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

详细信息    查看全文

• 作者：Dorien Deluyker ; Vesselina Ferferieva ; Jean-Paul Noben ; Quirine Swennen ; Annelies Bronckaers ; Ivo Lambrichts ; Jean-Michel Rigo ; Virginie Bito ; ^{Virginie.Bito@uhasselt.be" class="auth_mail" title="E-mail the corresponding author}
• 关键词：High molecular weight advanced glycation end products ; Echocardiography ; Fibrosis ; RAGE
• 刊名：International Journal of Cardiology
• 出版年：2016
• 出版时间：1 May 2016
• 年：2016
• 卷：210
• 期：Complete
• 页码：100-108
• 全文大小：997 K

文摘

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 hyperglycemia. 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.