Propofol Protects Myocardium From Ischemia/Reperfusion Injury by Inhibiting Ferroptosis Through the AKT/p53 Signaling Pathway

Abstract

The molecular mechanism underlying the protective role of propofol against myocardial ischemia/reperfusion (I/R) injury remains poorly understood. Previous studies have shown that ferroptosis is an imperative pathological process in myocardial I/R injury. We hypothesized that propofol prevents myocardial I/R injury by inhibiting ferroptosis via the AKT/p53 signaling pathway. The ferroptosis-inducing agent erastin (E) and AKT inhibitor MK2206 (MK) were used to investigate the role of propofol in myocardial I/R injury. H9C2 cells treated without any reagents, erastin for 24 h, propofol for 1 h before adding erastin were assigned as the control (C), E, and E + P group, respectively. Cell viability, reactive oxygen species (ROS), and the expression of antioxidant enzymes, including ferritin heavy chain 1 (FTH1), cysteine/glutamate transporter (XCT), and glutathione peroxidase 4 (GPX4) in H9C2 cells. Rat hearts from the I/R + P or I/R groups were treated with or without propofol for 20 min before stopping perfusion for 30 min and reperfusion for 60 min. Rat hearts from the I/R + P + MK or I/R + MK groups were treated with or without propofol for 20 min, with a 10-min treatment of MK2206 before stopping perfusion. Myocardial histopathology, mitochondrial structure, iron levels, and antioxidant enzymes expression were assessed. Our results demonstrated that erastin increased H9C2 cell mortality and reduced the expression of antioxidant enzymes. I/R, which reduced the expression of antioxidant enzymes and increased iron or p53 (p < 0.05), boosted myocardium pathological and mitochondrion damage. Propofol inhibited these changes; however, the effects of propofol on I/R injury were antagonized by MK (p < 0.05). In addition, AKT siRNA inhibited the propofol-induced expression of antioxidant enzymes (p < 0.05). Our findings confirm that propofol protects myocardium from I/R injury by inhibiting ferroptosis via the AKT/p53 signal pathway.

Targeting Ferroptosis as a Promising Therapeutic Strategy for Ischemia-Reperfusion Injury

“…Apart from these drugs/compounds, a variety of agents with different biological activities have been shown to inhibit ferroptosis in MIRI. Propofol, a frequently used anesthetic agent, has been shown to protect against myocardial injury by suppressing I/R-induced ferroptosis through the AKT/p53 signaling pathway [ 72 ]. Ferulic acid (FA), the main active component of Angelica sinensis , was reported to alleviate MIRI by enhancing AMPKα2 expression-mediated ferroptosis inhibition [ 73 ].…”

GPX4 Alleviates Diabetes Mellitus-Induced Erectile Dysfunction by Inhibiting Ferroptosis

“…Ferroptosis is a new-found form of cell death characterized by iron-dependent overwhelming lipid peroxidation [ 32 ]. It has been shown that ferroptosis is involved in various pathological conditions [ 33 , 34 ]. We also previously found that apoptosis is increased in the penis of diabetic rats, but the use of apoptosis inhibitors can only partially reduce cell death, and the improvement of penile erectile function was also not obvious, suggesting that apoptosis is not the predominant form of cell death in corpus cavernosum [ 26 ].…”

From Iron Metabolism to Ferroptosis: Pathologic Changes in Coronary Heart Disease

“…In one study, propofol inhibited ferroptosis via the AKT/P53 signaling pathway, thereby protecting CM from I/R injury. Specifically, it reduced SOD and iron accumulation, decreased lipid peroxidation levels, thereby increasing the expression of antioxidant enzymes [ 68 ]. Ferroptosis as one of the mechanisms of CM death after myocardial I/R has been widely demonstrated, and inhibiting ferroptosis may be an effective way to attenuate myocardial I/R injury.…”

“…Therefore, antioxidants may be the most promising ferroptosis inhibitors for widespread use. Excavating drugs with inhibiting ferroptosis from clinically available drugs may provide new options for treating CHD more quickly, such as vitamin E, fluvastatin, puerarin, dexmedetomidine, and propofol [ 41 , 60 , 65 , 67 , 68 ].…”