Glyoxalase I Is Critical for Human Retinal Capillary Pericyte Survival under Hyperglycemic Conditions

Miller, Antonia Grace; Smith, Duane H.; Bhat, Manjunatha B.; Nagaraj, Ram H.

doi:10.1074/jbc.m513813200

Cited by 96 publications

(88 citation statements)

References 53 publications

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“…Others have suggested that hyperglycemia causes pericyte loss by apoptosis (6)(7)(8). In this study, we postulated that hyperglycemia-induced Ang2 overexpression in endothelial cells, in turn, caused apoptotic cell death of pericytes.…”

Section: Discussionmentioning

confidence: 69%

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Angiopoietin 2 Induces Pericyte Apoptosis via α3β1 Integrin Signaling in Diabetic Retinopathy

et al. 2014

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Pericyte loss is an early characteristic change in diabetic retinopathy (DR). Despite accumulating evidence that hyperglycemia-induced angiopoietin 2 (Ang2) has a central role in pericyte loss, the precise molecular mechanism has not been elucidated. This study investigated the role of Ang2 in pericyte loss in DR. We demonstrated that pericyte loss occurred with Ang2 increase in the diabetic mouse retina and that the source of Ang2 could be the endothelial cell. Ang2 induced pericyte apoptosis via the p53 pathway under high glucose, whereas Ang2 alone did not induce apoptosis. Integrin, not Tie-2 receptor, was involved for Ang2-induced pericyte apoptosis under high glucose as an Ang2 receptor. High glucose changed the integrin expression pattern, which increased integrin α3 and β1 in the pericyte. Furthermore, Ang2-induced pericyte apoptosis in vitro was effectively attenuated via p53 suppression by blocking integrin α3 and β1. Although intravitreal injection of Ang2 induced pericyte loss in C57BL/6J mice retina in vivo, intravitreal injection of anti-integrin α3 and β1 antibodies attenuated Ang2-induced pericyte loss. Taken together, Ang2 induced pericyte apoptosis under high glucose via α3β1 integrin. Glycemic control or blocking Ang2/integrin signaling could be a potential therapeutic target to prevent pericyte loss in early DR.

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Section: Discussionmentioning

confidence: 69%

“…However, Ang2 plays a critical role in pericyte loss in DR. Hyperglycemia causes pericyte apoptosis and, ultimately, pericyte loss (6)(7)(8). Ang2 increases in the vitreous of patients with proliferative DR (9).…”

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confidence: 99%

Angiopoietin 2 Induces Pericyte Apoptosis via α3β1 Integrin Signaling in Diabetic Retinopathy

et al. 2014

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“…The over-production of NO not only provides an essential precursor for ONOO Ϫ generation, but also contributes to pericyte loss in diabetic retinopathy. 24 Therefore, we determined whether heavily oxidized and glycated LDL (HOG-LDL) induces iNOS expression and oxidative stress in cultured human retinal capillary pericytes. As shown in Figure 1, iNOS expression ( Figure 1A) and NO production ( Figure 1B) were very low in pericytes treated with vehicle or N-LDL.…”

Section: Hog-ldl Increases No Production Inos Expression and 3-nitrmentioning

confidence: 99%

Tyrosine Nitration of Prostacyclin Synthase Is Associated with Enhanced Retinal Cell Apoptosis in Diabetes

Zou

et al. 2011

The American Journal of Pathology

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The risk of diabetic retinopathy is associated with the presence of both oxidative stress and toxic eicosanoids. Whether oxidative stress actually causes diabetic retinopathy via the generation of toxic eicosanoids, however, remains unknown. The aim of the present study was to determine whether tyrosine nitration of prostacyclin synthase (PGIS) contributes to retinal cell death in vitro and in vivo. Exposure of human retinal pericytes to heavily oxidized and glycated LDL (HOG-LDL), but not native forms of LDL (N-LDL), for 24 hours significantly increased pericyte apoptosis, accompanied by increased tyrosine nitration of PGIS and decreased PGIS activity. Inhibition of the thromboxane receptor or cyclooxygenase-2 dramatically attenuated HOG-LDL-induced apoptosis without restoring PGIS activity. Administration of superoxide dismutase (to scavenge superoxide anions) or L-N G -nitroarginine methyl ester (L-NAME, a nonselective nitric oxide synthase inhibitor) restored PGIS activity and attenuated pericyte apoptosis. In Akita mouse retinas, diabetes increased intraretinal levels of oxidized LDL and glycated LDL, induced PGIS nitration, enhanced apoptotic cell death, and impaired blood-retinal barrier function. Chronic administration of tempol, a superoxide scavenger, reduced intraretinal oxidized LDL and glycated LDL levels, PGIS nitration, and retina cell apoptosis, thereby preserving the integrity of blood-retinal barriers. In conclusion, oxidized LDL-mediated PGIS nitration and associated thromboxane receptor stimulation might be important in the initiation and progression of dia- Loss of pericytes from retinal microvessels is an important event in the early stage of diabetic retinopathy, which is associated with increased pericyte apoptosis. Although the mechanisms responsible for pericyte apoptosis remain unclear, several studies have shown associations between dyslipidemia and the severity of diabetic retinopathy.1,2 Specifically, elevated levels of triglycerides, low density lipoprotein (LDL), and apolipoprotein B, a principal lipoprotein component of LDL, have been associated with diabetic retinopathy.1 However, these associations are relatively weak, leading us to hypothesize that the key contribution of lipoproteins to the propagation of diabetic retinopathy is not through changes in their plasma levels but, rather, through extravasation via a disrupted blood-retinal barrier and subsequent modification by glycation and oxidation. In support of this model, we have demonstrated that oxidized LDL is present in the retina in diabetic humans in proportion to the severity of diabetic retinopathy, 3 and in cell culture studies we have shown that oxidized LDL has injurious effects on retinal pericytes. 4,5

