Breakers of advanced glycation end products restore large artery properties in experimental diabetes

Wolffenbuttel, Bruce H. R.; Boulanger, Chantal M.; Crijns, F. R. L.; Huijberts, M. S. P.; Poitevin, Pierre; Swennen, Geertje; Vasan, Sara; Egan, John J.; Ulrich, Peter; Cerami, Anthony; Lévy, Bernard

doi:10.1073/pnas.95.8.4630

Cited by 385 publications

(273 citation statements)

References 34 publications

(35 reference statements)

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“…Apart from plasma AGE and haemoglobin-AGE assays, few tools are currently available for monitoring the effects of interventions aimed at reducing AGE accumulation, such as aminoguanidine or AGE-breakers [16,17,18]. The AFR could be a promising alternative for monitoring interventions for the following reasons: (i) disparate changes between plasma and tissue AGE levels may occur [19], and tissue AGE accumulation may be more relevant to the development of tissue damage than plasma levels; (ii) current plasma AGE assays are time-consuming and the results can be difficult to reproduce or standardise between laboratories.…”

Section: Discussionmentioning

confidence: 99%

“…In a DCCT substudy, skin AGE levels explained 19 to 36% of the variance in the incidence of long-term diabetic complications in intensively treated patients, and 14 to 51% in conventionally treated patients [8]. These associations remained after adjustment for HbA 1 c. Experimentally, prevention of AGE accumulation has been shown to reduce the development of several diabetic complications [16,17,18].…”

Section: Introductionmentioning

confidence: 99%

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Simple non-invasive assessment of advanced glycation endproduct accumulation

Meerwaldt¹,

Graaff

Oomen³

et al. 2004

Diabetologia

650

815

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Aims/hypothesis. The accumulation of AGE is thought to play a role in the pathogenesis of chronic complications of diabetes mellitus and renal failure. All current measurements of AGE accumulation require invasive sampling. We exploited the fact that several AGE exhibit autofluorescence to develop a non-invasive tool for measuring skin AGE accumulation, the Autofluorescence Reader (AFR). We validated its use by comparing the values obtained using the AFR with the AGE content measured in extracts from skin biopsies of diabetic and control subjects. Methods. Using the AFR with an excitation light source of 300-420 nm, fluorescence of the skin was measured at the arm and lower leg in 46 patients with diabetes (Type 1 and 2) and in 46 age-and sexmatched control subjects, the majority of whom were Caucasian. Autofluorescence was defined as the average fluorescence per nm over the entire emission spectrum (420-600 nm) as ratio of the average fluorescence per nm over the 300-420-nm range. Skin biopsies were obtained from the same site of the arm, and analysed for collagen-linked fluorescence (CLF) and specific AGE: pentosidine, N ε -(carboxymethyl)-lysine (CML) and N ε -(carboxyethyl)lysine (CEL).Results. Autofluorescence correlated with CLF, pentosidine, CML, and CEL (r=0.47-0.62, p≤0.002). In 32 of 46 diabetic patients (70%), autofluorescence values were above the 95% CI of the mean value in control subjects, and correlated with age, diabetes duration, mean HbA 1 c of the previous year and creatinine levels. Conclusions/interpretation. The AFR offers a simple alternative to invasive measurement of AGE accumulation and, to date, has been validated in non-pigmented skin. The AFR may prove to be a useful clinical tool for rapid risk assessment of AGE-related long-term complications in diabetes mellitus and in other conditions associated with AGE accumulation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Simple non-invasive assessment of advanced glycation endproduct accumulation

