Glyoxalase Centennial: 100 Years of Glyoxalase Research and Emergence of Dicarbonyl Stress
Reducing methylglyoxal as a therapeutic target for diabetic heart disease Branka Vulesevic*, Ross W. Milne† and Erik J. Suuronen*1 *Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Canada, K1Y 4W7 †Diabetes and Atherosclerosis Laboratory, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Canada, K1Y 4W7
Biochemical Society Transactions
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Abstract Diabetes is a well-known risk factor for the development of cardiovascular diseases. Diabetes affects cardiac tissue through several different, yet interconnected, pathways. Damage to endothelial cells from direct exposure to high blood glucose is a primary cause of deregulated heart function. Toxic by-products of nonenzymatic glycolysis, mainly methylglyoxal, have been shown to contribute to the endothelial cell damage. Methylglyoxal is a precursor for advanced glycation end-products, and, although it is detoxified by the glyoxalase system, this protection mechanism fails in diabetes. Recent work has identified methylglyoxal as a therapeutic target for the prevention of cardiovascular complications in diabetes. A better understanding of the glyoxalase system and the effects of methylglyoxal may lead to more advanced strategies for treating cardiovascular complications associated with diabetes.
Diabetes as a cardiovascular risk factor Diabetes is a major risk factor for cardiovascular morbidity and mortality. Some of the complications associated with diabetes include heart disease, stroke, peripheral arterial disease, nephropathy, retinopathy and neuropathy. Coronary heart disease (atherosclerosis), heart failure and/or diabetic cardiomyopathy are all forms of diabetic heart disease (Figure 1). The accelerated development of atherosclerosis in diabetes affects all clinically important sites, including coronary arteries, and increases the risk of myocardial infarction [1]. Small vessel disease in diabetic patients may lead to increased cardiac load and compromise cardiac performance (impaired ventricular blood volume turnover and myocardial contractility), leading to heart failure [2]. In diabetic cardiomyopathy, diabetes causes damage to cardiac muscle in addition to, or in the absence of, coronary atherosclerosis. A common finding in biopsies of the diabetic heart is interstitial fibrosis and myocyte hypertrophy that occurs following the loss of cardiomyocytes [3]. These findings are a consequence of cardiac muscle change, and also ED (endothelial dysfunction), autonomic neuropathy, peripheral insulin resistance, hyperglycaemia and abnormal metabolism of fatty acids by the heart muscle. A major initiating cause in the pathogenesis of both vascular and heart disease in diabetes is considered to be ED [4], which also impairs angiogenic repair responses [5]. The
Key words: cardiovascular disease, diabetes, endothelial dysfunction, glyoxalase, methylglyoxal. Abbreviations: AGE, advanced glycation end-product; EC, endothelial cell; ED, endothelial dysfunction; Glo, glyoxalase; ICAM, intercellular adhesion molecule; JNK, c-Jun N-terminal kinase; MG, methylglyoxal; NAC, N-acetylcysteine; NF-κB, nuclear factor κB; RAGE, receptor for AGEs; ROS, reactive oxygen species; STZ, streptozotocin; VCAM, vascular cell adhesion molecule. 1 To whom correspondence should be addressed (email [email protected]).
Biochem. Soc. Trans. (2014) 42, 523–527; doi:10.1042/BST20130254
endothelial cell layer of the blood vessel regulates multiple aspects of vascular physiology such as maintenance of a semipermeable blood–tissue barrier, co-ordination of leucocyte trafficking, prevention of thrombosis and adjustment of vascular tone; and in the heart, it also provides humoral support for cardiomyocytes.
