Xanthohumol Protects the Rat Myocardium against Ischemia/Reperfusion Injury-Induced Ferroptosis

Abstract

Ferroptosis is an iron-dependent form of cell death caused by the inactivation of glutathione peroxidase 4 (GPX4) and accumulation of lipid peroxides. Ferroptosis has been found to participate in the ischemia-reperfusion (I/R) injury, leading to heart dysfunction and myocardial cell death. Xanthohumol (XN), a prenylated flavonoid isolated from Humulus lupulus, has multiple pharmacological activities, such as anti-inflammatory and antioxidant. This study is aimed at investigating whether XN could attenuate the I/R-induced ferroptosis in cardiomyocytes and the underlying mechanisms. Cardiomyocytes were treated with Fe-SP and RSL3, and the rat hearts were treated with I/R. The results from the present study show that XN was able to protect cardiomyocytes against Fe-SP- and RSL3-induced ferroptotic cell death by decreasing the production of lipid peroxidation and ROS, chelating iron, reducing the NRF2 protein level, and modulating the protein levels of GPX4. Moreover, XN significantly decreased the mRNA levels of ferroptosis markers, Ptgs2 and Acsl4, and the protein levels of ACSL4 and NRF2 and modulated the protein levels of GPX4 in I/R-treated hearts. The findings from the present study suggest that XN might have the therapeutic potential for the I/R-induced ferroptosis injury.

The underlying pathological mechanism of ferroptosis in the development of cardiovascular disease

“…Additionally, although indicators of ferroptosis have predictive capacity on the prognosis of amyotrophic lateral sclerosis ( 144 ), ferroptosis biomarkers for predicting early diagnosis and prognosis of CVDs have not yet been reported clinically. Classic CVD-related ferroptosis biomarkers validated in animal models include GPX4, ROS, 4-HNE, COX-2, and iron levels, but there are still some limitations of detection ( 35 , 45 , 86 ). First, the activity of ferroptosis metabolites is time-sensitive and should be detected in time after the onset of CVDs.…”

“…Besides, the ferroptosis inhibitor ferrostatin-1 markedly prevented pathological myocardial remodeling and fibrosis in angiotensin II-induced hypertensive cardiomyopathy by attenuating the upregulation of ferrous ion levels and lipid peroxidation in mouse microvascular endothelial cells (ECs) through modulating the xCT/GPX4 signaling ( 43 ). The Chinese herbal medicine, Tongxinluo, prevented atherosclerosis, and the xanthohumol reduced myocardial I/R injury as well, both through modulating GPX4 expression to decrease ROS ( 44 , 45 ). Thus, chemicals targeting GPX4 signaling pathway could act as potential drugs to various CVDs by suppressing ferroptosis.…”

Roles of Ferroptosis in Cardiovascular Diseases

“…C3G reduced the Fe 2+ content, down-regulated TfR1 and up-regulated ferritin heavy chain1 (FTH1), inhibited ferroptosis and alleviated myocarial injury in I/RI models ( 56 ). Likewise, Xanthohumol (XN) isolated from Humulus lupulus had also been shown to protect ischemic/reperfusion myocardium from ferroptosis ( 57 ). Besides, exosomal long noncoding RNA (lncRNA) MIR9-3 host gene (Mir9-3hg) derived from bone MSCs mitigated ferroptosis in I/RI mice by regulating pumilio RNA binding family member two (Pum2)/peroxiredoxin 6 (PRDX6) axis and showed cardioprotective effects both in vitro and in vivo ( 58 ).…”

Ferroptosis, a Rising Force against Renal Fibrosis

“…Ferroptosis was proposed in 2012, and its involvement in the pathological progression of diseases such as ischemiareperfusion injury (IRI), stroke, inflammatory bowel disease, organ failure, and tumor progression has been widely demonstrated [5][6][7][8][9][10][11][12]. As research progressed, the following characteristics of ferroptosis were widely recognized and validated: cellular iron overload, GSH and GPX4 depletion, accumulation of lipid peroxides such as malondialdehyde and 4-hydroxynonenal and mitochondrial damage (volume reduction, outer membrane rupture, increased membrane density, and cristae reduction or disappearance) [13][14][15].…”