Low TNF α Expression Protects the Mouse Heart from Palmitate Induced Systolic Dysfunction

• Published in: The FASEB journal 2007, Vol.21 (6), p.A1425-A1425
• Main Authors: Cebova, Martina, Knowles, Catherine J., Jackson, Shelley, Pinz, Ilka M.
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.21.6.A1425-c

Obesity increases tumor necrosis factor α (TNFα) and free fatty acids (FFA). It is not known whether this contributes to cardiomyopathy. To test that TNFα and FFA change ceramide (Cer) and sphingomyelin (Sph) content of the plasma membrane, and that this leads to contractile dysfunction, a high palmitate fed (HPD) mouse model with low over‐expression of TNFα (TIA‐1−/−) was used. All experiments were performed prior to onset of atherosclerosis and morphologic changes to the heart. Wild type (WT) and TIA‐1−/− mice were fed HPD or a medium chain triglyceride control diet (MCTD), with comparable caloric intake from fat, for 12 weeks. To determine contractile performance, hearts were perfused in the isovolumic Langendorff mode in the presence of varying extracellular [Ca2+] (1.5 – 4 mM). Total lipid extracts were used to measure Cer and Sph content by mass spectrometry. In HPD WT hearts all indices of systolic performance were decreased: systolic pressure −26%, rate pressure product −27%, and +dP/dt −39% all compared to MCTD WT mice. In TIA‐1−/− mice HPD did not affect contractile performance. HPD WT hearts showed a 2fold increase in C18 Cer and C18 Sph. In contrast, TIA‐1−/− hearts maintained normal Cer and Sph content. We conclude that low TNFα prevents a shift in the Cer and Sph profile of cellular membranes likely by activation of sphingomyelinase and thus protects the heart from palmitate induced systolic dysfunction.