic with streptozotocin and aortic lesion formation, and atherogenic pathways were assessed after 10 and 20 weeks of diabetes. Aortic proinflammatory and profibrotic markers were determined by both quantitative reverse-transcription polymerase chain reaction analysis after 10 weeks of diabetes and immunohistochemical analysis after 10 and 20 weeks of diabetes. Sham-injected nondiabetic counterparts served as controls. Atherosclerotic lesions within the aortic sinus region, as well as arch, thoracic, and abdominal lesions, were significantly increased in diabetic ApoE-/- GPx1-/- aortas compared with diabetic ApoE-/- aortas. This increase was accompanied by increased macrophages, alpha-smooth muscle actin, receptors for advanced glycation end products, and various proinflammatory (vascular cell adhesion molecule-1) and profibrotic (vascular endothelial growth factor and connective tissue growth factor) markers. Quantitative reverse-transcription polymerase chain reaction analysis showed increased expression of receptors for advanced glycation end products (RAGE), vascular cell adhesion molecule-1, vascular endothelial growth factor, and connective tissue growth factor. Nitrotyrosine levels were significantly increased in diabetic ApoE-/- GPx1-/- mouse aortas. These findings were observed despite upregulation of other antioxidants. CONCLUSIONS: Lack of functional GPx1 accelerates diabetes-associated atherosclerosis via upregulation of proinflammatory and profibrotic pathways in ApoE-/- mice. Our study provides evidence of a protective role for GPx1 and establishes GPx1 as an important antiatherogenic therapeutic target in patients with or at risk of diabetic macrovascular disease. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/17420349/Lack_of_the_antioxidant_enzyme_glutathione_peroxidase_1_accelerates_atherosclerosis_in_diabetic_apolipoprotein_E_deficient_mice_ L2 - https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.106.664250?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -