Cardiac inflammation associated with a Western diet is mediated via activation of RAGE by AGEs.
A diet high in fat induces cardiac hypertrophy, inflammation, and oxidative stress. Although 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 C57BL6J and RAGE knockout mice were placed on either a standard diet (7% fat) or a Western "fast-food" diet (21% fat). Animals receiving a high-fat diet were further randomized to receive the AGE inhibitor alagebrium chloride (1 mg.kg(-1).day(-1)) and followed for 16 wk. A Western diet was associated with cardiac hypertrophy, inflammation, mitochondrial-dependent superoxide production, and cardiac AGE accumulation in wild-type mice. Although RAGE-KO mice fed a Western diet also became obese and accumulated intramyocardial lipid, cardiomyocyte hypertrophy, inflammation, and oxidative stress were attenuated compared with wild-type mice. Similarly, mice of both strains 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.
Tikellis
Christos
C
Baker Medical Research Institute, Melbourne, Victoria 8008, Australia.
Thomas
Merlin C
MC
Harcourt
Brooke E
BE
Coughlan
Melinda T
MT
Pete
Josepha
J
Bialkowski
Katarzyna
K
Tan
Adeline
A
Bierhaus
Angelika
A
Cooper
Mark E
ME
Forbes
Josephine M
JM
D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage* / Q000378:metabolism; D004719:Endomyocardial Fibrosis / Q000378:metabolism / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007150:Immunohistochemistry; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D011897:Random Allocation; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology
D002316:Cardiotonic Agents; D004041:Dietary Fats; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013844:Thiazoles; D013481:Superoxides; C406794:alagebrium