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

Advanced glycation end product (AGE) accumulations as well as a high fat diet are associated with cardiovascular 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 pro-inflammatory state. The hypothesis of this study was that metabolic stress due to a high fat diet results in the development of aortic valve stenosis and that knockout of RAGE should be protective. 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 32weeks. Weight gain was determined weekly. At the start of the experiment and after 2, 4 and 7months, echocardiographic assessments of the aortic valve were made. At the end of the experiment, plasma lipid levels and histological changes of the valves were determined. The high fat diet resulted in accelerated weight gain. However, after 7month, only C57BL/6 mice developed increased trans-aortic-valve velocities, leaflet thickness and reduced valve area index (p<0.0001). Immunohistochemistry of the aortic valves revealed in C57BL/6N mice on a high fat diet more calcification, AGE accumulation and RAGE expression when compared to normal fed control. Hearts and aortic valves of RAGE-/- mice showed less morphometric changes, calcification and AGE accumulation. After 7months of high fat feeding C57BL/6 mice (p<0.0001) as well as RAGE-/- mice (p=0.007) had significantly increased cholesterol levels compared to normal fed control, however RAGE-/- mice were probably protected due to a better HDL/LDL ratio when compared to wild type animals (p=0.003). These data suggest that AGEs and RAGE are involved in the development of obesity, hypercholesterolemia and aortic valve changes due to metabolic stress from high fat intake.