An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness

Asif, Mohammad; Egan, John J.; Vasan, Sara; Jyothirmayi, G. N.; Masurekar, Malthi; Lopez, Santos; Williams, Chandra; Torres, Ramón L.; Wagle, Dilip; Ulrich, Peter; Cerami, Anthony; Brines, Michael; Regan, Timothy J.

doi:10.1073/pnas.040558497

Cited by 314 publications

(214 citation statements)

References 16 publications

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“…Alternatively, AGE-directed therapy can consist of so-called AGE-breakers (64). Thiazolium compounds such as N-phenacylthiazolium bromide and phenyl-4,5-dimethylthiazolium chloride, which have been reported to break dicarbonyl-containing AGEs, showed efficacy in reversing AGE-related tendon crosslinking and cardiac stiffness (65,66). Despite the fact that these therapies are relatively new, they provide proof that inhibition or reversal of AGE formation can have beneficial effects in AGE-mediated pathologies.…”

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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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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“…Proof for the involvement of AGEs in structural stiffness remains fairly indirect but has been fueled by animal and a recent clinical trial found that a breaker of AGE (ALT-711) improves vascular distensibility, 52,53 and perhaps ventricular diastolic distensibility ( Figure 5A). 54 Last, we recently reported that enhancement of protein kinase G activation by inhibiting PDE5a may provide a novel approach to ventricular-arterial stiffening. 55 PDE5a is the enzymatic target of sildenafil, which is widely used to treat erectile dysfunction.…”

Section: Destiffening Strategiesmentioning

confidence: 99%

Ventricular Arterial Stiffening

2005

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Abstract-Vascular stiffening of the large arteries is a common feature of aging and is exacerbated by many common disorders such as hypertension, diabetes, and renal disease. This change influences the phasic mechanical stresses imposed on the blood vessels that in turn is important to regulating smooth muscle tone, endothelial function, and vascular health. In addition, the heart typically adapts to confront higher and later systolic loads by both hypertrophy and ventricular systolic stiffening. This creates altered coupling between heart and vessel that importantly affects cardiovascular reserve function. In this overview, I discuss the notion of a coupling disease in which stiffness of both heart and arteries interact to limit performance and generate clinical symptoms. This involves changes in the mechanical interaction of both systems, changes in signaling within the arteries themselves, and alterations in coronary flow regulation. Lastly, I briefly review recent development in de-stiffening strategies that may pave the way to treat this syndrome and its clinical manifestations.

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“…In diabetic rats, collagen III was found to decrease, collagen solubility to increase, and RAGE and AGE-R3 mRNA levels to decrease when compared to the animals receiving vehicle after 4 weeks of treatment with ALT-711 [11,12]. In vivo studies showed that ALT-711 improves LV function, decreases ventricular collagen, and decreases the rigidity of LV in elder diabetic rats with increasing the survival time [13,14].…”

Section: • Toprak Et Al In Vitromentioning

confidence: 92%

Functional Effects of Alagebrium (ALT-711)–Isolated Rat Carotid Artery

2017

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Objective: In our study, the effects of glycosylated protein cross-link breaker, alagebrium was investigated on isolated rat carotid artery using myography. Alagebrium showed vasodilator effect on carotid artery rings; particularly, this effect was significantly increased in endothelium-intact rings. Materials and Methods:To clarify the vasodilator mechanism of alagebrium, different antagonists such as N(G)-Nitro-L-arginine methyl ester (L-NAME), glibenclamide, indomethacin, metoprolol, propranolol, tetraethylammonium, and calcium channel activator BAYK-8644 were used to reverse this effect.Results: Relaxation% responses to alagebrium were more significantly increased in intact endothelium than in denuded arteries. Blocking vasodilation related to channels (K-ATP, PGI2, BKca) and receptors (ß1, ß2) did not reverse the relaxation response to alagebrium. Vasodilator response to alagebrium was only slightly decreased after L-NAME incubation and significantly decreased after BAYK-8644 incubation. Conclusion:Results of present study suggest that the mechanism of alagebrium-induced vasodilator effect may include the blockage of L-type calcium channels and partially of the nitric oxide synthase enzyme.Keywords: Alagebrium, calcium channel blockage, carotid artery, nitric oxide, vasodilatation ÖZ Amaç: Çalışmamızda, glikozile protein çapraz bağ kırıcısı olan alagebriumun sıçanlardan elde edilen karotis arter preparatları üzerindeki etkisi myograf yöntemi ile araştırılmıştır. Alagebrium karotis arter preparatlarında vazodilatör etki göstermiş ve bu etkinin özellikle endoteli sağlam damarlarda arttığı gözlenmiştir.Gereç ve Yöntem: Alagebriumun vazodilatör mekanizmasını aydınlatmak amacıyla N(G)-Nitro-L-arginine methyl ester (L-NAME), glibenklamid, indometazin, metoprolol, propranolol, tetraetilamonyum gibi antagonistler ve kalsiyum kanal aktivatörü olan BAYK 8644 bu etkiyi geri çevirmek amacıyla kullanılmıştır. Bulgular: Alagebrium % gevşeme yanıtları, endoteli sağlam damarlarda endoteli bozulmuş damarlara göre anlamlı derecede artmıştır.. Vazodilatasyon ile ilgili kanalların (KATP, PGI2, BKca) ve reseptörlerin (ß1,ß2) bloke edilmesi de alagebrium un gevşeme yanıtını geri çevirememiştir. Alagebriuma vazodilatör cevap L-NAME uygulanması ile hafif derecede azalırken BAYK-8644 uygulanması ile anlamlı derecede azalmıştır.Sonuç: Çalışmamızın sonuçları; alagebriuma bağlı vazodilatör etki mekanizmasının L-tipi kalsiyum kanal blokajı ve kısmen de nitrik oksit sentaz enzim blokajına bağlı olduğunu göstermektedir.Anahtar Kelimeler: Alagebrium, nitrik oksit, kalsiyum kanal blokajı, karotis arter, vazodilatasyon Eurasian J Med 2017; 49: 188-92

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An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness

Cited by 314 publications

References 16 publications

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

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

Ventricular Arterial Stiffening

Functional Effects of Alagebrium (ALT-711)–Isolated Rat Carotid Artery

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