Meerwaldt¹,

Graaff

Oomen³

et al. 2004

Diabetologia

650

815

View full text Add to dashboard Cite

show abstract

“…In particular, tissue strength is dependent upon the number of crosslinks present (15). Accumulation of AGEs is correlated with increased tissue stiffness in arteries, lenses, skin, tendons (23)(24)(25)(26)(27), and articular cartilage (20,28). Moreover, an increase in AGEs renders tissue increasingly brittle, and thus more prone to mechanical damage.…”

mentioning

confidence: 99%

Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis

DeGroot¹,

Verzijl²,

Wijk

et al. 2004

Arthritis & Rheumatism

181

114

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Objective. Osteoarthritis (OA) is one of the most prevalent and disabling chronic conditions affecting the elderly. Its etiology is largely unknown, but age is the most prominent risk factor. The current study was designed to test whether accumulation of advanced glycation end products (AGEs), which are known to adversely affect cartilage turnover and mechanical properties, provides a molecular mechanism by which aging contributes to the development of OA.Methods. The hypothesis that elevated AGE levels predispose to the development of OA was tested in the canine anterior cruciate ligament transection (ACLT) model of experimental OA. Cartilage AGE levels were enhanced in young dogs by intraarticular injections of ribose. This mimics the accumulation of AGEs without the interference of other age-related changes. The severity of OA was then assessed 7 weeks after ACLT surgery in dogs with normal versus enhanced AGE levels.Results. Intraarticular injections of ribose enhanced cartilage AGE levels ϳ5-fold, which is similar to the normal increase that is observed in old dogs. ACLT surgery resulted in more-pronounced OA in dogs with enhanced AGE levels. This was observed as increased collagen damage and enhanced release of proteoglycans. The attempt to repair the matrix damage was impaired; proteoglycan synthesis and retention were decreased at enhanced AGE levels. Mankin grading of histology sections also revealed more-severe OA in animals with enhanced AGE levels.Conclusion. These findings demonstrate increased severity of OA at higher cartilage AGE levels and provide the first in vivo experimental evidence for a molecular mechanism by which aging may predispose to the development of OA.The population of Western society is aging rapidly. Consequently, age-related diseases will increase greatly over the coming decades and will have a great impact on the quality of life of the elderly. Osteoarthritis (OA) is one of the most prevalent and disabling chronic conditions affecting the elderly and poses a significant public health problem (1). The most prominent feature of OA is the progressive destruction of articular cartilage, resulting in impaired joint motion, severe pain, and, ultimately, disability (2). As yet, the etiology of OA remains largely unknown. The incidence of OA increases with age: Ͼ50% of the population over 60 years of age is affected (3,4). Although age is identified as the main risk factor for the development of OA, the mechanism by which aging is involved remains unclear. Age-related changes in the articular cartilage are expected to play an important role in the susceptibility of cartilage to OA.Articular cartilage derives its mechanical properties from its extracellular matrix. This matrix is composed of type II collagen, which forms a 3-dimensional network that provides the cartilage with resistance to tensile forces (5).

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“…67 Recently, compounds have also been developed that are capable of breaking pre-established AGE proteinprotein crosslinks. [79][80][81] Two crosslink breaker compounds are undergoing evaluation: 3-phenacylthiazolium bromide (PTB) and 4.5-dimethyl-3-phenacylthiazolium chloride (DPTC) (ALT-711). These compounds, which share a common thiazolium structure, have the ability to reduce tissue content of AGEs in experimental diabetes, 80 ameliorate age-related myocardial stiffness, 81 and reverse hyperglycaemia-related arterial distensibility.…”

Section: Protein Glycationmentioning

confidence: 99%

“…[79][80][81] Two crosslink breaker compounds are undergoing evaluation: 3-phenacylthiazolium bromide (PTB) and 4.5-dimethyl-3-phenacylthiazolium chloride (DPTC) (ALT-711). These compounds, which share a common thiazolium structure, have the ability to reduce tissue content of AGEs in experimental diabetes, 80 ameliorate age-related myocardial stiffness, 81 and reverse hyperglycaemia-related arterial distensibility. 73,82 Oxidation Free radicals are unstable chemical derivatives of oxygen that carry unpaired electrons and are the by-products of metabolism, especially mitochondrial oxidative phosphorylation.…”

Section: Protein Glycationmentioning

confidence: 99%