Aminoguanidine Prevents Diabetes-Induced Arterial Wall Protein Cross-Linking

Brownlee, Michael; Vlassara, Helen; Kooney, A.; Ulrich, Peter; Cerami, Anthony

doi:10.1126/science.3487117

Cited by 1,122 publications

(650 citation statements)

References 28 publications

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“…Numerous studies have demonstrated that aminoguanidine is an inhibitor of many manifestations of nonenzymatic glycation (28,45,60,61), and it recently entered second phase III clinical trials for ameliorating the complications of diabetes (11,61). Our recent kinetic studies confirmed that aminoguanidine is a potent inhibitor of antigenic AGE formation induced by high glucose concentrations (44).…”

Section: Discussionsupporting

confidence: 56%

In Vitro Kinetic Studies of Formation of Antigenic Advanced Glycation End Products (AGEs)

Booth

Khalifah

Todd

et al. 1997

Journal of Biological Chemistry

263

194

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Section: Discussionsupporting

confidence: 56%

In Vitro Kinetic Studies of Formation of Antigenic Advanced Glycation End Products (AGEs)

Booth

Khalifah

Todd

et al. 1997

Journal of Biological Chemistry

263

194

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“…2d). Second, we used aminoguanidine, which prevents the formation of AGE [27]. Prolonged incubation of apoA-I with aminoguanidine enhanced the ability of apoA-I to promote cholesterol efflux; however, cholesterol efflux was similar for apoA-I and apoA-I modified in the presence of aminoguanidine (Fig.…”

Section: Resultsmentioning

confidence: 99%

Advanced glycation of apolipoprotein A-I impairs its anti-atherogenic properties

et al. 2007

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Aims/hypothesis AGE contribute to the pathogenesis of diabetic complications, including dyslipidaemia and atherosclerosis. However, the precise mechanisms remain to be established. In the present study, we examined whether AGE modification of apolipoprotein A-I (apoA-I) affects its functionality, thus altering its cardioprotective profile. Materials and methods The ability of AGE-modified apoA-I to facilitate cholesterol and phospholipid efflux, stabilise ATP-binding cassette transporter A1 (ABCA1) and inhibit expression of adhesion molecules in human macrophages and monocytes was studied. Results The ability of AGE-modified apoA-I to promote cholesterol efflux from THP-1 macrophages, isolated human monocytes and from ABCA1-transfected HeLa cells was significantly reduced (>70%) compared with unmodified apoA-I. This effect was reversed by preventing AGE formation with aminoguanidine or reversing AGE modification using the cross-link breaker alagebrium chloride. AGEmodification of HDL also reduced its capacity to promote cholesterol efflux. AGE-apoA-I was also less effective than apoA-I in stabilising ABCA1 in THP-1 cells as well as in inhibiting expression of CD11b in human monocytes. Conclusions/interpretation AGE modification of apoA-I considerably impairs its cardioprotective, antiatherogenic properties, including the ability to promote cholesterol efflux, stabilise ABCA1 and inhibit the expression of adhesion molecules. These findings provide a rationale for targeting AGE in the management of diabetic dyslipidaemia.

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“…The recognition of NEG as a molecular mechanism that contributes to the development of OA provides new opportunities for therapies directed at the prevention of OA by inhibiting or reversing AGE formation. Inhibition of AGE formation by prophylactic treatment with compounds such as aminoguanidine, pyridoxamine, tenilsetam, or simple amino acids (e.g., lysine or arginine) has been shown to prevent AGErelated pathologies such as vascular stiffening, heart collagen accumulation, and protein crosslinking (59)(60)(61)(62)(63). Alternatively, AGE-directed therapy can consist of so-called AGE-breakers (64).…”

Section: Discussionmentioning

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

182

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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Aminoguanidine Prevents Diabetes-Induced Arterial Wall Protein Cross-Linking

Cited by 1,122 publications

References 28 publications

In Vitro Kinetic Studies of Formation of Antigenic Advanced Glycation End Products (AGEs)

In Vitro Kinetic Studies of Formation of Antigenic Advanced Glycation End Products (AGEs)

Advanced glycation of apolipoprotein A-I impairs its anti-atherogenic properties

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

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