Role of endothelial cells in cardiac function Two principal types of ECs (endothelial cells) are present in the heart: the endocardial and the vascular ECs. Both types can affect cardiac performance because of their close proximity to adjacent cardiomyocytes. Myocardial contractions are modulated by the endothelium through cardioactive agents [nitric oxide (NO), prostanoids, endothelin, natriuretic peptides, angiotensin II and ROS (reactive oxygen species)] [6]. In cardiac diseases, damage to the ECs disrupts their regulation of heart function. Endothelial damage and dysfunction have been observed in myocardial capillaries in hypertension, hyperlipidaemia and ischaemia/reperfusion linked to diabetes [7]. In diabetic patients, signs of activation and a lower anti-inflammatory response in the heart’s endothelium is often followed by dysfunction of ECs and cardiomyocytes and, eventually, early stage cardiac failure [8]. EC apoptosis may also play a role in the pathophysiology of heart failure; ED can lead to repeated episodes of myocardial ischaemia and small infarcts that ultimately contribute to the development of heart failure [9]. ECs in the heart can directly regulate cardiomyocyte apoptosis induced by ROS, through neuregulin-1β/ErbB4 signalling [10]. In addition, an electronegative subfraction of low-density lipoprotein in the plasma may indirectly induce cardiomyocyte apoptosis by enhancing the secretion of harmful chemokines from ECs [11]. C The
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Figure 1 Cardiovascular complications in diabetes can lead to diabetic heart disease through several interconnected pathways
AGEs (advanced glycation end-products) and MG (methylglyoxal) in cardiovascular complications ECs are directly exposed to the excessive and/or fluctuating glucose levels in the blood. It is believed that ECs are ‘glucose-blind’ and very slowly regulate GLUT1 (facilitated glucose transporter member 1), resulting in a slow adjustment to increased glucose uptake [12]. The high-glucose-induced cellular injury that follows is, in part, a consequence of the generation of ROS, the accumulation of toxic byproducts of non-enzymatic glycolysis and the formation of AGEs [13]. AGEs are involved in the development of cardiovascular complications both through receptor-mediated and receptorindependent effects. Through RAGE (receptor for AGEs), AGEs can induce the expression of pro-inflammatory cytokines via pathways that depend on NF-κB (nuclear factor κB). In the vasculature of diabetic patients, an up-regulation of RAGE can be found on ECs, smooth muscle cells, mononuclear phagocytes and atherosclerotic plaques [14]. Receptor-independent effects of AGEs include extracellular matrix modification, NO scavenging and the glycation of signalling proteins [15]. AGE modification of collagens and elastins causes vascular stiffness and contributes to vascular stress [16]. The intracellular glycation of proteins has direct cytotoxic effects on the cells [17] through oxidation. This produces superoxide radicals, hydrogen peroxide and ROS, as well as RNS (reactive nitrogen species) [18]. When incubated with AGE before experimental ischaemia and reperfusion, primary rat cardiac microvascular ECs showed an increased release of LDH (lactate dehydrogenase) and increased caspase activity, generation of oxidative stress and formation of superoxide and peroxynitrite [19]. Among the most abundant precursors of AGE formation is the reactive α-oxoaldehyde MG. Increased formation of MG can promote the pathology of diabetic complications C The
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even in the presence of good glycaemic control [20]. Higher plasma levels of MG have been detected under postprandial conditions, as a consequence of increased dietary sugar [21]. Intracellularly produced MG crosses cell membranes, probably by passive diffusion, and humoral MG is mainly cell-derived. Additionally, minor amounts of MG might arise from ketone metabolism in the body, the degradation of threonine and lipid peroxidation. The involvement of ketone metabolism may explain why the highest levels of MG are found in Type 1 diabetes [22]. A reaction between reactive dicarbonyl compounds (3-deoxyglucasone, glyoxal and MG) and proteins and lipids generates AGEs and ALEs (advanced lipoxidation end-products), leading to a condition that has been termed ‘dicarbonyl stress’ [23]. Under normal physiological conditions, tissue levels of MG are maintained at a low level through catabolism to D-lactate by the glutathione-dependent glyoxalase system including Glo1 (glyoxalase I), reduced glutathione (GSH) and Glo2 (glyoxalase II) [24]. Aside from the glyoxalase system, several other enzymes are involved in the detoxification of MG, but to a lesser extent, including aldose reductase, betaine-aldehyde dehydrogenase, and 2-oxoaldehyde dehydrogenase [25]. In diabetes, both hyperglycaemia and oxidative stress are associated with glutathione depletion. This may be one of the reasons for impaired detoxification of MG and consequently its increased production and accumulation in the diabetic state. The sustained increase in the MG level and activation of RAGE may itself lead to decreased activities of the detoxification pathways [19]. Dicarbonyl stress activates a series of inflammatory responses that lead to accelerated vascular and cardiomyocyte damage in diabetes (Figure 2). Dicarbonyl stress is possibly playing a crucial role in impaired endothelium-dependent vasorelaxation, and in the development of long-term vascular complications [26]. MG-induced AGEs of mitochondrial proteins lead to a decline in mitochondrial function and have been hypothesized to contribute to ‘metabolic memory’ [27].
