Increased de novo ceramide synthesis and accumulation in failing myocardium
Ruiping Ji, … , Ira J. Goldberg, P. Christian Schulze
Ruiping Ji, … , Ira J. Goldberg, P. Christian Schulze
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e82922. https://doi.org/10.1172/jci.insight.82922.
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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 3

Increased levels of circulating and myocardial ceramides 2 weeks and 10 weeks following MI.

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Increased levels of circulating and myocardial ceramides 2 weeks and 10 ...
(A) Increased serum levels of total ceramides and various ceramide subspecies 2 weeks after MI (n = 4–5). (B) Increased myocardial levels of total ceramides and various ceramide subspecies 2 weeks after MI (n = 4–5). (C) Lipidomic analysis of ceramide subspecies showing profiles of circulating levels of ceramides in animals 10 weeks after MI (n = 10–12). (D) Lipidomic analysis of myocardial ceramides 10 weeks after MI (n = 20). (E) Western blot analysis of key enzymes of cellular ceramide synthesis (n = 6–9). (F) Quantitative analysis of key enzymes of ceramide synthesis (n = 6–9 per group). Two-tailed Student’s t test was used (*P < 0.05, **P < 0.01, ***P < 0.001 versus sham).