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.
View: Text | PDF | Addendum
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

×

Figure 1

Analysis of circulating and myocardial ceramides in patients with HF.

Options: View larger image (or click on image) Download as PowerPoint
Analysis of circulating and myocardial ceramides in patients with HF. (A...
(A) Absolute circulating ceramide levels in patients with HF (n = 64) and controls (n = 22). (B) Lipidomic analysis (LC/MS) of circulating ceramide species in patients with HF and controls. (C) Total cholesterol, LDL, and HDL cholesterol and triglyceride levels in patients with moderate (n = 30-31) and severe HF (n = 28-32) and controls (n = 11-12). (D) Heatmap illustrating serum ceramide species in controls and patients with HF. Variabilities of ceramide levels are expressed in comparison with controls and blotted individually. (E) Absolute myocardial ceramide levels in patients with severe HF (n = 15) and controls (n = 7). (F) Myocardial ceramide species in patients with HF and controls. (G) Heatmap illustrating myocardial ceramide species normalized for controls. (H) Relative changes in key proteins of cellular ceramide synthesis (n = 4–7). (I) Western blot analysis of key proteins of ceramide synthesis pathways. Please note that some lanes of the HF group were used in Figure 2H to illustrate the HF Pre-VAD pattern. 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).