Glyoxalase Centennial: 100 Years of Glyoxalase Research and Emergence of Dicarbonyl Stress
Figure 2 Effects of MG accumulation in ECs MG-formed AGEs activate RAGEs and the inflammatory response in cells. MG-AGEs of mitochondrial proteins lead to the formation of ROS. MG also affects the DNA in ECs. MG increases oxidative stress in cardiomyocytes (CM), modifies Ca2 + handling and augments fibrosis of the extracellular matrix (ECM). Furthermore, MG induces the recruitment of monocytes in the microvasculature, causing an inflammatory condition related to diabetic vascular complications.
A period of 24 weeks of diabetes in rats can induce early signs of mild cardiac alterations: an increase in oxidative stress, inflammation and fibrosis which are mediated, at least partially, by glycation [28]. Accumulation of MG-formed AGEs can impair the activation of cell survival pathways during ischaemia: MG pre-sensitized cultured cardiomyocytes after exposure to experimental ischaemia/reperfusion injury lose thioredoxin, a cytoprotective molecule with anti-apoptotic function, probably due to its glycation [29]. Aldehydemediated dicarbonyl stress may also facilitate the formation of lipid-laden (foam) cells in the artery wall [30]. MG can also be involved directly in the pathophysiology of diabetes. It can activate various signalling pathways such as NF-κB, JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) pathways in ECs and leucocytes [31]. MG induces leucocyte recruitment to the microvasculature by increasing EC adhesion molecule expression, leading to increased inflammation [31]. In addition, MG can modify antioxidant enzymes such as glutathione reductase and glutathione peroxidase, and can increase superoxide formation in the mitochondria, both contributing to increased oxidative stress [32,33]. Potentially exacerbating the oxidative stress, MG can modify the antioxidant enzyme GAPDH (glyceraldehyde-3-phosphate dehydrogenase), thus inhibiting its activity [34]. MG also post-translationally modifies regulatory proteins [35]. An increase in intracellular MG can interfere with insulin signalling through inhibition of insulin-stimulated phosphorylation of PKB (protein kinase B) [36]. The glycation of insulin by MG reduces insulin production, leading to insulin resistance [37]. Carbonylation has also been identified to contribute to SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2 + ATPase 2a) activity loss and diastolic dysfunction in Type 1 diabetes [38]. Another target of MG identified in cardiovascular complications of diabetes is DNA. MG can cross-link
guanine residues of DNA with lysine or cysteine residues. Cross-linking events near the binding site of the DNA polymerase during DNA synthesis can severely inhibit DNA replication [39]. The direct effect of MG on neovascularization was shown in hypoxic EPCs (endothelial progenitor cells) cultured in high glucose, where ARNT1 (aryl hydrocarbon receptor nuclear translocator 1) modification by MG interrupted HIF-1α (hypoxia-inducible factor 1α) binding to its relevant promoters, resulting in reduced expression of CXCR4 (CXC chemokine receptor 4) (receptor for stromal-cell-derived factor-1) and eNOS (endothelial nitric oxide synthase) [5]. High glucose and diabetes also increases angiopoietin-2 transcription in ECs through MG modification of the co-repressor mSin3A, thus worsening vascular reactivity [40].
