sRAGE levels correlate with strain in a rat model of cardiac dysfunction

Abstract

INTRODUCTION Several clinical and experimental studies have demonstrated that advanced glycation end products (AGEs) are associated with adverse outcome (1, 2). Animal models using exogenous AGEs injections have already been used to investigate their role in organ (dys)function. However, the direct role of AGEs on cardiac function in particular, remains elusive. In most studies, deleterious effects of AGEs are investigated when diabetes is present. However, growing evidence suggests that advanced glycation end products and their receptor (RAGE) play a pivotal role in the development and progression of cardiovascular diseases, independent of diabetes (3, 4). sRAGE, the soluble form of RAGE, is thought to be a predictive biomarker for the severity of the cardiac dysfunction but data are conflicting (5). In this study, we investigated whether an increased circulating AGEs independent of diabetes, leads to cardiac dysfunction and second whether sRAGE levels are associated with the severity of the cardiac phenotype. MATERIALS AND METHODS Adult Sprague-Dawley rats underwent daily injections of BSA-modified AGEs (20 mg/kg ip, n=8) or control-BSA (n=4). BSA-modified AGEs were prepared by incubating 7 mg/ml BSA (fatty acid-free and low endotoxin) with 90 mM glycolaldehyde in PBS. After 6 weeks injection, cardiac function was evaluated with echocardiography and plasma levels of glucose, AGEs and sRAGE were measured respectively with Analox GM7 (Analis SA, Belgium) and ELISA (MyBiosource, USA). Data are shown as mean ± SEM. Comparison between data was performed using Student´s two-tailed unpaired test with Tukey post-hoc analysis. p<0.05 was considered statistically significant. RESULTS As expected after 6 weeks injection, AGEs-injected animals showed a sustained higher plasma level of circulating AGEs compared to control animals (30.17 µg/ml vs 10.9 µg/ml, p<0.05). Despite daily injections of glycated products, plasma glucose levels remained within the physiological range in both groups. In addition, AGEs-injected animals displayed a significant increase in anterior and posterior wall thicknesses (1.83 ± 0.06 mm and 2.01 ± 0.16 mm in AGEs-injected animals vs 1.50 ± 0.07 mm and 1.69 ± 0.07 mm in control animals for AWT and PWT respectively, p<0.05). As shown by a preserved ejection fraction and fractional shortening, six weeks AGEs injections did not lead to altered global cardiac performance. Circumferential strain (Scirc), as a measure of cardiac deformation, was reduced in AGEs-injected animals (-16.40 ± 1.89% vs -21.65 ± 2.79% at baseline, p<0.05). Plasma sRAGE levels, the soluble form of RAGE were 3 times higher in the AGEs-injected group (3.90 ng/ml vs 1.80 ng/ml, p<0.05) and correlated the decreased Scirc.

CONCLUSION Our data show that an increased circulating AGEs leads to cardiac hypertrophy. In addition, despite a preserved overall cardiac function, AGEs lead to cardiac dysfunction, as shown by a reduced strain. Finally, in this setting, increased sRAGE levels were a predictor for early LV remodelling and altered cardiac function. Our data demonstrate that an increased circulating AGEs per se plays a role in cardiac remodeling and dysfunction, independent of confounding factors such as elevated circulating glucose levels. REFERENCES 1. Koyama, Y. et al. High serum level of pentosidine, an advanced glycation end product (AGE), is a risk factor of patients with heart failure. Journal of cardiac failure, 13(3), 199-206, 2007. 2. Willemsen, S. et al. The role of advanced glycation end-products and their receptor on outcome in heart failure patients with preserved and reduced ejection fraction. American heart journal, 164(5), 742-9.e3, 2012. 3. Umadevi S, Gopi V, Elangovan V. Regulatory mechanism of gallic acid against advanced glycation end products induced cardiac remodeling in experimental rats. Chemico-biological interactions, 208, 28-36, 2014. 4. Yu, L. et al. Advanced Glycation End Product (AGE)-AGE Receptor (RAGE) System Upregulated Connexin43 Expression in Rat Cardiomyocytes via PKC and Erk MAPK Pathways. International Journal Molecular Sciences, 14(2), 2242-2257, 2013. 5. Selvin E. et al. sRAGE and risk of diabetes, cardiovascular disease, and death. Diabetes, 62(6), 2116-2121, 2013.