Abstract P1074: High-fat High-sugar Diet Promotes Expression Of The Stress Response Protein REDD1 In Cardiomyocytes By Activation Of A PERK/ATF4 Signaling Axis

Abstract

Obesity and type 2 diabetes represent a surging public health crisis, impacting nearly half of American adults. Heart failure is a leading cause of mortality and morbidity in patients with diabetes and obesity. Much remains unknown regarding the molecular players that contribute to heart failure, but at the cellular level ER stress and inflammation are considered key hallmarks of cardiomyocyte dysfunction. The stress response protein regulated in development and DNA damage 1 (REDD1) is upregulated as a consequence of ER stress in multiple pathological conditions and was recently shown to promote inflammatory signaling. However, a role for diabetes-induced REDD1 in the context of heart failure has yet to be explored. Herein, we investigated the hypothesis that consumption of a pro-diabetogenic diet enhances REDD1 expression in cardiomyocytes by promoting ER stress. C57BL6/N mice were fed either a control chow or a high-fat high-sugar (HFHS, 42% kcal fat, 34% sucrose by weight) diet for 12 weeks. Mice fed a HFHS diet developed obesity and glucose intolerance. Hearts of mice fed a HFHS diet had an abundance of REDD1 mRNA and exhibited an increase in ER stress and inflammation characterized by phosphorylation of the ER kinase PERK, XBP-1 splicing, and IL-1β expression. We found that exposing both rat H9c2 and human AC16 cardiomyocytes to the saturated fatty acid palmitate and/or hyperglycemic conditions enhanced REDD1 mRNA and protein expression concomitant with an increase in markers of ER stress. PERK inhibition was sufficient to prevent the increase in REDD1 mRNA expression in cardiomyocytes exposed to hyperlipidemic conditions. Similarly, the transcription factor ATF4 was required for the increase in REDD1 mRNA and protein in cells exposed to hyperlipidemic conditions. We also found that REDD1 deletion was sufficient to reduce pro-inflammatory cytokine expression in human cardiomyocytes exposed to hyperglycemic and hyperlipidemic conditions. Overall, the findings provide evidence that HFHS environments contribute to the development of inflammation in cardiomyocytes by promoting REDD1 expression via activation of a PERK/ATF4 signaling axis.