PMID- 24157879
OWN - NLM
STAT- MEDLINE
DCOM- 20140312
LR  - 20211021
IS  - 2041-4889 (Electronic)
VI  - 4
IP  - 10
DP  - 2013 Oct 24
TI  - Epoxyeicosatrienoic acids protect cardiac cells during starvation by modulating 
      an autophagic response.
PG  - e885
LID - 10.1038/cddis.2013.418 [doi]
AB  - Epoxyeicosatrienoic acids (EETs) are cytochrome P450 epoxygenase metabolites of 
      arachidonic acid involved in regulating pathways promoting cellular protection. 
      We have previously shown that EETs trigger a protective response limiting 
      mitochondrial dysfunction and reducing cellular death. Considering it is unknown 
      how EETs regulate cell death processes, the major focus of the current study was 
      to investigate their role in the autophagic response of HL-1 cells and neonatal 
      cardiomyocytes (NCMs) during starvation. We employed a dual-acting synthetic 
      analog UA-8 (13-(3-propylureido)tridec-8-enoic acid), possessing both EET-mimetic 
      and soluble epoxide hydrolase (sEH) inhibitory properties, or 14,15-EET as model 
      EET molecules. We demonstrated that EETs significantly improved viability and 
      recovery of starved cardiac cells, whereas they lowered cellular stress responses 
      such as caspase-3 and proteasome activities. Furthermore, treatment with EETs 
      resulted in preservation of mitochondrial functional activity in starved cells. 
      The protective effects of EETs were abolished by autophagy-related gene 7 (Atg7) 
      short hairpin RNA (shRNA) or pharmacological inhibition of autophagy. Mechanistic 
      evidence demonstrated that sarcolemmal ATP-sensitive potassium channels (pmKATP) 
      and enhanced activation of AMP-activated protein kinase (AMPK) played a crucial 
      role in the EET-mediated effect. Our data suggest that the protective effects of 
      EETs involve regulating the autophagic response, which results in a healthier 
      pool of mitochondria in the starved cardiac cells, thereby representing a novel 
      mechanism of promoting survival of cardiac cells. Thus, we provide new evidence 
      highlighting a central role of the autophagic response in linking EETs with 
      promoting cell survival during deep metabolic stress such as starvation.
FAU - Samokhvalov, V
AU  - Samokhvalov V
AD  - Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, 
      Alberta, Canada.
FAU - Alsaleh, N
AU  - Alsaleh N
FAU - El-Sikhry, H E
AU  - El-Sikhry HE
FAU - Jamieson, K L
AU  - Jamieson KL
FAU - Chen, C B
AU  - Chen CB
FAU - Lopaschuk, D G
AU  - Lopaschuk DG
FAU - Carter, C
AU  - Carter C
FAU - Light, P E
AU  - Light PE
FAU - Manne, R
AU  - Manne R
FAU - Falck, J R
AU  - Falck JR
FAU - Seubert, J M
AU  - Seubert JM
LA  - eng
GR  - R01 GM031278/GM/NIGMS NIH HHS/United States
GR  - MOP115037/CAPMC/CIHR/Canada
GR  - GM31278/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20131024
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 ((13-(3-propylureido)tridec-8-enoic acid))
RN  - 0 (Amino Acids)
RN  - 0 (Benzamides)
RN  - 0 (Cardiotonic Agents)
RN  - 0 (Oleic Acids)
RN  - 0 (Potassium Channels)
RN  - 81276-03-1 (14,15-epoxy-5,8,11-eicosatrienoic acid)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - AAU99UZB44 (HMR 1098)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - FC398RK06S (8,11,14-Eicosatrienoic Acid)
SB  - IM
MH  - 8,11,14-Eicosatrienoic Acid/*analogs & derivatives/pharmacology
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Adenosine Triphosphate/pharmacology
MH  - Amino Acids/*deficiency
MH  - Animals
MH  - Animals, Newborn
MH  - Autophagy/*drug effects
MH  - Benzamides/pharmacology
MH  - Cardiotonic Agents/*pharmacology
MH  - Cell Line
MH  - Cell Survival/drug effects
MH  - Cytoprotection/*drug effects
MH  - Enzyme Activation/drug effects
MH  - Mitochondria, Heart/drug effects/metabolism/ultrastructure
MH  - Myocytes, Cardiac/*cytology/drug effects/enzymology/ultrastructure
MH  - Oleic Acids/*pharmacology
MH  - Phosphorylation/drug effects
MH  - Potassium Channels/metabolism
MH  - Rats
MH  - Stress, Physiological/drug effects
PMC - PMC3920965
EDAT- 2013/10/26 06:00
MHDA- 2014/03/13 06:00
PMCR- 2013/10/01
CRDT- 2013/10/26 06:00
PHST- 2013/05/22 00:00 [received]
PHST- 2013/09/21 00:00 [revised]
PHST- 2013/09/26 00:00 [accepted]
PHST- 2013/10/26 06:00 [entrez]
PHST- 2013/10/26 06:00 [pubmed]
PHST- 2014/03/13 06:00 [medline]
PHST- 2013/10/01 00:00 [pmc-release]
AID - cddis2013418 [pii]
AID - 10.1038/cddis.2013.418 [doi]
PST - epublish
SO  - Cell Death Dis. 2013 Oct 24;4(10):e885. doi: 10.1038/cddis.2013.418.