Details

Autor(en) / Beteiligte

• Deluyker, Dorien
• Ferferieva, Vesselina
• Noben, Jean-Paul
• Swennen, Quirine
• Bronckaers, Annelies
• Lambrichts, Ivo
• Rigo, Jean-Michel
• Bito, Virginie

Titel

Cross-linking versus RAGE: How do high molecular weight advanced glycation products induce cardiac dysfunction?

Ist Teil von

• International journal of cardiology, 2016-05, Vol.210, p.100-108

Ort / Verlag

Netherlands: Elsevier Ireland Ltd

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• Abstract Background Several clinical and experimental studies have demonstrated that advanced glycation end products (AGEs) are associated with adverse cardiac outcome. Growing evidence shows that high molecular weight AGEs (HMW-AGEs) might be as important as the characterized low molecular weight AGEs. To date, the role of HMW-AGEs in the pathogenesis of cardiac remodeling remains unknown. In this study, we investigated whether HMW-AGEs are involved in cardiac dysfunction. Methods Healthy rats were daily ip injected with 20 mg/kg BSA-derived HMW-AGEs or, as a control, unmodified BSA, during 6 weeks. Cardiac function was assessed with echocardiography. Plasma levels of glucose, AGEs and soluble RAGE (sRAGE) were measured. AGEs, RAGE and lysyl oxidase (LOX) expression were determined by western blot. Results After 6 weeks, animals displayed a sustained increase in circulating total AGEs without hyperglycaemia. HMW-AGEs injections induced cardiac dysfunction characterized by wall hypertrophy, increased heart sphericity, reduced strain and strain rate with preserved ejection fraction. Plasma sRAGE levels were significantly higher compared to control and correlated significantly with decreased strain. RAGE expression, TNF-α and IL-6 remained unchanged. Finally, HMW-AGEs induced prominent cardiac fibrosis associated with an increased LOX expression. Conclusion Our data demonstrate that rather than via a specific activation of RAGE, the deleterious effects of HMW-AGEs are likely mediated via an increased collagen cross-linking responsible for the observed cardiac stiffness. Additionally, we show that in the setting of elevated HMW-AGEs, increased sRAGE levels are markers of altered cardiac function.