1. Academic Validation
  2. MK-886 protects against cardiac ischaemia/reperfusion injury by activating proteasome-Keap1-NRF2 signalling

MK-886 protects against cardiac ischaemia/reperfusion injury by activating proteasome-Keap1-NRF2 signalling

  • Redox Biol. 2023 Apr 20;62:102706. doi: 10.1016/j.redox.2023.102706.
Kai-Na Shi 1 Pang-Bo Li 1 Hui-Xiang Su 1 Jing Gao 1 Hui-Hua Li 2
Affiliations

Affiliations

  • 1 Department of Emergency Medicine, Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China.
  • 2 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.
Abstract

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 β5i, 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.

Keywords

Immunoproteasome; Keap1/NRF2; MK-886; Mitochondrial dynamics; Myocardial ischaemia/reperfusion injury; Oxidative stress.

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