Increased de novo ceramide synthesis and accumulation in failing myocardium
Ruiping Ji, Hirokazu Akashi, Konstantinos Drosatos, Xianghai Liao, Hongfeng Jiang, Peter J. Kennel, Danielle L. Brunjes, Estibaliz Castillero, Xiaokan Zhang, Lily Y. Deng, Shunichi Homma, Isaac J. George, Hiroo Takayama, Yoshifumi Naka, Ira J. Goldberg, P. Christian Schulze
Ruiping Ji, Hirokazu Akashi, Konstantinos Drosatos, Xianghai Liao, Hongfeng Jiang, Peter J. Kennel, Danielle L. Brunjes, Estibaliz Castillero, Xiaokan Zhang, Lily Y. Deng, Shunichi Homma, Isaac J. George, Hiroo Takayama, Yoshifumi Naka, Ira J. Goldberg, P. Christian Schulze
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Research Article Cardiology Metabolism

Increased de novo ceramide synthesis and accumulation in failing myocardium

Abstract

Abnormal lipid metabolism may contribute to myocardial injury and remodeling. To determine whether accumulation of very long–chain ceramides occurs in human failing myocardium, we analyzed myocardial tissue and serum from patients with severe heart failure (HF) undergoing placement of left ventricular assist devices and controls. Lipidomic analysis revealed increased total and very long–chain ceramides in myocardium and serum of patients with advanced HF. After unloading, these changes showed partial reversibility. Following myocardial infarction (MI), serine palmitoyl transferase (SPT), the rate-limiting enzyme of the de novo pathway of ceramide synthesis, and ceramides were found increased. Blockade of SPT by the specific inhibitor myriocin reduced ceramide accumulation in ischemic cardiomyopathy and decreased C16, C24:1, and C24 ceramides. SPT inhibition also reduced ventricular remodeling, fibrosis, and macrophage content following MI. Further, genetic deletion of the SPTLC2 gene preserved cardiac function following MI. Finally, in vitro studies revealed that changes in ceramide synthesis are linked to hypoxia and inflammation. In conclusion, cardiac ceramides accumulate in the failing myocardium, and increased levels are detectable in circulation. Inhibition of de novo ceramide synthesis reduces cardiac remodeling. Thus, increased de novo ceramide synthesis contributes to progressive pathologic cardiac remodeling and dysfunction.

Authors

Ruiping Ji, Hirokazu Akashi, Konstantinos Drosatos, Xianghai Liao, Hongfeng Jiang, Peter J. Kennel, Danielle L. Brunjes, Estibaliz Castillero, Xiaokan Zhang, Lily Y. Deng, Shunichi Homma, Isaac J. George, Hiroo Takayama, Yoshifumi Naka, Ira J. Goldberg, P. Christian Schulze

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Figure 4

Effects of SPTLC1 and SPTLC2 overexpression on cellular ceramide levels, viability, and metabolism.

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Effects of SPTLC1 and SPTLC2 overexpression on cellular ceramide levels,...
(A) Increased levels of total and individual ceramide species in response to SPTLC1 and SPTLC2 overexpression in AC16 cells (n = 4). (B) Increased cellular apoptosis in response to SPTLC1 and -2 overexpression compared with controls. Percentage of apoptotic cells quantified by annexin-V staining (n = 4, 20×). (C) Analysis of cellular oxidative metabolism by Seahorse analysis. Oxygen consumption rates were measured continuously throughout the experimental period starting at baseline and after addition of oligomycin (Oligo, 1 μM) and carbonylcyanide p-trifluoromethoxyphenylhydrazone (FFCP1, 1 μM). Rot, rotenone; anti, antimycin. (D) Averaged data of basal respiration, ATP turnover, H+ leak, and respiratory capacity in AC16 cells in response to SPTLC1 and SPTLC2 overexpression and controls (n = 3). (E) Cellular ceramide levels in AC16 cells in response to myriocin treatment (n = 5–8 per group). Two-tailed Student’s t test was used for 2 group comparisons ,and one-way ANOVA was used for 3 group comparisons (*P < 0.05, **P < 0.01, ***P < 0.001 versus control).