Effect of Glo1 overexpression and MG scavengers Studies that use Glo1 overexpression models have been able to very precisely help tease out the effects that glyoxal and MG have on different cells and tissues in diabetes. In vitro, Glo1 overexpression reduced oxidative stress in mouse renal mesangial cells cultured under conditions of high glucose [41]. In vivo, overexpression of the Glo1 enzyme reduced hyperglycaemia-induced oxidative stress in diabetic rats [42]. Our recent study suggests that reducing MG by overexpression of Glo1 in bone marrow cells can reverse the defective neovascularization associated with diabetes [43]. In addition, Glo1-overexpressing mice exposed for 8 weeks to STZ (streptozotocin)-induced insulin-dependent hyperglycaemia were resistant to ED [Glo1 overexpression reduced circulating E-selectin, ICAM (intercellular adhesion molecule) and VCAM (vascular cell adhesion molecule) levels], despite high blood glucose levels (21±3.4 mmol/l; Table 1). Glo1 overexpression was also shown to prevent C The
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Table 1 Levels of E-selectin, VCAM and ICAM in blood serum
Perspectives
collected from mice 8 weeks after STZ injection Four groups of mice were examined for endothelial dysfunction: Glo1-overexpressing mice and their wild-type (WT) littermates, injected
The need for protection of the heart’s vasculature in diabetes is crucial. Healthy ECs contribute to the prevention of atherosclerosis and small blood vessel dysfunction. Healthy blood vessels not only provide a good supply of oxygen and nutrients, but also play a role in homoeostasis and support cardiomyocytes. ECs exposed to dicarbonyl stress are in danger of functional loss and also, through passive diffusion, are a source of MG or glycation products for surrounding cells. The self-protective mechanisms of ECs can be impaired as a result of ROS, AGEs or direct reactions of regulating proteins or DNA with MG. The changes that follow can promote inflammation, cell death and fibrosis. MG reduction either through Glo1 overexpression or pharmacological AGE-detoxifying agents has led to increased survival and function of cardiomyocytes as well as ECs, despite diabetes. There is currently no gold standard treatment for ED in the diabetic or non-diabetic setting. Increasingly, pharmacological and non-pharmacological approaches are being developed as potential treatments for ED in diabetes. These are being designed to prevent the formation of AGEs or to scavenge AGEs or its precursor MG. Given the important contribution of EC function to vascular and cardiac cell biology, we expect an intensification of future research towards directly treating ECs in diabetes, subsequently lessening the burden of cardiovascular complications in diabetic patients.
with STZ (diabetic) or sodium citrate (control). Using an ELISA kit (Raybiotech), the concentration of adhesion molecules was measured and values normalized to WT-control (*P 0.043; **P 0.02 compared with all other groups). WT-control
Glo1-control
WT-diabetic
Glo1-diabetic
E-selectin VCAM
1.00 1.00
1.05 1.03
1.32* 1.12*
1.09 0.99
ICAM
1.00
1.00
6.66**
2.23**
CEL [N-(carboxyethyl)lysine] and MG-H1 (MG-derived hydroimidazolone) accumulation when compared with wildtype diabetic counterparts [44]. Using Glo1-overexpressing and Glo1-knockdown mice, it was shown that Glo1 activity regulates the sensitivity of the kidneys to diabetes-induced renal pathology, and, more interestingly, that the change in the rate of MG detoxification can determine when signs of diabetic nephropathy occur, even without the presence of hyperglycaemia [45]. Because of the known role of AGEs in vascular complications, the development of potential pharmacological inhibitors that can target already formed AGEs and/or prevent the formation of these glycated products and accumulation of its precursors is of particular interest. Several compounds have already been developed and tested, including aminoguanidine, ALT-946, ALT-711 (alagebrium), LR-90, fisetin and curcumin. The reduction of cardiovascular complications has been shown with the use of ALT-711. It successfully reduced systolic hypertension, by reducing large artery stiffness, enhancing cardiac output, left ventricular mass and cardiac expression of brain natriuretic peptide, and improving left ventricular diastolic distensibility [46]. Despite these beneficial outcomes, it has not yet been shown whether ALT711 can bind to MG directly, and in that way prevent its toxic effects. The often-prescribed insulin sensitizer metformin has been shown to reduce neointima formation in carotid arteries of insulin-resistant rats after balloon catheter injury by suppressing JNK and NF-κB pathway activation [47]. It can bind directly to some potent glycating agents such as MG [48]. The product of metformin/MG binding has been detected in the blood of metformin-treated diabetic patients [49]. NAC (N-acetylcysteine) normalizes blood pressure by binding directly to excess MG, thus restoring Ca2 + channel function, cytosolic Ca2 + and NO. NAC also leads to increased levels of tissue glutathione [21]. Treatment with the antioxidant NAC normalized oxidative-stress-mediated overexpression of myocardial PKCβ2 (protein kinase Cβ2) and overexpression of connective tissue growth factor, and attenuated the development of myocardial hypertrophy in rats with STZ-induced diabetes [50]. C The
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Funding This work was supported by the Heart and Stroke Foundation of Ontario [grant-in-aid number 000225 (to E.J.S. and R.W.M.)]. B.V. is the recipient of a Canadian Graduate Scholarship from the Canadian Institutes of Health Research.
