Submitted on January 14, 2008
Accepted on May 8, 2008
Cardiac inflammation associated with a Western diet
is mediated via activation of RAGE by AGEs
Christos Tikellis1, Merlin C THOMAS1*, Brooke Harcourt1, Melinda T Coughlan1, Josepha Pete1, Katarzyna Bialkowski1, Adeline Tan1, Angelika Bierhaus2, Mark E Cooper1, and Josephine M Forbes1
1 Diabetes Complications, Baker Heart Research Institute, Melbourne, Victoria, Australia
2 Department of Medicine 1, University of Heidelberg, Heidelberg, Germany; , Germany
* To whom correspondence should be addressed. E-mail: mthomas{at}baker.edu.au.
A diet high in fat induces cardiac hypertrophy, inflammation, and oxidative stress. While such actions have largely been ascribed to fat deposition, the accumulation of advanced glycation end-products (AGEs) and subsequent activation of the Receptor for AGEs (RAGE) may also represent important mediators of cardiac injury following exposure to a Western diet. In this study, Male C57BL6JJ and RAGE knockout mice were placed on either a standard diet (SD; 7% fat) or a Western fast food diet (WD; 21% fat). Animals receiving a HF diet were further randomized to receive the AGE inhibitor, alagebrium chloride (1mg/kg/day) and followed for 16 weeks. A Western diet was associated with cardiac hypertrophy, inflammation, mitochondrial-dependent superoxide production and cardiac AGE accumulation in wild type mice. While RAGE KO mice fed a Western diet also became obese and accumulated intramyocardial lipid, cardiomyocyte hypertrophy, inflammation and oxidative stress were attenuated when compared to RAGE KO. Similarly, mice receiving alagebrium chloride had reduced levels of inflammation and oxidative stress, in association with a reduction in cardiac AGEs and RAGE. This study suggests that AGEs represent important mediators of cardiac injury associated with a Western fast food diet. These data point to the potential utility of AGE-reducing strategies in the prevention and management of cardiac disease.
