Glyoxalase I (Glo1) and its metabolites in vascular disease

Wortmann, Markus; Peters, Andreas S.; Hakimi, Maani; Böckler, Dittmar; Dihlmann, Susanne

doi:10.1042/bst20140003

Cited by 12 publications

(8 citation statements)

References 48 publications

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“…Immunohistochemical analyses of the aortic wall by an anatomopathologist showed that the main CCL18-producing cells are macrophages, with a few endothelial cells and fibroblasts. CCL18 is chemotactic for T and B cells (20), is detected in atherosclerosis plaques in regions rich in macrophages (21) and was also reported as a fibro-inflammatory mediator able to stimulate collagen production by lung and dermal fibroblasts (22). In this study, the plasma levels of CCL18 were significantly higher in the AAA population compared with healthy individuals, with the highest concentrations being measured in A+ patients.…”

Section: Discussionsupporting

confidence: 52%

Gene Expression Study in Positron Emission Tomography-Positive Abdominal Aortic Aneurysms Identifies CCL18 as a Potential Biomarker for Rupture Risk

Courtois

Nusgens

Hustinx

et al. 2014

Mol Med

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Rupture of abdominal aortic aneurysm (AAA) is a cause of significant mortality and morbidity in aging populations. Uptake of 18-fluorodeoxyglucose (FDG) detected by positron emission tomography (PET) is observed in the wall of 12% of AAA (A+), with most of them being symptomatic. We previously showed that the metabolically active areas displayed adventitial inflammation, medial degeneration and molecular alterations prefacing wall rupture. The aim of this study was to identify new factors predictive of rupture. Transcriptomic analyses were performed in the media and adventitia layers from three types of samples: AAA without FDG uptake (A0) and with FDG uptake (A+), both at the positive spot (A+ Pos ) and at a paired distant negative site (A+ Neg ) of the same aneurysm. Follow-up studies included reverse-transcriptase-polymerase chain reaction (RT-PCR), immunohistochemical staining and enzyme-linked immunosorbent assay (ELISA). A large number of genes, including matrix metalloproteinases, collagens and cytokines as well as genes involved in osteochondral development, were differentially expressed in the A+ Pos compared with A+ Neg . Moreover, a series of genes (notably CCL18) was differentially expressed both in the A+ Neg and A+ Pos compared with the A0. A significant increase of CCL18 was also found at the protein level in the aortic wall and in peripheral blood of A+ patients compared with A0. In conclusion, new factors, including CCL18, involved in the progression of AAA and, potentially, in their rupture were identified by a genome-wide analysis of PET-positive and -negative human aortic tissue samples. Further work is needed to study their role in AAA destabilization and weakening.

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Section: Discussionsupporting

confidence: 52%

Gene Expression Study in Positron Emission Tomography-Positive Abdominal Aortic Aneurysms Identifies CCL18 as a Potential Biomarker for Rupture Risk

Courtois

Nusgens

Hustinx

et al. 2014

Mol Med

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“…Glo1, the ubiquitous key enzyme in the detoxification of α-oxoaldehydes, including MG, is emerging as another major downstream target by which Nrf2 exerts its cytoprotective stress response functions [29] . Indeed, transcriptional control of Glo1 by Nrf2 provides a stress-responsive defense against MG-mediated glycative and oxidative stress, which has been implicated in the pathophysiology of various cellular dysfunctions and diseases, including brain microvascular endothelial barrier dysfunction and vascular diseases [46] , [47] , [48] . Specifically, there is clear evidence that MG accumulation at supra-physiological levels causes chemical modifications of proteins, nucleic acids and lipids [31] , and intensifies the mitochondrial production of ROS [58] , [101] , ultimately exposing cells to glycative and oxidative stress and consequent pleiotropic effects, including cellular dysfunctions, DNA damage and apoptosis [42] , [58] , [59] .…”

Section: Discussionmentioning

confidence: 99%

“…These apparently divergent functions imply that MG, like other reactive species, may exert different or even opposite biological effects, depending on its levels and the cellular context. Interestingly, Glo1 and MG-derived AGEs have been shown to play major and complex roles in vascular physiology and pathophysiology, including the pathogenesis of brain microvascular endothelial barrier dysfunctions [46] , [47] , [48] .…”

Section: Introductionmentioning

confidence: 99%

KRIT1 loss-of-function induces a chronic Nrf2-mediated adaptive homeostasis that sensitizes cells to oxidative stress: Implication for Cerebral Cavernous Malformation disease