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“…40 for review), which certainly play a role in diseases such as diabetes (41), very recent findings showed that methylglyoxal also causes protein modifications that can lead to signal transduction and regulation of gene expression (42). Thus, it is possible that allosteric regulation of PfGloI might play a role in the conversion of 2-oxoaldehydes as signal molecules.…”

mentioning

confidence: 99%

Allosteric Coupling of Two Different Functional Active Sites in Monomeric Plasmodium falciparum Glyoxalase I

Deponte

Sturm

Mittler

et al. 2007

Journal of Biological Chemistry

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Glyoxalase I (GloI) catalyzes the glutathione-dependent conversion of 2-oxoaldehydes to S-2-hydroxyacylglutathione derivatives. Studies on GloI from diverse organisms such as man, bacteria, yeast, and different parasites show striking differences among these potentially isofunctional enzymes as far as metal content and the number of active sites per subunit are concerned. So far, it is not known whether this structural variability is linked to catalytic or regulatory features in vivo. Here we show that recombinant GloI from the malaria parasite Plasmodium falciparum has a high-and a low-affinity binding site for the diastereomeric hemithioacetals formed by addition of glutathione to methylglyoxal. Both active sites of the monomeric enzyme are functional and have similar k cat app values. Proteolytic susceptibility studies and detailed analyses of the steady-state kinetics of active-site mutants suggest that both reaction centers can adopt two discrete conformations and are allosterically coupled. As a result of the positive homotropic allosteric coupling, P. falciparum GloI has an increased affinity at low substrate concentrations and an increased activity at higher substrate concentrations. This could also be the case for GloI from yeast and other organisms. Potential physiologically relevant differences between monomeric GloI and homodimeric GloI are discussed. Our results provide a strong basis for drug development strategies and significantly enhance our understanding of GloI kinetics and structure-function relationships. Furthermore, they extend the current knowledge on allosteric regulation of monomeric proteins in general.The ubiquitous glyoxalase system comprises two enzymes that catalyze the sequential glutathione (or in rare cases, trypanothione)-dependent conversion of methylglyoxal and other 2-oxoaldehydes to 2-hydroxycarboxylic acids. In this reaction, rate-determining dehydration of hydrated 2-oxoaldehyde is followed by the spontaneous formation of diastereomeric hemithioacetals between GSH and the 2-oxoaldehyde (Fig. 1A) (1, 2). The first enzyme, glyoxalase I (GloI 2 ; EC 4.4.1.5), isomerizes both hemithioacetal adducts to a single diastereomeric thioester. The second enzyme, glyoxalase II (EC 3.1.2.6), hydrolyzes the thioester, releasing GSH and 2-hydroxycarboxylic acid (see Ref. 3 for review). Thus, GSH acts as a coenzyme and is not consumed in the overall reaction. Despite decades of intensive research, the physiological functions of the glyoxalase system and the sources, toxicities, and potential functions of its substrates are still a matter of debate.To date, GloI from different organisms can be roughly subdivided into three different groups according to the type of divalent cation bound at the active site and the number of subunits forming the functional enzyme (Fig. 1B). For example, GloI from human and yeast (4) and Plasmodium falciparum (5) prefers Zn 2ϩ , whereas GloI from several bacteria such as Escherichia coli (6) and Yersinia pestis, Pseudomonas aeruginosa, and Neisseria meningitid...

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Glyoxalase I Is Critical for Human Retinal Capillary Pericyte Survival under Hyperglycemic Conditions

Cited by 96 publications

References 53 publications

Angiopoietin 2 Induces Pericyte Apoptosis via α3β1 Integrin Signaling in Diabetic Retinopathy

Angiopoietin 2 Induces Pericyte Apoptosis via α3β1 Integrin Signaling in Diabetic Retinopathy

Tyrosine Nitration of Prostacyclin Synthase Is Associated with Enhanced Retinal Cell Apoptosis in Diabetes

Allosteric Coupling of Two Different Functional Active Sites in Monomeric Plasmodium falciparum Glyoxalase I

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