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Reducing methylglyoxal as a therapeutic target for diabetic heart disease Branka Vulesevic*, Ross W. Milne† and Erik J. Suuronen*1 *Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Canada, K1Y 4W7 †Diabetes and Atherosclerosis Laboratory, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Canada, K1Y 4W7
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Abstract Diabetes is a well-known risk factor for the development of cardiovascular diseases. Diabetes affects cardiac tissue through several different, yet interconnected, pathways. Damage to endothelial cells from direct exposure to high blood glucose is a primary cause of deregulated heart function. Toxic by-products of nonenzymatic glycolysis, mainly methylglyoxal, have been shown to contribute to the endothelial cell damage. Methylglyoxal is a precursor for advanced glycation end-products, and, although it is detoxified by the glyoxalase system, this protection mechanism fails in diabetes. Recent work has identified methylglyoxal as a therapeutic target for the prevention of cardiovascular complications in diabetes. A better understanding of the glyoxalase system and the effects of methylglyoxal may lead to more advanced strategies for treating cardiovascular complications associated with diabetes.
Diabetes as a cardiovascular risk factor Diabetes is a major risk factor for cardiovascular morbidity and mortality. Some of the complications associated with diabetes include heart disease, stroke, peripheral arterial disease, nephropathy, retinopathy and neuropathy. Coronary heart disease (atherosclerosis), heart failure and/or diabetic cardiomyopathy are all forms of diabetic heart disease (Figure 1). The accelerated development of atherosclerosis in diabetes affects all clinically important sites, including coronary arteries, and increases the risk of myocardial infarction [1]. Small vessel disease in diabetic patients may lead to increased cardiac load and compromise cardiac performance (impaired ventricular blood volume turnover and myocardial contractility), leading to heart failure [2]. In diabetic cardiomyopathy, diabetes causes damage to cardiac muscle in addition to, or in the absence of, coronary atherosclerosis. A common finding in biopsies of the diabetic heart is interstitial fibrosis and myocyte hypertrophy that occurs following the loss of cardiomyocytes [3]. These findings are a consequence of cardiac muscle change, and also ED (endothelial dysfunction), autonomic neuropathy, peripheral insulin resistance, hyperglycaemia and abnormal metabolism of fatty acids by the heart muscle. A major initiating cause in the pathogenesis of both vascular and heart disease in diabetes is considered to be ED [4], which also impairs angiogenic repair responses [5]. The
Key words: cardiovascular disease, diabetes, endothelial dysfunction, glyoxalase, methylglyoxal. Abbreviations: AGE, advanced glycation end-product; EC, endothelial cell; ED, endothelial dysfunction; Glo, glyoxalase; ICAM, intercellular adhesion molecule; JNK, c-Jun N-terminal kinase; MG, methylglyoxal; NAC, N-acetylcysteine; NF-κB, nuclear factor κB; RAGE, receptor for AGEs; ROS, reactive oxygen species; STZ, streptozotocin; VCAM, vascular cell adhesion molecule. 1 To whom correspondence should be addressed (email [email protected]).
Biochem. Soc. Trans. (2014) 42, 523–527; doi:10.1042/BST20130254
endothelial cell layer of the blood vessel regulates multiple aspects of vascular physiology such as maintenance of a semipermeable blood–tissue barrier, co-ordination of leucocyte trafficking, prevention of thrombosis and adjustment of vascular tone; and in the heart, it also provides humoral support for cardiomyocytes.
