Abstract 17347: De novo Ceramide Synthesis is Upregulated by Cardiac Ischemia and is Associated With Cardiomyocyte Apoptosis and Mitochondrial Dysfunction
Background: Serine palmitoyltransferase (SPT) is the rate-limiting enzyme of de novo ceramide formation.However, ceramides can be produced through various pathways. The role of de novo ceramide synthesis via SPT in cardiac ceramide synthesis in ischemic cardiomyopathy has not been conclusively studied.
Hypothesis: Ceramide synthesis via SPT may be linked to myocardial infarction-induced mitochondrial dysfunction and cardiac remodeling.
Methods: Left coronary artery ligation and sham surgery was performed in C57BL/6J (8 wks, n=69) and Sptlc2 gene deletion mice (8 wks, n=9). Echocardiography confirmed MI-related cardiomyopathy at 2 and 8 wks. Groups of mice were treated either with SPT inhibitor, myriocin (300 ug/kg/d) or placebo for 8 wks. Ceramides were analyzed by LC/MS lipidomics. Sptlc2 (p3xFLAG-CMv7) overexpression in AC16 human cardiomyocyte-like cells was assessed.
Results: Post-MI, total cardiac ceramides and certain species increased (total: +19%; C16: +19%; C24: +39%; C24:1: +44%; all p<0.05 vs sham), consistent with cardiac Sptlc2 protein levels (+68% vs sham; p<0.05). Sptlc2 overexpression, in cells, also resulted in increased ceramides (total: +33%; p<0.05), C14 (+66%; p<0.001), C16 (+39%; p<0.01), C16:1(+47%; p<0.001) and C24:1 (+37%; p<0.01), increased apoptosis (+64%; p<0.01), decreased cellular respiration (-69%; p<0.001) and lowered respiratory capacity (-36%; p<0.001). Myriocin treatment resulted in reduced LV dilation (4.8±0.3 vs 5.9±0.3 mm in placebo; p<0.05), improved fractional shortening (19.8±2.4% vs 13.4±2.2 in placebo; p<0.05), decreased myocardial collagen (0.08% vs 0.7%, p<0.05) and prevented the increase of ceramides, post-MI (+4% vs. +17% in placebo; p<0.05). C16, C24:1, and C24 ceramides decreased by 19, 20, and 32%, respectively (all p<0.05 vs placebo). Sptlc2 KO mice trended towards less progressive remodeling with reduced fractional shortening compared to WT post-MI (-7% vs -14%; p=0.06).
Conclusion: Pharmacologic and genetic inhibition of de novo ceramide synthesis decreases cardiac ceramides and prevents cardiac remodeling post-MI. Increased ceramides induce apoptosis and mitochondrial dysfunction. Inhibition of ceramide synthesis can be a supplemental therapy for heart failure treatment.
Author Disclosures: R. Ji: None. X. Liao: None. X. Zhang: None. H. Jiang: None. K. Drosatos: None. P.J. Kennel: None. E. Castillero: None. J.Y. Chang: None. S. Homma: None. I. Goldberg: None. P. Schulze: None.
- © 2015 by American Heart Association, Inc.