Journal
JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH
Volume 15, Issue 5, Pages 1129-1142Publisher
SPRINGER
DOI: 10.1007/s12265-022-10224-1
Keywords
ESCRT-III; Necroptosis; Ischemic stroke; Brain; Polymyxin B
Funding
- National Natural Science Foundation of China [82073849, 82173815, 81872873]
- Natural Science Foundation of Hunan Province, China [2021JJ30032, 2020JJ4770]
- Changsha Municipal Natural Science Foundation [kq2014145]
- Fundamental Research Funds for the Central Universities of Central South University [1053320184093]
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Polymyxin B can reduce brain injury and necroptosis in stroke rats by enhancing the ESCRT-III machinery and suppressing the RIPK1/RIPK3/MLKL pathway simultaneously.
Endosomal sorting complex required for transport III (ESCRT-III) machinery is a key component to counteract the mixed lineage kinase domain-like pseudokinase (MLKL)-induced plasma membrane broken in cells undergoing necroptosis. Based on the bioinformatics analysis, polymyxin B, a polypeptide antibiotic, is predicted to simultaneously interact with ESCRT-III subunits and necroptosis-relevant proteins. This study aims to explore whether polymyxin B could reduce necroptosis in the stroke rat brain via enhancing the ESCRT-III machinery and/or suppressing the RIPK1/RIPK3/MLKL pathway. The stroke rats showed evident brain injury, concomitant with the downregulation of ESCRT-III subunits and the upregulation of necroptosis-relevant proteins. Post-ischemic administration of polymyxin B could alleviate the brain injury, accompanied by restoration of the levels of ESCRT-III subunits and suppression of necroptosis-relevant proteins. And, polymyxin B exerted similar effects in hypoxia-treated HT22 cells. We conclude that polymyxin B can reduce necroptosis in the stroke rat brain via enhancing the ESCRT-III machinery and suppressing the RIPK1/RIPK3/MLKL pathway simultaneously.
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