ALOX15-launched PUFA-phospholipids peroxidation increases the susceptibility of ferroptosis in ischemia-induced myocardial damage

  • Signal Transduct Target Ther. 2022 Aug 15;7(1):288. doi: 10.1038/s41392-022-01090-z.
Xiao-Hui Ma  1  2  3  4 ,  Jiang-Han-Zi Liu  1  2  3 ,  Chun-Yu Liu  1  2  3 ,  Wan-Yang Sun  1  2  3 ,  Wen-Jun Duan  1  2  3 ,  Guan Wang  5 ,  Hiroshi Kurihara  1  2  3 ,  Rong-Rong He  6  7  8 ,  Yi-Fang Li  9  10  11 ,  Yang Chen  12 ,  Hongcai Shang  13
Affiliations
  • 1. Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China.
  • 2. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China.
  • 3. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Jinan University, Guangzhou, 510632, China.
  • 4. Institute of Traditional Chinese Medicine, Xinjiang Medical University, Urumqi, 830054, China.
  • 5. Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 6. Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China. [email protected].
  • 7. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China. [email protected].
  • 8. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Jinan University, Guangzhou, 510632, China. [email protected].
  • 9. Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China. [email protected].
  • 10. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China. [email protected].
  • 11. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Jinan University, Guangzhou, 510632, China. [email protected].
  • 12. College of Pharmacy, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. [email protected].
  • 13. Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100700, Beijing, China. [email protected].
PMID: 35970840 DOI: 10.1038/s41392-022-01090-z
Abstract

Myocardial ischemia/reperfusion (I/R) injury is a classic type of Cardiovascular Disease characterized by injury to cardiomyocytes leading to various forms of cell death. It is believed that irreversible myocardial damage resulted from I/R occurs due to oxidative stress evoked during the reperfusion phase. Here we demonstrate that ischemia triggers a specific redox reaction of polyunsaturated fatty acids (PUFA)-phospholipids in myocardial cells, which acts as a priming signaling that initiates the outbreak of robust oxidative damage in the reperfusion phase. Using animal and in vitro models, the crucial lipid species in I/R injury were identified to be oxidized PUFAs enriched phosphatidylethanolamines. Using multi-omics, arachidonic acid 15-lipoxygenase-1 (ALOX15) was identified as the primary mediator of ischemia-provoked phospholipid peroxidation, which was further confirmed using chemogenetic approaches. Collectively, our results reveal that ALOX15 induction in the ischemia phase acts as a "burning point" to ignite phospholipid oxidization into ferroptotic signals. This finding characterizes a novel molecular mechanism for myocardial ischemia injury and offers a potential therapeutic target for early intervention of I/R injury.

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