Role of endothelial cells in cardiac function Two principal types of ECs (endothelial cells) are present in the heart: the endocardial and the vascular ECs. Both types can affect cardiac performance because of their close proximity to adjacent cardiomyocytes. Myocardial contractions are modulated by the endothelium through cardioactive agents [nitric oxide (NO), prostanoids, endothelin, natriuretic peptides, angiotensin II and ROS (reactive oxygen species)] [6]. In cardiac diseases, damage to the ECs disrupts their regulation of heart function. Endothelial damage and dysfunction have been observed in myocardial capillaries in hypertension, hyperlipidaemia and ischaemia/reperfusion linked to diabetes [7]. In diabetic patients, signs of activation and a lower anti-inflammatory response in the heart’s endothelium is often followed by dysfunction of ECs and cardiomyocytes and, eventually, early stage cardiac failure [8]. EC apoptosis may also play a role in the pathophysiology of heart failure; ED can lead to repeated episodes of myocardial ischaemia and small infarcts that ultimately contribute to the development of heart failure [9]. ECs in the heart can directly regulate cardiomyocyte apoptosis induced by ROS, through neuregulin-1β/ErbB4 signalling [10]. In addition, an electronegative subfraction of low-density lipoprotein in the plasma may indirectly induce cardiomyocyte apoptosis by enhancing the secretion of harmful chemokines from ECs [11]. C The
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Figure 1 Cardiovascular complications in diabetes can lead to diabetic heart disease through several interconnected pathways
AGEs (advanced glycation end-products) and MG (methylglyoxal) in cardiovascular complications ECs are directly exposed to the excessive and/or fluctuating glucose levels in the blood. It is believed that ECs are ‘glucose-blind’ and very slowly regulate GLUT1 (facilitated glucose transporter member 1), resulting in a slow adjustment to increased glucose uptake [12]. The high-glucose-induced cellular injury that follows is, in part, a consequence of the generation of ROS, the accumulation of toxic byproducts of non-enzymatic glycolysis and the formation of AGEs [13]. AGEs are involved in the development of cardiovascular complications both through receptor-mediated and receptorindependent effects. Through RAGE (receptor for AGEs), AGEs can induce the expression of pro-inflammatory cytokines via pathways that depend on NF-κB (nuclear factor κB). In the vasculature of diabetic patients, an up-regulation of RAGE can be found on ECs, smooth muscle cells, mononuclear phagocytes and atherosclerotic plaques [14]. Receptor-independent effects of AGEs include extracellular matrix modification, NO scavenging and the glycation of signalling proteins [15]. AGE modification of collagens and elastins causes vascular stiffness and contributes to vascular stress [16]. The intracellular glycation of proteins has direct cytotoxic effects on the cells [17] through oxidation. This produces superoxide radicals, hydrogen peroxide and ROS, as well as RNS (reactive nitrogen species) [18]. When incubated with AGE before experimental ischaemia and reperfusion, primary rat cardiac microvascular ECs showed an increased release of LDH (lactate dehydrogenase) and increased caspase activity, generation of oxidative stress and formation of superoxide and peroxynitrite [19]. Among the most abundant precursors of AGE formation is the reactive α-oxoaldehyde MG. Increased formation of MG can promote the pathology of diabetic complications C The
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even in the presence of good glycaemic control [20]. Higher plasma levels of MG have been detected under postprandial conditions, as a consequence of increased dietary sugar [21]. Intracellularly produced MG crosses cell membranes, probably by passive diffusion, and humoral MG is mainly cell-derived. Additionally, minor amounts of MG might arise from ketone metabolism in the body, the degradation of threonine and lipid peroxidation. The involvement of ketone metabolism may explain why the highest levels of MG are found in Type 1 diabetes [22]. A reaction between reactive dicarbonyl compounds (3-deoxyglucasone, glyoxal and MG) and proteins and lipids generates AGEs and ALEs (advanced lipoxidation end-products), leading to a condition that has been termed ‘dicarbonyl stress’ [23]. Under normal physiological conditions, tissue levels of MG are maintained at a low level through catabolism to D-lactate by the glutathione-dependent glyoxalase system including Glo1 (glyoxalase I), reduced glutathione (GSH) and Glo2 (glyoxalase II) [24]. Aside from the glyoxalase system, several other enzymes are involved in the detoxification of MG, but to a lesser extent, including aldose reductase, betaine-aldehyde dehydrogenase, and 2-oxoaldehyde dehydrogenase [25]. In diabetes, both hyperglycaemia and oxidative stress are associated with glutathione depletion. This may be one of the reasons for impaired detoxification of MG and consequently its increased production and accumulation in the diabetic state. The sustained increase in the MG level and activation of RAGE may itself lead to decreased activities of the detoxification pathways [19]. Dicarbonyl stress activates a series of inflammatory responses that lead to accelerated vascular and cardiomyocyte damage in diabetes (Figure 2). Dicarbonyl stress is possibly playing a crucial role in impaired endothelium-dependent vasorelaxation, and in the development of long-term vascular complications [26]. MG-induced AGEs of mitochondrial proteins lead to a decline in mitochondrial function and have been hypothesized to contribute to ‘metabolic memory’ [27].
