Icariin inhibits hypoxia/reoxygenation‐induced ferroptosis of cardiomyocytes via regulation of the Nrf2/HO‐1 signaling pathway

• Published in: FEBS open bio Vol. 11; no. 11; pp. 2966 - 2976
• Main Authors: Liu, Xiu‐Juan, Lv, Yan‐Fei, Cui, Wen‐Zhu, Li, Yan, Liu, Yang, Xue, Yi‐Tao, Dong, Feng
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.11.2021; John Wiley and Sons Inc; Wiley
• Subjects: Apoptosis; Apoptosis - drug effects; Bioengineering; Blood flow; Cardiomyocytes; Cell death; Cell Hypoxia - drug effects; Cell Hypoxia - physiology; Cell Line; Cell Survival - drug effects; Dehydrogenases; Endoplasmic reticulum; Ferroptosis; Flavonoids - metabolism; Flavonoids - pharmacology; Heart attacks; Hypoxia; Hypoxia - drug therapy; Hypoxia - metabolism; hypoxia/reoxygenation; icariin; Iron; Ischemia; L-Lactate dehydrogenase; lactate dehydrogenase; Lactic acid; Membranes; Myocardial infarction; Myocardial Reperfusion Injury - metabolism; Myocardium; Myocytes, Cardiac - drug effects; NF-E2-Related Factor 2 - drug effects; NF-E2-Related Factor 2 - metabolism; Nrf2/HO‐1 pathway; Oxidative stress; Oxidative Stress - drug effects; Plaques; protective effect; Proteins; Reactive oxygen species; Reactive Oxygen Species - metabolism; Signal transduction; Signal Transduction - drug effects; Software; viability; United States > US; China; Germany; cardiomyocytes; icariin; Nrf2/HO-1 pathway; ferroptosis; oxidative stress; hypoxia/reoxygenation
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.13276

Myocardial infarction (MI) is caused by the formation of plaques in the arterial walls, leading to a decrease of blood flow to the heart and myocardium injury as a result of hypoxia. Ferroptosis is a crucial event in myocardial injury, and icariin (ICA) exerts protective effects against myocardial injury. Here, we investigated the protective mechanism of ICA in hypoxia/reoxygenation (H/R)‐induced ferroptosis of cardiomyocytes. H9C2 cells were subjected to H/R induction. The content of lactate dehydrogenase and the levels of oxidative stress and intracellular ferrous ion Fe2+ were measured. The levels of ferroptosis markers (ACSL4 and GPX4) were detected. H/R‐induced H9C2 cells were cultured with ICA in the presence or absence of ferroptosis inducer (erastin). Znpp (an HO‐1 inhibitor) was added to ICA‐treated H/R cells to verify the role of the Nrf2/HO‐1 pathway. H/R‐induced H9C2 cells showed reduced viability, enhanced oxidative stress and lactate dehydrogenase content, increased levels of Fe2+ and ACSL4, and decreased levels of GPX4. ICA inhibited H/R‐induced ferroptosis and oxidative stress in cardiomyocytes. Erastin treatment reversed the inhibitory effect of ICA on ferroptosis in H/R cells. The expression of Nrf2 and HO‐1 in H/R‐induced H9C2 cells was reduced, whereas ICA treatment reversed this trend. Inhibition of the Nrf2/HO‐1 pathway reversed the protective effect of ICA on H/R‐induced ferroptosis. Collectively, our results suggest that ICA attenuates H/R‐induced ferroptosis of cardiomyocytes by activating the Nrf2/HO‐1 signaling pathway. Hypoxia/reoxygenation can induce ferroptosis in cardiomyocytes. Here, we report that icariin can activate the Nrf2/HO‐1 signaling pathway and inhibit hypoxia/reoxygenation‐induced ferroptosis in cardiomyocytes.