期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 179, 期 -, 页码 133-143出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2021.12.001
关键词
-
资金
- NIH [R01 HL089958, R01 GM111337, R01 GM125212, R01 GM126165]
- University of Arizona College of Pharmacy start-up fund
- Holsclaw Endowment
Myocardial infarction is a common form of acute coronary syndrome, characterized by coronary artery blockage and subsequent cell death. Revascularization combined with pharmacotherapy is effective in relieving symptoms and reducing mortality. Oxidative stress plays a role in damaging mitochondria and cell death, while the Nrf2 transcription factor is important in protecting mitochondria and preserving energy metabolism.
Myocardial infarction is the most common form of acute coronary syndrome. Blockage of a coronary artery due to blood clotting leads to ischemia and subsequent cell death in the form of necrosis, apoptosis, necroptosis and ferroptosis. Revascularization by coronary artery bypass graft surgery or non-surgical percutaneous coronary intervention combined with pharmacotherapy is effective in relieving symptoms and decreasing mortality. However, reactive oxygen species (ROS) are generated from damaged mitochondria, NADPH oxidases, xanthine oxidase, and inflammation. Impairment of mitochondria is shown as decreased metabolic activity, increased ROS production, membrane permeability transition, and release of mitochondrial proteins into the cytoplasm. Oxidative stress activates Nrf2 transcription factor, which in turn mediates the expression of mitofusin 2 (Mfn 2) and proteasomal genes. Increased expression of Mfn2 and inhibition of mitochondrial fission due to decreased Drp1 protein by proteasomal degradation contribute to mitochondrial hyperfusion. Damaged mitochondria can be removed by mitophagy via Parkin or p62 mediated ubiquitination. Mitochondrial biogenesis compensates for the loss of mitochondria, but requires mitochondrial DNA replication and initiation of transcription or translation of mitochondrial genes. Experimental evidence supports a role of Nrf2 in mitophagy, via up-regulation of PINK1 or p62 gene expression; and in mitochondrial biogenesis, by influencing the expression of PGC-1 alpha, NResF1, NResF2, TFAM and mitochondrial genes. Oxidative stress causes Nrf2 activation via Keap1 dissociation, de novo protein translation, and nuclear translocation related to inactivation of GSK3 beta. The mechanism of Keap 1 mediated Nrf2 activation has been hijacked for Nrf2 activation by small molecules derived from natural products, some of which have been shown capable of mitochondrial protection. Multiple lines of evidence support the importance of Nrf2 in protecting mitochondria and preserving or renewing energy metabolism following tissue injury.
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