PMID- 37098317
OWN - NLM
STAT- MEDLINE
DCOM- 20230512
LR  - 20230610
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 62
DP  - 2023 Jun
TI  - MK-886 protects against cardiac ischaemia/reperfusion injury by activating 
      proteasome-Keap1-NRF2 signalling.
PG  - 102706
LID - S2213-2317(23)00107-6 [pii]
LID - 10.1016/j.redox.2023.102706 [doi]
LID - 102706
AB  - Oxidative stress is considered a key factor contributing to the initiation and 
      development of cardiac injury following ischaemia‒reperfusion (I/R). Arachidonate 
      5-lipoxygenase (ALOX5) is a rate-limiting enzyme for leukotriene biosynthesis. 
      MK-886 is an inhibitor of ALOX5 that exhibits anti-inflammatory and antioxidant 
      activities. However, the significance of MK-886 in preventing I/R-mediated 
      cardiac injury and the underlying mechanism remain unclear. Cardiac I/R model was 
      produced by ligation/release of the left anterior descending artery. MK-886 
      (20 mg/kg) was administered intraperitoneally into mice at 1 and 24 h before I/R. 
      Our results indicated that MK-886 treatment significantly attenuated I/R-mediated 
      cardiac contractile dysfunction and decreased the infarct area, myocyte 
      apoptosis, and oxidative stress accompanied with reduction of Kelch-like 
      ECH-associated protein 1 (keap1) and upregulation of nuclear factor erythroid 
      2-related factor 2 (NRF2). Conversely, administration of the proteasome inhibitor 
      epoxomicin and NRF2 inhibitor ML385 greatly abrogated MK-886-mediated 
      cardioprotection after I/R injury. Mechanistically, MK-886 enhanced the 
      expression of the immunoproteasome subunit beta5i, which interacted with keap1 and 
      enhanced its degradation, leading to activation of the NRF2-dependent antioxidant 
      response and improvement of mitochondrial fusion-fission balance in the 
      I/R-treated heart. In summary, our present findings indicated that MK-886 could 
      protect the heart against I/R injury and highlight that MK-886 may represent a 
      promising therapeutic candidate for preventing ischaemic disease.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Shi, Kai-Na
AU  - Shi KN
AD  - Department of Emergency Medicine, Beijing Key Laboratory of Cardiopulmonary 
      Cerebral Resuscitation, Beijing Chao-Yang Hospital, Capital Medical University, 
      Beijing, 100020, China.
FAU - Li, Pang-Bo
AU  - Li PB
AD  - Department of Emergency Medicine, Beijing Key Laboratory of Cardiopulmonary 
      Cerebral Resuscitation, Beijing Chao-Yang Hospital, Capital Medical University, 
      Beijing, 100020, China.
FAU - Su, Hui-Xiang
AU  - Su HX
AD  - Department of Emergency Medicine, Beijing Key Laboratory of Cardiopulmonary 
      Cerebral Resuscitation, Beijing Chao-Yang Hospital, Capital Medical University, 
      Beijing, 100020, China.
FAU - Gao, Jing
AU  - Gao J
AD  - Department of Emergency Medicine, Beijing Key Laboratory of Cardiopulmonary 
      Cerebral Resuscitation, Beijing Chao-Yang Hospital, Capital Medical University, 
      Beijing, 100020, China.
FAU - Li, Hui-Hua
AU  - Li HH
AD  - Department of Emergency Medicine, Beijing Key Laboratory of Cardiopulmonary 
      Cerebral Resuscitation, Beijing Chao-Yang Hospital, Capital Medical University, 
      Beijing, 100020, China. Electronic address: hhli1935@aliyun.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230420
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (Antioxidants)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 080626SQ8C (MK-886)
RN  - 0 (Keap1 protein, mouse)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Kelch-Like ECH-Associated Protein 1/genetics/metabolism
MH  - *Antioxidants/pharmacology/metabolism
MH  - Proteasome Endopeptidase Complex/metabolism
MH  - NF-E2-Related Factor 2/genetics/metabolism
MH  - Oxidative Stress/physiology
MH  - *Reperfusion Injury
MH  - Apoptosis
PMC - PMC10149391
OTO - NOTNLM
OT  - Immunoproteasome
OT  - Keap1/NRF2
OT  - MK-886
OT  - Mitochondrial dynamics
OT  - Myocardial ischaemia/reperfusion injury
OT  - Oxidative stress
COIS- Declaration of competing interest The authors have declared that they have no 
      conflicts of interest.
EDAT- 2023/04/26 00:42
MHDA- 2023/05/12 07:06
PMCR- 2023/04/20
CRDT- 2023/04/25 18:02
PHST- 2023/02/28 00:00 [received]
PHST- 2023/04/09 00:00 [revised]
PHST- 2023/04/18 00:00 [accepted]
PHST- 2023/05/12 07:06 [medline]
PHST- 2023/04/26 00:42 [pubmed]
PHST- 2023/04/25 18:02 [entrez]
PHST- 2023/04/20 00:00 [pmc-release]
AID - S2213-2317(23)00107-6 [pii]
AID - 102706 [pii]
AID - 10.1016/j.redox.2023.102706 [doi]
PST - ppublish
SO  - Redox Biol. 2023 Jun;62:102706. doi: 10.1016/j.redox.2023.102706. Epub 2023 Apr 
      20.