Modulation of aldose reductase activity through S-thiolation by physiological thiols

Cappiello, Mario; Amodeo, Pietro; Méndez, Blanca López; Scaloni, Andrea; Vilardo, Pier Giuseppe; Cecconi, I; Monte, Massimo Dal; Banditelli, S; Talamo, Fabio; Micheli, Vanna; Giblin, Frank J.; Corso, Antonella Del; Mura, Umberto

doi:10.1016/s0009-2797(00)00286-6

Cited by 20 publications

(9 citation statements)

References 24 publications

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“…The partial inhibitory effect of alrestatin could be attributable to posttranscriptional modification of AR such as S-thiolation, which makes this enzyme less sensitive to inhibitors. 43 Our finding that HG increased ERK1/2 and p38 MAPK phosphorylation and that the inhibitors of ERK1/2 but not the inhibitors of p38 MAPK or dominant-negative p38 MAPK minimized a HG-induced increase in Ang II levels suggests that HG or AGEs via ERK1/2, but not p38 MAPK, activation could increase rVCh activity and Ang II generation. However, ERK1/2 activation either by HG or by AGEs 7 was transient.…”

Section: Lavrentyev Et Al Hg Stimulates Ang II Generation In Rat Vsmcsmentioning

confidence: 74%

Mechanism of High Glucose–Induced Angiotensin II Production in Rat Vascular Smooth Muscle Cells

Lavrentyev

Estes

Malik

2007

Circulation Research

116

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Abstract-Angiotensin II (Ang II), a circulating hormone that can be synthesized locally in the vasculature, has been implicated in diabetes-associated vascular complications. This study was conducted to determine whether high glucose (HG) (Ϸ23.1 mmol/L), a diabetic-like condition, stimulates Ang II generation and the underlying mechanism of its production in rat vascular smooth muscle cells. The contribution of various enzymes involved in Ang II generation was investigated by silencing their expression with small interfering RNA in cells exposed to normal glucose (Ϸ4.1 mmol/L) and HG. Angiotensin I (Ang I) was generated from angiotensinogen by cathepsin D in the presence of normal glucose or HG. Although HG did not affect the rate of angiotensinogen conversion, it decreased expression of angiotensinconverting enzyme (ACE), downregulated ACE-dependent Ang II generation, and upregulated rat vascular chymasedependent Ang II generation. The ACE inhibitor captopril reduced Ang II levels in the media by 90% in the presence of normal glucose and 19% in HG, whereas rat vascular chymase silencing reduced Ang II production in cells exposed to HG but not normal glucose. The glucose transporter inhibitor cytochalasin B, the aldose reductase inhibitor alrestatin, and the advanced glycation end product formation inhibitor aminoguanidine attenuated HG-induced Ang II generation. HG caused a transient increase in extracellular signal-regulated kinase (ERK)1/2 phosphorylation, and ERK1/2 inhibitors reduced Ang II accumulation by HG. These data suggest that polyol pathway metabolites and AGE can stimulate rat vascular chymase activity via ERK1/2 activation and increase Ang II production. In addition, decreased Ang II degradation, which, in part, could be attributable to a decrease in angiotensin-converting enzyme 2 expression observed in HG, contributes to increased accumulation of Ang II in vascular smooth muscle cells by HG. (Circ Res. 2007;101:455-464.)Key Words: ACE Ⅲ vascular chymase Ⅲ angiotensin Ⅲ VSMC Ⅲ high glucose A ngiotensin (Ang) II, a biologically active component of the renin-angiotensin system (RAS), plays an important role in regulating salt, water, and vascular homeostasis. 1 According to the classical view of RAS, Ang II is cleaved from angiotensin I (Ang I) by angiotensin-converting enzyme (ACE), 2 which is localized on the surface of endothelial cells but also has been shown to be present in the media of aorta and to a lesser degree in adventitia. 3 A soluble form of ACE can be found in plasma. 4 Ang I is formed from the circulating precursor angiotensinogen (AGT) secreted from the liver and is cleaved by renin secreted from the juxtaglomerular cells of the kidney. 5 The presence of local RAS has also been demonstrated in several tissues including vascular wall. 6 AGT is the only known precursor of Ang I and Ang II and is synthesized in vascular smooth muscle cells (VSMCs). 7 Evidence for the presence of renin in vascular tissue has been documented, 8 but renin-like activity in aortic tissue falls to very low ...