Glyoxalase Centennial: 100 Years of Glyoxalase Research and Emergence of Dicarbonyl Stress
Figure 2 Effects of MG accumulation in ECs MG-formed AGEs activate RAGEs and the inflammatory response in cells. MG-AGEs of mitochondrial proteins lead to the formation of ROS. MG also affects the DNA in ECs. MG increases oxidative stress in cardiomyocytes (CM), modifies Ca2 + handling and augments fibrosis of the extracellular matrix (ECM). Furthermore, MG induces the recruitment of monocytes in the microvasculature, causing an inflammatory condition related to diabetic vascular complications.
A period of 24 weeks of diabetes in rats can induce early signs of mild cardiac alterations: an increase in oxidative stress, inflammation and fibrosis which are mediated, at least partially, by glycation [28]. Accumulation of MG-formed AGEs can impair the activation of cell survival pathways during ischaemia: MG pre-sensitized cultured cardiomyocytes after exposure to experimental ischaemia/reperfusion injury lose thioredoxin, a cytoprotective molecule with anti-apoptotic function, probably due to its glycation [29]. Aldehydemediated dicarbonyl stress may also facilitate the formation of lipid-laden (foam) cells in the artery wall [30]. MG can also be involved directly in the pathophysiology of diabetes. It can activate various signalling pathways such as NF-κB, JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) pathways in ECs and leucocytes [31]. MG induces leucocyte recruitment to the microvasculature by increasing EC adhesion molecule expression, leading to increased inflammation [31]. In addition, MG can modify antioxidant enzymes such as glutathione reductase and glutathione peroxidase, and can increase superoxide formation in the mitochondria, both contributing to increased oxidative stress [32,33]. Potentially exacerbating the oxidative stress, MG can modify the antioxidant enzyme GAPDH (glyceraldehyde-3-phosphate dehydrogenase), thus inhibiting its activity [34]. MG also post-translationally modifies regulatory proteins [35]. An increase in intracellular MG can interfere with insulin signalling through inhibition of insulin-stimulated phosphorylation of PKB (protein kinase B) [36]. The glycation of insulin by MG reduces insulin production, leading to insulin resistance [37]. Carbonylation has also been identified to contribute to SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2 + ATPase 2a) activity loss and diastolic dysfunction in Type 1 diabetes [38]. Another target of MG identified in cardiovascular complications of diabetes is DNA. MG can cross-link
guanine residues of DNA with lysine or cysteine residues. Cross-linking events near the binding site of the DNA polymerase during DNA synthesis can severely inhibit DNA replication [39]. The direct effect of MG on neovascularization was shown in hypoxic EPCs (endothelial progenitor cells) cultured in high glucose, where ARNT1 (aryl hydrocarbon receptor nuclear translocator 1) modification by MG interrupted HIF-1α (hypoxia-inducible factor 1α) binding to its relevant promoters, resulting in reduced expression of CXCR4 (CXC chemokine receptor 4) (receptor for stromal-cell-derived factor-1) and eNOS (endothelial nitric oxide synthase) [5]. High glucose and diabetes also increases angiopoietin-2 transcription in ECs through MG modification of the co-repressor mSin3A, thus worsening vascular reactivity [40].