Antognelli

Trapani

Monache

et al. 2018

Free Radical Biology and Medicine

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KRIT1 (CCM1) is a disease gene responsible for Cerebral Cavernous Malformations (CCM), a major cerebrovascular disease of proven genetic origin affecting 0.3–0.5% of the population.Previously, we demonstrated that KRIT1 loss-of-function is associated with altered redox homeostasis and abnormal activation of the redox-sensitive transcription factor c-Jun, which collectively result in pro-oxidative, pro-inflammatory and pro-angiogenic effects, suggesting a novel pathogenic mechanism for CCM disease and raising the possibility that KRIT1 loss-of-function exerts pleiotropic effects on multiple redox-sensitive mechanisms.To address this possibility, we investigated major redox-sensitive pathways and enzymatic systems that play critical roles in fundamental cytoprotective mechanisms of adaptive responses to oxidative stress, including the master Nrf2 antioxidant defense pathway and its downstream target Glyoxalase 1 (Glo1), a pivotal stress-responsive defense enzyme involved in cellular protection against glycative and oxidative stress through the metabolism of methylglyoxal (MG). This is a potent post-translational protein modifier that may either contribute to increased oxidative molecular damage and cellular susceptibility to apoptosis, or enhance the activity of major apoptosis-protective proteins, including heat shock proteins (Hsps), promoting cell survival.Experimental outcomes showed that KRIT1 loss-of-function induces a redox-sensitive sustained upregulation of Nrf2 and Glo1, and a drop in intracellular levels of MG-modified Hsp70 and Hsp27 proteins, leading to a chronic adaptive redox homeostasis that counteracts intrinsic oxidative stress but increases susceptibility to oxidative DNA damage and apoptosis, sensitizing cells to further oxidative challenges. While supporting and extending the pleiotropic functions of KRIT1, these findings shed new light on the mechanistic relationship between KRIT1 loss-of-function and enhanced cell predisposition to oxidative damage, thus providing valuable new insights into CCM pathogenesis and novel options for the development of preventive and therapeutic strategies.

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“…However, the function of Glo1 in macrovascular disease, particularly atherosclerosis, still remains uncertain [ 6 ]. While large epidemiologic studies have not been able to detect effects of different SNPs of the Glo1 gene on formation of atherosclerosis [ 12 , 13 ], Hanssen et al reported higher levels of advanced glycation end products in human carotid atherosclerotic plaques associated with a higher risk of plaque rupture [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…As recently reviewed by us [ 6 ], there is increasing evidence that the balance between production of MG and its detoxification by Glo1 might be involved in the formation and progression of atherosclerotic lesions. In addition, chemical inhibition of Glo1 has been shown to induce atherosclerosis in ApoE deficient mice [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

A Glyoxalase-1 Knockdown Does Not Have Major Short Term Effects on Energy Expenditure and Atherosclerosis in Mice

Wortmann

Hakimi

Fleming

et al. 2016

Journal of Diabetes Research

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Objective. Glyoxalase-1 is an enzyme detoxifying methylglyoxal (MG). MG is a potent precursor of advanced glycation endproducts which are regarded to be a key player in micro- and macrovascular damage. Yet, the role of Glo1 in atherosclerosis remains unclear. In this study, the effect of Glo1 on mouse metabolism and atherosclerosis is evaluated. Methods. Glo1 knockdown mice were fed a high fat or a standard diet for 10 weeks. Body weight and composition were investigated by Echo MRI. The PhenoMaster system was used to measure the energy expenditure. To evaluate the impact of Glo1 on atherosclerosis, Glo1KD mice were crossed with ApoE-knockout mice and fed a high fat diet for 14 weeks. Results. Glo1 activity was significantly reduced in heart, liver, and kidney lysates derived from Glo1KD mice. Yet, there was no increase in methylglyoxal-derived AGEs in all organs analyzed. The Glo1 knockdown did not affect body weight or body composition. Metabolic studies via indirect calorimetry did not show significant effects on energy expenditure. Glo1KD mice crossed to ApoE−/− mice did not show enhanced formation of atherosclerosis. Conclusion. A Glo1 knockdown does not have major short term effects on the energy expenditure or the formation of atherosclerotic plaques.

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Glyoxalase I (Glo1) and its metabolites in vascular disease

Cited by 12 publications

References 48 publications

Gene Expression Study in Positron Emission Tomography-Positive Abdominal Aortic Aneurysms Identifies CCL18 as a Potential Biomarker for Rupture Risk

Gene Expression Study in Positron Emission Tomography-Positive Abdominal Aortic Aneurysms Identifies CCL18 as a Potential Biomarker for Rupture Risk

KRIT1 loss-of-function induces a chronic Nrf2-mediated adaptive homeostasis that sensitizes cells to oxidative stress: Implication for Cerebral Cavernous Malformation disease

A Glyoxalase-1 Knockdown Does Not Have Major Short Term Effects on Energy Expenditure and Atherosclerosis in Mice

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