The cross-link breaker, N-phenacylthiazolium bromide prevents vascular advanced glycation end-product accumulation

Cooper, Mark E.; Thallas, Vicki; Forbes, Josephine M.; Scalbert, Elizabeth; Sastra, Stephen A.; Darby, Ian A.; Soulis, T

doi:10.1007/s001250051355

Cited by 89 publications

(57 citation statements)

References 15 publications

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“…The chemical diversity of AGE production is striking, but a major consequence of these reactions is the cross-linking of collagen molecules in connective tissues and especially vascular tissue, a key factor in the arterial inelasticity accompanying diabetes (Thorpe and Baynes, 2003). The prototype compounds in the crosslink breaker class, N-phenacylthiazolium bromide and 4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride (ALT-711), improve a number of disease endpoints in animal models of diabetes as well as aged nondiabetic animals, producing reductions in AGE levels in renal and vascular tissue, declines in myocardial and aortic stiffness, and diminished collagen deposition in a range of tissues (Cooper et al, 2000;Vaitkevicius et al, 2001). At present, the extent to which "cross-link cleavage" contributes to the clinical improvements in these animal models is subject to debate, because these compounds improve a number of biological endpoints in target tissues (e.g., reduction in inflammatory markers, profibrotic cytokines, etc.)…”

Section: Discussionmentioning

confidence: 99%

Hydralazine Inhibits Rapid Acrolein-Induced Protein Oligomerization: Role of Aldehyde Scavenging and Adduct Trapping in Cross-Link Blocking and Cytoprotection

Burcham¹,

Pyke²

2005

Mol Pharmacol

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Hydralazine strongly suppresses the toxicity of acrolein, a reactive aldehyde that contributes to numerous health disorders. At least two mechanisms may underlie the cytoprotection, both of which involve the nucleophilic hydrazine possessed by hydralazine. Under the simplest scenario, hydralazine directly scavenges free acrolein, decreasing intracellular acrolein availability and thereby suppressing macromolecular adduction. In a second "adduct-trapping" mechanism, the drug forms hydrazones with acrolein-derived Michael adducts in cell proteins, preventing secondary reactions of adducted proteins that may trigger cell death. To identify the most important mechanism, we explored these two pathways in mouse hepatocytes poisoned with the acrolein precursor allyl alcohol. Intense concentration-dependent adduct-trapping in cell proteins accompanied the suppression of toxicity by hydralazine. However, protective concentrations of hydralazine did not alter extracellular free acrolein levels, cellular glutathione loss, or protein carbonylation, suggesting that the cytoprotection is not due to minimization of intracellular acrolein availability. To explore ways whereby adduct-trapping might confer cytoprotection, the effect of hydralazine on acrolein-induced protein crosslinking was examined. Using bovine pancreas ribonuclease A as a model protein, acrolein caused rapid time-and concentration-dependent cross-linking, with dimerized protein detectable within 45 min of commencing protein modification. Lysine adduction in monomeric protein preceded the appearance of oligomers, whereas reductive methylation of protein amine groups abolished both adduction and oligomerization. Hydralazine inhibited cross-linking if added 30 min after commencing acrolein exposure but was ineffective if added after a 90-min delay. Adduct-trapping closely accompanied the inhibition of cross-linking by hydralazine. These findings suggest that cross-link blocking may contribute to hydralazine cytoprotection.

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Section: Discussionmentioning

confidence: 99%

Hydralazine Inhibits Rapid Acrolein-Induced Protein Oligomerization: Role of Aldehyde Scavenging and Adduct Trapping in Cross-Link Blocking and Cytoprotection

Burcham¹,

Pyke²

2005

Mol Pharmacol

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“…207) have been shown to improve arterial compliance in humans. 208 Animal and human studies have shown that AGE cross-link breakers, such as ALT-711 and alagebrium, decrease AGE levels 209,210 and tissue AGEs, 211,212 reverse their effects, [213][214][215][216] such as aortic stiffness, calcification, 195 and extracellular matrix accumulation, 212 and improve renal function by facilitating urinary excretion of the end products. (Table 1).…”

