RAGE influences the development of aortic valve stenosis in mice on a high fat diet

Abstract

Background: Advanced glycation end products (AGEs) are stable products of the condensation of an aldehyde i.e. glucose and amines such as amino acids (Maillard reaction). Their accumulation is considered as biomarker of ageing and is also associated with several degenerative diseases. AGEs are recognized by several receptor molecules of which the receptor of AGEs (RAGE) is currently the most intensively studied. Activation of RAGE causes an unfavorable proinflammatory state. AGEs as well as high fat diet are associated with cardiovascular diseases. The hypothesis of this study was that high fat diet results in development of aortic valve stenosis and that knockout of RAGE should be protective. Materials and methods: Six week old male C57BL/6N and C57BL/6N RAGE -/- mice (n = 28) were randomly assigned to 4 groups and fed with normal or high fat diet for 32 weeks. Weight gain was determined weekly. At the start of the experiment and after 2, 4 and 7 months, echocardiographic assessments of the aortic valve were made. At the end of the experiment, histological and immunohistochemical analysis of the valves was performed. Results: The absence of RAGE resulted in accelerated weight gain. However, after 7 month, both - C57BL/6 and C57BL/6 RAGE -/- -mice on high fat diet had nearly the same weight. Immunohistochemistry analysis of the aortic valves revealed that C57BL/6N mice on a high fat diet had significantly more calcification (p = 0.018), higher AGE accumulation (p = 0.005) and RAGE expression (p = 0.01) when compared to the normal fat control. Aortic valves of RAGE -/- mice showed less calcification, less AGE accumulation and less collagen, however this was not significant. Conclusion: These data suggest that AGE and RAGE are involved in the development of obesity and aortic valve stenosis.