Critical Role Of MCP‐1 In n‐6 Polyunsaturated Fatty Acids (PUFA)‐Induced Cardiac ER Stress In Diet‐Induced Obesity

Abstract

Pathways by which excess n‐6 PUFAs promotes cardiac inflammation and apoptosis is unclear. We predicted a role for ER stress in inducing such cardiotoxicity. Female C57/Bl6 mice were fed normal chow or high‐fat (40%) diets rich either in n‐6 PUFA or monounsaturated fatty acids (MUFA) for 5 weeks. Immunoblotting revealed upregulation of proteins like IRE‐1α, BiP, PERK and calnexin in the heart of n‐6 PUFA but not in MUFA fed hearts. Further, upregulation of CHOP‐1, caspase‐12, TUNEL and ubiquitinated protein expressions confirmed elevated apoptosis in n‐6 PUFA fed hearts. Interestingly, MCPIP [monocyte chemotactic protein‐1 (MCP‐1) induced protein], a nuclear transcription factor was also induced with n‐6 PUFA. As MCP‐1 is key in cardiac inflammation we hypothesized that n‐6 PUFA triggers cardiac ER stress in an MCP‐1 dependent manner. MCP‐1−/− mice hearts demonstrated significantly less ER stress and undetectable MCPIP levels in response to high n‐6 PUFA than MCP‐1+/+ hearts. Deletion of MCP‐1 also attenuated CHOP‐1, caspase‐12 and ubiquitinated proteins in response to n‐6 PUFA. These results indicate that dietary excess of n‐6 PUFA may lead to cardiac ER stress and apoptosis during diet induced obesity via MCP‐1 signaling. These data may provide an insight into possible mechanisms for cardiotoxicity of dietary oils like corn and sunflower oils in the western diet.