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 2

Mechanical unloading decreases circulating and myocardial ceramides in patients with HF.

Options: View larger image (or click on image) Download as PowerPoint
Mechanical unloading decreases circulating and myocardial ceramides in p...
(A) Absolute circulating ceramide levels in patients with advanced HF before (n = 15) and after (n = 15) VAD implantation (n = 15 paired samples). (B) Relative differences in circulating ceramide species in patients with advanced HF before and after VAD implantation (n = 15, paired). (C) Heatmap illustrating dynamics in total and individual serum ceramide levels (expressed as ratio of levels at the time of explantation versus implantation of VAD). (D) Absolute myocardial ceramide levels in patients at the time of VAD implantation (n = 15) compared with VAD explantation (n = 15). (E) Dynamics in myocardial ceramide species levels during the time of VAD support (analysis before versus after VAD) (n = 15). (F) Heatmap illustrating dynamics in myocardial ceramide species (expressed as ratio of levels at the time of explantation compared with implantation). (G) Relative differences in key proteins of ceramide synthesis (n = 4–7). (H) Western blot analysis of key proteins of various ceramide synthesis pathways. Please note that some lanes of the HF Pre-VAD group were used in Figure 1I to illustrate the HF pattern. VAD, ventricular assist device. Two-tailed Student’s t test was used for analyzing data (*P < 0.05, ** P < 0.01 versus Pre-VAD).