Effect of Glo1 overexpression and MG scavengers Studies that use Glo1 overexpression models have been able to very precisely help tease out the effects that glyoxal and MG have on different cells and tissues in diabetes. In vitro, Glo1 overexpression reduced oxidative stress in mouse renal mesangial cells cultured under conditions of high glucose [41]. In vivo, overexpression of the Glo1 enzyme reduced hyperglycaemia-induced oxidative stress in diabetic rats [42]. Our recent study suggests that reducing MG by overexpression of Glo1 in bone marrow cells can reverse the defective neovascularization associated with diabetes [43]. In addition, Glo1-overexpressing mice exposed for 8 weeks to STZ (streptozotocin)-induced insulin-dependent hyperglycaemia were resistant to ED [Glo1 overexpression reduced circulating E-selectin, ICAM (intercellular adhesion molecule) and VCAM (vascular cell adhesion molecule) levels], despite high blood glucose levels (21±3.4 mmol/l; Table 1). Glo1 overexpression was also shown to prevent C The
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Table 1 Levels of E-selectin, VCAM and ICAM in blood serum
Perspectives
collected from mice 8 weeks after STZ injection Four groups of mice were examined for endothelial dysfunction: Glo1-overexpressing mice and their wild-type (WT) littermates, injected
The need for protection of the heart’s vasculature in diabetes is crucial. Healthy ECs contribute to the prevention of atherosclerosis and small blood vessel dysfunction. Healthy blood vessels not only provide a good supply of oxygen and nutrients, but also play a role in homoeostasis and support cardiomyocytes. ECs exposed to dicarbonyl stress are in danger of functional loss and also, through passive diffusion, are a source of MG or glycation products for surrounding cells. The self-protective mechanisms of ECs can be impaired as a result of ROS, AGEs or direct reactions of regulating proteins or DNA with MG. The changes that follow can promote inflammation, cell death and fibrosis. MG reduction either through Glo1 overexpression or pharmacological AGE-detoxifying agents has led to increased survival and function of cardiomyocytes as well as ECs, despite diabetes. There is currently no gold standard treatment for ED in the diabetic or non-diabetic setting. Increasingly, pharmacological and non-pharmacological approaches are being developed as potential treatments for ED in diabetes. These are being designed to prevent the formation of AGEs or to scavenge AGEs or its precursor MG. Given the important contribution of EC function to vascular and cardiac cell biology, we expect an intensification of future research towards directly treating ECs in diabetes, subsequently lessening the burden of cardiovascular complications in diabetic patients.
with STZ (diabetic) or sodium citrate (control). Using an ELISA kit (Raybiotech), the concentration of adhesion molecules was measured and values normalized to WT-control (*P 0.043; **P 0.02 compared with all other groups). WT-control
Glo1-control
WT-diabetic
Glo1-diabetic
E-selectin VCAM
1.00 1.00
1.05 1.03
1.32* 1.12*
1.09 0.99
ICAM
1.00
1.00
6.66**
2.23**
CEL [N-(carboxyethyl)lysine] and MG-H1 (MG-derived hydroimidazolone) accumulation when compared with wildtype diabetic counterparts [44]. Using Glo1-overexpressing and Glo1-knockdown mice, it was shown that Glo1 activity regulates the sensitivity of the kidneys to diabetes-induced renal pathology, and, more interestingly, that the change in the rate of MG detoxification can determine when signs of diabetic nephropathy occur, even without the presence of hyperglycaemia [45]. Because of the known role of AGEs in vascular complications, the development of potential pharmacological inhibitors that can target already formed AGEs and/or prevent the formation of these glycated products and accumulation of its precursors is of particular interest. Several compounds have already been developed and tested, including aminoguanidine, ALT-946, ALT-711 (alagebrium), LR-90, fisetin and curcumin. The reduction of cardiovascular complications has been shown with the use of ALT-711. It successfully reduced systolic hypertension, by reducing large artery stiffness, enhancing cardiac output, left ventricular mass and cardiac expression of brain natriuretic peptide, and improving left ventricular diastolic distensibility [46]. Despite these beneficial outcomes, it has not yet been shown whether ALT711 can bind to MG directly, and in that way prevent its toxic effects. The often-prescribed insulin sensitizer metformin has been shown to reduce neointima formation in carotid arteries of insulin-resistant rats after balloon catheter injury by suppressing JNK and NF-κB pathway activation [47]. It can bind directly to some potent glycating agents such as MG [48]. The product of metformin/MG binding has been detected in the blood of metformin-treated diabetic patients [49]. NAC (N-acetylcysteine) normalizes blood pressure by binding directly to excess MG, thus restoring Ca2 + channel function, cytosolic Ca2 + and NO. NAC also leads to increased levels of tissue glutathione [21]. Treatment with the antioxidant NAC normalized oxidative-stress-mediated overexpression of myocardial PKCβ2 (protein kinase Cβ2) and overexpression of connective tissue growth factor, and attenuated the development of myocardial hypertrophy in rats with STZ-induced diabetes [50]. C The
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Funding This work was supported by the Heart and Stroke Foundation of Ontario [grant-in-aid number 000225 (to E.J.S. and R.W.M.)]. B.V. is the recipient of a Canadian Graduate Scholarship from the Canadian Institutes of Health Research.
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