Abstract 17595: Characterization of Cardiac Lipotoxic Stress
Introduction: Accumulation of lipids in the heart, or cardiac steatosis, has been demonstrated in both insulin resistant and diabetic patients and is associated with diastolic dysfunction. However, the pathological mechanisms causing this cardiac lipotoxicity have yet to be fully elucidated. High fat diets have been shown to induce endoplasmic reticulum (ER) stress in a variety of tissues including liver, skeletal muscle and brain. Here we were interested in characterizing the ER stress response in primary cardiomyocytes treated with lipids as well as hearts from high fat fed mice.
Methods and Results: We evaluated ER stress in mouse neonatal cardiomyocytes (mNCMs) treated with either saturated (palmitate) or mono-unsaturated (oleate) fatty acids, as well as in cardiac tissue from C57bl/6 mice fed a high fat diet. We evaluated the expression of Atf-4 & -6, Grp78, spliced Xbp1, Dnajb9, and Herp mRNA levels as well as protein levels of Atf6, Grp78 and phosphorylated Perk. We demonstrated significant induction of ER stress in palmitate, but not in oleate treated cardiomyocytes (Figure). Because prolonged ER stress can lead to apoptosis, we assessed activation of apoptotic pathways as well. Specifically, we found that palmitate induced Chop (mRNA and protein) and Ero1 (mRNA) as well as caspase-3 activation. Lipotoxic induced ER stress was also observed in vivo. Indeed, mice fed a high fat diet for 8 months exhibited several markers of ER stress in cardiac tissue including elevated spliced Xbp1 and Chop mRNA as well as and Atf6 and Chop protein levels and this was associated with significant cardiac hypertrophy and diastolic dysfunction (impaired compliance) as determined with echocardiography.
Conclusion: Lipotoxic stimuli induce ER stress in both cultured primary cardiomyocytes treated with saturated fatty acids as well as in cardiac tissue from high fat diet fed mice. This is associated with activation of apoptotic pathways and cardiac dysfunction in vivo.
- © 2013 by American Heart Association, Inc.