Advanced glycation end products accelerate rat vascular calcification through RAGE/oxidative stress

BMC Cardiovascular Disorders - Tập 13 Số 1 - 2013
Wei Qin1, Xiaomei Ren2, Yibo Jiang3, Hong Jin1, Naifeng Liu1, Jie Li2
1Department & Institute of Cardiology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, 210009, P.R. China
2Department of Geratology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, 210009, P.R. China
3Department of Cardiology, Taixing Hospital affiliated with Yangzhou University, Jiangsu, 225400, P.R. China

Tóm tắt

Abstract Background Arterial media calcification (AMC) is highly prevalent and is a major cause of morbidity, mortality, stroke and amputation in patients with diabetes mellitus (DM). Previous research suggests that advanced glycation end products (AGEs) are responsible for vascular calcification in diabetic patients. The potential link between oxidative stress and AGEs-induced vascular calcification, however, has not been examined. Methods Male Wistar rats received a high fat diet for 8 weeks followed by a single dose of streptozotocin to induce DM (DM). Calcification was induced with Vitamin D3 and nicotine (VDN). We started VDN treatment at 1 week after the initial streptozotocin injection (DM+VDN). Age-matched rats were used as controls (CON). Metabolic parameters, aortic calcium content, alkaline phosphatase (ALP) protein, malondialdehyde (MDA) content, Cu/Zn superoxide dismutase (SOD) activity, aorta receptor for advanced glycation end products (RAGE) and aorta AGEs levels were measured. In vitro, vascular smooth muscle cells (VSMCs) were cultured with AGEs in DMEM containing 10 mmol·L-1 ß -glycerophosphate (ß-GP). Calcium content and ALP activity were used to identify osteoblastic differentiation and mineralization. Western blots were used to examine protein expression of Cu/Zn SOD, NADPH oxidase Nox1 and RAGE. In addition, the intracellular reactive oxygen species (ROS) generation was evaluated using fluorescent techniques with dihydroethidine (DHE) method. Results The DM+VDN group showed a significant increase in aortic calcium content, levels of aorta AGEs, MDA content, ALP protein levels and RAGE expression, although Cu/Zn SOD activity decreased significantly. In vitro, enhanced Nox1, RAGE expression as well as the production of intracellular superoxide anions, and reduced expression of Cu/Zn SOD induced by AGEs were attenuated by the anti-RAGE antibody or a ROS inhibitor. Furthermore, the AGEs-stimulated ROS increase was also significantly inhibited by a SOD mimetic. Increased ALP activity and calcium deposition were also inhibited markedly by the ROS inhibitor and the anti-RAGE antibody. Conclusions These results suggest that AGEs enhance vascular calcification partly through a RAGE/oxidative stress pathway.

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Tài liệu tham khảo

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BMC Cardiovascular Disorders

Tập 13 Số 1

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