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Section: Lavrentyev Et Al Hg Stimulates Ang II Generation In Rat Vsmcsmentioning

confidence: 74%

Mechanism of High Glucose–Induced Angiotensin II Production in Rat Vascular Smooth Muscle Cells

Lavrentyev

Estes

Malik

2007

Circulation Research

116

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“…The first enzyme of the polyol pathway is aldose reductase, which converts glucose to sorbitol through an NADPH-dependent reaction. Interestingly, aldose reductase activity appears to be regulated by S -glutathionylation (Table 2; Cappiello et al, 2001), providing an additional link between GSH and these disease states. Changes in GSH-dependent enzyme activities, such as glutathione peroxidase, γ-glutamyl transpeptidase, and glutathione S -transferase are also noted in diabetes.…”

Section: Diabetes Mellitusmentioning

confidence: 99%

Glutathione dysregulation and the etiology and progression of human diseases

Ballatori

Krance

Notenboom

et al. 2009

BCHM

910

679

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Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and as a result, disturbances in GSH homeostasis are implicated in the etiology and/or progression of a number of human diseases, including cancer, diseases of aging, cystic fibrosis, and cardiovascular, inflammatory, immune, metabolic, and neurodegenerative diseases. Owing to the pleiotropic effects of GSH on cell functions, it has been quite difficult to define the role of GSH in the onset and/or the expression of human diseases, although significant progress is being made. GSH levels, turnover rates, and/or oxidation state can be compromised by inherited or acquired defects in the enzymes, transporters, signaling molecules, or transcription factors that are involved in its homeostasis, or from exposure to reactive chemicals or metabolic intermediates. GSH deficiency or a decrease in the GSH/glutathione disulfide ratio manifests itself largely through an increased susceptibility to oxidative stress, and the resulting damage is thought to be involved in diseases, such as cancer, Parkinson's disease, and Alzheimer's disease. In addition, imbalances in GSH levels affect immune system function, and are thought to play a role in the aging process. Just as low intracellular GSH levels decrease cellular antioxidant capacity, elevated GSH levels generally increase antioxidant capacity and resistance to oxidative stress, and this is observed in many cancer cells. The higher GSH levels in some tumor cells are also typically associated with higher levels of GSH-related enzymes and transporters. Although neither the mechanism nor the implications of these changes are well defined, the high GSH content makes cancer cells chemoresistant, which is a major factor that limits drug treatment. The present report highlights and integrates the growing connections between imbalances in GSH homeostasis and a multitude of human diseases.

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“…GSH synthesis and metabolism are known to be altered during hyperglycemia and diabetes. Interestingly, aldose reductase activity appears to be regulated by S-glutathionylation providing an additional link between GSH and these disease states (Cappiello et al, 2001;Giral et al, 2008). GSH levels appear to be diminished by at least two different mechanisms: direct effects of glucose and insulin on GSH synthesis, and by the consumption of a cofactor required for GSH regeneration from GSSG (i.e., NAPDH) via the polyol pathway.…”

Section: Th1/th2 Immune Responses and The Role Of Gsh In Human Patholmentioning

confidence: 99%

Glutathione and glutathione derivatives in immunotherapy

Fraternale

Brundu

Magnani

2016

Biological Chemistry

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Reduced glutathione (GSH) is the most prevalent non-protein thiol in animal cells. Its de novo and salvage synthesis serves to maintain a reduced cellular environment, which is important for several cellular functions. Altered intracellular GSH levels are observed in a wide range of pathologies, including several viral infections, as well as in aging, all of which are also characterized by an unbalanced Th1/Th2 immune response. A central role in influencing the immune response has been ascribed to GSH. Specifically, GSH depletion in antigen-presenting cells (APCs) correlates with altered antigen processing and reduced secretion of Th1 cytokines. Conversely, an increase in intracellular GSH content stimulates IL-12 and/or IL-27, which in turn induces differentiation of naive CD4+ T cells to Th1 cells. In addition, GSH has been shown to inhibit the replication/survival of several pathogens, i.e. viruses and bacteria. Hence, molecules able to increase GSH levels have been proposed as new tools to more effectively hinder different pathogens by acting as both immunomodulators and antimicrobials. Herein, the new role of GSH and its derivatives as immunotherapeutics will be discussed.

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Modulation of aldose reductase activity through S-thiolation by physiological thiols

Cited by 20 publications

References 24 publications

Mechanism of High Glucose–Induced Angiotensin II Production in Rat Vascular Smooth Muscle Cells

Mechanism of High Glucose–Induced Angiotensin II Production in Rat Vascular Smooth Muscle Cells

Glutathione dysregulation and the etiology and progression of human diseases

Glutathione and glutathione derivatives in immunotherapy

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