Kindlin-2/Otub1/Slc7a11 Axis Improved Cardiac Ischemia Reperfusion Injury by Inhibiting Cardiomyocyte Ferroptosis

Abstract

Aims:

The study aimed to determine if the Kindlin-2/Otub1/Slc7a11 cascade could improve cardiac ischemia reperfusion injury by inhibiting ferroptosis.

Results:

The cardiac tissues of ischemia — reperfusion (I/R) mice, ischemic cardiomyopathy (ICM) patients, and cardiomyocytes underwent hypoxia/reoxygenation stimulation, and the Kindlin-2 levels decreased. Cardiomyocyte-specific Kindlin-2 overexpression alleviated I/R injury by inhibiting cardiomyocyte ferroptosis in vivo while cardiomyocyte-specific low expression of Kindlin-2 impaired cardiac functions, and this was accompanied by cardiomyocyte ferroptosis and reversed by Fer-1. In addition, in vitro experiments verified that Kindlin-2 prevented ferroptosis in cardiomyocytes treated with hypoxia/reoxygenation. An endogenous Kindlin-2 deficiency in cardiomyocytes was subsequently identified to spontaneously induce ferroptosis without exogenous stimulation, which is also prevented by Fer-1. Mechanistically, Kindlin-2 accelerated the interaction between Otub1 and Slc7a11. Consequently, deubiquitinated Slc7a11 contributed to the activation of glutathione (GSH) and Gpx4 to exert the anti-ferroptosis effect. Slc7a11/GSH/Gpx4 cascades strengthened by Kindlin-2 were abolished by Otub1 knock down. Moreover, Otub1 rescued cardiomyocyte ferroptosis and cardiac injury due to the Kindlin-2 deficiency.

Innovation:

Kindlin-2 accelerated the interaction between Otub1 and Slc7a11. Therefore, Slc7a11/GSH/GPX4 cascades were reinforced to improve the deteriorated tissues of I/R hearts by ameliorating ferroptosis.

Conclusions:

Our research revealed that the Kindlin-2/Otub1/Slc7a11 cascade improved cardiac I/R injury by inhibiting ferroptosis; hence, it may be a potential therapeutic target for ICM. Antioxid. Redox Signal. 43, 727–744.

Keywords

Ferroptosis I/R injury Kindlin-2 Otub1 Slc7a11 Cardiomyocyte

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