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 5

Effects of myriocin and Sptlc2 gene deletion on left ventricular remodeling following MI and of inhibition of ceramide synthesis in ischemic cardiomyopathy by myriocin on cardiac lipid composition.

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Effects of myriocin and Sptlc2 gene deletion on left ventricular remodel...
(A) Comparison of LVEDD in sham and MI on myriocin and placebo (**P < 0.01, ***P < 0.001, compare to sham, n = 4–9). (B) Dynamics in LVEDD following MI in animals treated with myriocin and placebo (change in LVEDD: *P < 0.05 versus 2 weeks placebo) and change in LVEDD in MI placebo versus MI myriocin compared with 2 weeks after MI (n = 4–9). (C) Comparison of FS in sham and MI on myriocin and placebo (n = 4–9). (D) Dynamics in FS following MI in animals treated with myriocin and placebo at 10 weeks after MI compared with 2 weeks after MI (change in FS: *P < 0.05 versus 2 weeks placebo, n = 4–9). (E) Quantitative analysis of myocardial collagen staining using Masson’s trichrome stain (100×, *P < 0.05 versus sham myriocin, n = 7–14). (F) Macrophage staining using Mac3 antibody (100×, *P < 0.05 versus sham myriocin, n = 4–6). (G) Apoptosis staining using the TUNEL protocol (400×, n = 5–6). (H) Lipidomic analysis of total and individual ceramides in the noninfarcted myocardium 12 weeks after MI in animals treated with myriocin compared with placebo (*P < 0.05, **P < 0.01, ***P < 0.001 versus chow, n = 9). (I) Lipidomic analysis of total and individual ceramides in the Spltlc2-KO mice compared with floxed mice (*P < 0.05, **P < 0.01 versus floxed, n = 6). (J) Preservation of FS following MI in Sptlc2-KO compared with control mice at 2 weeks after MI to 10 weeks after MI (change in FS: *P < 0.05). (K) Reduced LV dilation following MI in Sptlc2-KO compared with control mice from 2 weeks after MI to 10 weeks after MI (change in LVEDD: P = 0.08, n = 5–8). Two-tailed Student’s t test was used for 2 group comparisons, and one-way ANOVA was used for 3 group comparisons. LVEDD, left ventricular end diastolic diameter; FS, fraction shortening; MI, myocardial infarction.