Section: Increasing the Breakdown Of Agesmentioning

confidence: 99%

Uremic Toxicity of Advanced Glycation End Products in CKD

Stinghen

Massy

Vlassara

et al. 2016

Journal of the American Society of Nephrology

184

165

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Advanced glycation end products (AGEs), a heterogeneous group of compounds formed by nonenzymatic glycation reactions between reducing sugars and amino acids, lipids, or DNA, are formed not only in the presence of hyperglycemia, but also in diseases associated with high levels of oxidative stress, such as CKD. In chronic renal failure, higher circulating AGE levels result from increased formation and decreased renal clearance. Interactions between AGEs and their receptors, including advanced glycation end product-specific receptor (RAGE), trigger various intracellular events, such as oxidative stress and inflammation, leading to cardiovascular complications. Although patients with CKD have a higher burden of cardiovascular disease, the relationship between AGEs and cardiovascular disease in patients with CKD is not fully characterized. In this paper, we review the various deleterious effects of AGEs in CKD that lead to cardiovascular complications and the role of these AGEs in diabetic nephropathy. We also discuss potential pharmacologic approaches to circumvent these deleterious effects by reducing exogenous and endogenous sources of AGEs, increasing the breakdown of existing AGEs, or inhibiting AGE-induced inflammation. Finally, we speculate on preventive and therapeutic strategies that focus on the AGE-RAGE axis to prevent vascular complications in patients with CKD.

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“…The reduction in collagen pepsin solubility (as a result of the increased number of acid-stable cross-links in diabetic collagen) is reflected in a marked increase in acid-insoluble collagen in diabetic tissue (9). Cleavage of AGE-induced cross-links by agents such as N-phenacylthiazolium bromide and ALT-711 restores collagen solubility (10,11) associated with a reduction in matrix accumulation within the kidney (11).…”

Section: Age and Extracellular Matrix Proteinsmentioning

confidence: 99%

Role of Advanced Glycation End Products in Diabetic Nephropathy

Forbes

Cooper

Oldfield

et al. 2003

Journal of the American Society of Nephrology

296

182

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Abstract. Nonenzymatic reactions between sugars and the free amino groups on proteins, lipids, and nucleic acids result in molecular dysfunction through the formation of advanced glycation end products (AGE). AGE have a wide range of chemical, cellular, and tissue effects through changes in charge, solubility, and conformation that characterize molecular senescence. AGE also interact with specific receptors and binding proteins to influence the expression of growth factors and cytokines, including TGF-␤1 and CTGF, thereby regulating the growth and proliferation of the various renal cell types. It seems that many of the pathogenic changes that occur in diabetic nephropathy may be induced by AGE. Drugs that either inhibit the formation of AGE or break AGE-induced cross-links have been shown to be renoprotective in experimental models of diabetic nephropathy. AGE are able to stimulate directly the production of extracellular matrix and inhibit its degradation. AGE modification of matrix proteins is also able to disrupt matrix-matrix and matrix-cell interactions, contributing to their profibrotic action. In addition, AGE significantly interact with the renin-angiotensin system. Recent studies have suggested that angiotensin-converting enzyme inhibitors are able to reduce the accumulation of AGE in diabetes, possibly via the inhibition of oxidative stress. This interaction may be a particularly important pathway for the development of AGE-induced damage, as it also can be attenuated by antioxidant therapy. In addition to being a consequence of oxidative stress, it is now clear that AGE can promote the generation of reactive oxygen species. It is likely that therapies that inhibit the formation of AGE will form an important part of future therapy in patients with diabetes, acting synergistically with conventional approaches to prevent diabetic renal injury.

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The cross-link breaker, N-phenacylthiazolium bromide prevents vascular advanced glycation end-product accumulation

Cited by 89 publications

References 15 publications

Hydralazine Inhibits Rapid Acrolein-Induced Protein Oligomerization: Role of Aldehyde Scavenging and Adduct Trapping in Cross-Link Blocking and Cytoprotection

Hydralazine Inhibits Rapid Acrolein-Induced Protein Oligomerization: Role of Aldehyde Scavenging and Adduct Trapping in Cross-Link Blocking and Cytoprotection

Uremic Toxicity of Advanced Glycation End Products in CKD

Role of Advanced Glycation End Products in Diabetic Nephropathy

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