Cell Hypertrophy and MEK/ERK Phosphorylation are Regulated by Glyceraldehyde-Derived AGEs in Cardiomyocyte H9c2 Cells

Abstract

Diabetic cardiomyopathy has been shown to promote hypertrophy, leading to heart failure. Recent studies have reported a correlation between diabetic cardiomyopathy and oxidative stress, suggesting that the accumulation of advanced glycation end products (AGEs) induces the production of reactive oxygen species (ROS). In a clinical setting, AGEs have been shown to increase the risk of cardiovascular disease; however, the relationship between AGEs and cardiac hypertrophy remains unclear. This study sought to identify the role of AGEs in cardiac hypertrophy by treating H9c2 cells with glyceraldehyde-derived AGEs (200 μg/ml) or H2O2 (50 μM) for 96 h. Our results demonstrate that AGEs significantly increased protein levels and cell size. These effects were effectively blocked with PD98059 (10 μM; MEK/ERK inhibitor) pretreatment, suggesting that AGEs caused cell hypertrophy via the MEK/ERK pathway. We then treated cells with AGEs and H2O2 for 0-120 min and employed the Odyssey infrared imaging system to detect MEK/ERK phosphorylation. Our results show that AGEs up-regulated MEK/ERK phosphorylation. However, this effect was blocked by NAC (5 mM; ROS inhibitor), indicating that AGEs regulate MEK/ERK phosphorylation via ROS. Our findings suggest that glyceraldehyde-derived AGEs are closely related to cardiac hypertrophy and further identify a molecular mechanism underlying the promotion of diabetic cardiomyopathy by AGEs.

Suppression of antioxidant Nrf-2 and downstream pathway in H9c2 cells by advanced glycation end products (AGEs) via ERK phosphorylation

“…However, the role of AGEs in the pathogenesis of diabetic cardiomyopathy remains unclear. Findings in our previous study suggest that AGEs regulate ERK phosphorylation via ROS [40]. In the current report, we provide additional evidence to support the contention that AGEs are closely associated with the pathogenesis of diabetic cardiomyopathy.…”

“…It has been demonstrated that MEK/ERK promotes cardiac hypertrophy in transgenic mice [56], which is a characteristic of diabetic cardiomyopathy [57,58]. Our previous study demonstrated that AGEs regulate ERK phosphorylation via ROS and induce cell hypertrophy [40]. The results obtained in the current study demonstrate that AGEs and H 2 O 2 increase ERK phosphorylation; however, the effects of AGEs are inhibited by pretreatment with NAC or PD98059.…”

“…The expression of antioxidant genes Nrf-2, HO-1, and NQO-1 is down regulated by glyceraldehyde-derived AGEs. Importantly, AGEs regulate Nrf-2 via the ERK pathway, which suggests that AGEs induce cell hypertrophy through ROS via ERK activation [40]. This subsequently increases the production of ROS, leading to cell death and the development of diabetic cardiomyopathy.…”

“…Our previous study demonstrated that glyceraldehyde-derived AGEs increase cell hypertrophy via ERK phosphorylation [40]. This suggests that a strong correlation exists between AGEs and diabetic cardiomyopathy.…”

The Role of ERK1/2 in the Development of Diabetic Cardiomyopathy

“…Consistent changes of hypertrophy and ERK1/2 expressions were also observed in STZ-induced myocardium of diabetic rats [62]. It is believed that ERK1/2 activation in response to hyperglycemia results in cardiac hypertrophy [63,64]. …”