TY - JOUR
T1 - Altering Sphingolipid Metabolism Attenuates Cell Death and Inflammatory Response after Myocardial Infarction
AU - Hadas, Yoav
AU - Vincek, Adam S.
AU - Youssef, Elias
AU - Żak, Magdalena M.
AU - Chepurko, Elena
AU - Sultana, Nishat
AU - Sharkar, Mohammad Tofael Kabir
AU - Guo, Ningning
AU - Komargodski, Rinat
AU - Kurian, Ann Anu
AU - Kaur, Keerat
AU - Magadum, Ajit
AU - Fargnoli, Anthony
AU - Katz, Michael G.
AU - Hossain, Nadia
AU - Kenigsberg, Ephraim
AU - Dubois, Nicole C.
AU - Schadt, Eric
AU - Hajjar, Roger
AU - Eliyahu, Efrat
AU - Zangi, Lior
N1 - Publisher Copyright:
© 2020 The Authors.
PY - 2020/3/17
Y1 - 2020/3/17
N2 - Background: Sphingolipids have recently emerged as a biomarker of recurrence and mortality after myocardial infarction (MI). The increased ceramide levels in mammalian heart tissues during acute MI, as demonstrated by several groups, is associated with higher cell death rates in the left ventricle and deteriorated cardiac function. Ceramidase, the only enzyme known to hydrolyze proapoptotic ceramide, generates sphingosine, which is then phosphorylated by sphingosine kinase to produce the prosurvival molecule sphingosine-1-phosphate. We hypothesized that Acid Ceramidase (AC) overexpression would counteract the negative effects of elevated ceramide and promote cell survival, thereby providing cardioprotection after MI. Methods: We performed transcriptomic, sphingolipid, and protein analyses to evaluate sphingolipid metabolism and signaling post-MI. We investigated the effect of altering ceramide metabolism through a loss (chemical inhibitors) or gain (modified mRNA [modRNA]) of AC function post hypoxia or MI. Results: We found that several genes involved in de novo ceramide synthesis were upregulated and that ceramide (C16, C20, C20:1, and C24) levels had significantly increased 24 hours after MI. AC inhibition after hypoxia or MI resulted in reduced AC activity and increased cell death. By contrast, enhancing AC activity via AC modRNA treatment increased cell survival after hypoxia or MI. AC modRNA-treated mice had significantly better heart function, longer survival, and smaller scar size than control mice 28 days post-MI. We attributed the improvement in heart function post-MI after AC modRNA delivery to decreased ceramide levels, lower cell death rates, and changes in the composition of the immune cell population in the left ventricle manifested by lowered abundance of proinflammatory detrimental neutrophils. Conclusions: Our findings suggest that transiently altering sphingolipid metabolism through AC overexpression is sufficient and necessary to induce cardioprotection post-MI, thereby highlighting the therapeutic potential of AC modRNA in ischemic heart disease.
AB - Background: Sphingolipids have recently emerged as a biomarker of recurrence and mortality after myocardial infarction (MI). The increased ceramide levels in mammalian heart tissues during acute MI, as demonstrated by several groups, is associated with higher cell death rates in the left ventricle and deteriorated cardiac function. Ceramidase, the only enzyme known to hydrolyze proapoptotic ceramide, generates sphingosine, which is then phosphorylated by sphingosine kinase to produce the prosurvival molecule sphingosine-1-phosphate. We hypothesized that Acid Ceramidase (AC) overexpression would counteract the negative effects of elevated ceramide and promote cell survival, thereby providing cardioprotection after MI. Methods: We performed transcriptomic, sphingolipid, and protein analyses to evaluate sphingolipid metabolism and signaling post-MI. We investigated the effect of altering ceramide metabolism through a loss (chemical inhibitors) or gain (modified mRNA [modRNA]) of AC function post hypoxia or MI. Results: We found that several genes involved in de novo ceramide synthesis were upregulated and that ceramide (C16, C20, C20:1, and C24) levels had significantly increased 24 hours after MI. AC inhibition after hypoxia or MI resulted in reduced AC activity and increased cell death. By contrast, enhancing AC activity via AC modRNA treatment increased cell survival after hypoxia or MI. AC modRNA-treated mice had significantly better heart function, longer survival, and smaller scar size than control mice 28 days post-MI. We attributed the improvement in heart function post-MI after AC modRNA delivery to decreased ceramide levels, lower cell death rates, and changes in the composition of the immune cell population in the left ventricle manifested by lowered abundance of proinflammatory detrimental neutrophils. Conclusions: Our findings suggest that transiently altering sphingolipid metabolism through AC overexpression is sufficient and necessary to induce cardioprotection post-MI, thereby highlighting the therapeutic potential of AC modRNA in ischemic heart disease.
KW - acid ceramidase
KW - cardioprotective agents
KW - mRNA
KW - myocardial infarction
KW - sphingolipids
UR - http://www.scopus.com/inward/record.url?scp=85082146198&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.119.041882
DO - 10.1161/CIRCULATIONAHA.119.041882
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C2 - 31992066
AN - SCOPUS:85082146198
SN - 0009-7322
VL - 141
SP - 916
EP - 930
JO - Circulation
JF - Circulation
IS - 11
ER -