Improved DCD Heart Transplant Function Through Ferroptosis Blockade in a Model of Experimental Normothermic Ex Vivo Perfusion.

Abstract

BACKGROUND: Adopting donation after circulatory death (DCD) hearts can increase the donor pool. However, DCD hearts experience severe ischemia-reperfusion injury (IRI). Ferroptosis is a key contributor to organ IRI. Liproxstatin-1 (Lip-1), a selective ferroptosis inhibitor, markedly suppresses this form of cell death. This study evaluated the cardioprotective effect of Lip-1 on DCD hearts preserved with normothermic ex vivo heart perfusion (EVHP) in a rat heart transplantation model. METHODS: The donor hearts of Lewis rats were subjected to the DCD procedure by suffering a 15-min warm ischemia injury, subsequently preserved with EVHP for 3 h, and then heterotopically transplanted into recipient rats. Dimethyl sulfoxide or Lip-1 was added to the perfusate of normothermic EVHP in the control or Lip-1 group. Cardiac function was assessed during EVHP and 4 h after heart transplantation. We investigated the histological changes and the levels of oxidative stress, inflammation, apoptosis, CD31 expression, and ferroptosis in the posttransplant DCD hearts. RESULTS: compared with the control group, Lip-1 treatment significantly improved the cardiac function of DCD hearts in the first hour of EVHP and 4 h after heart transplantation, attenuated the levels of myocardial ferroptosis (glutathione peroxidase 4, SLC7A11, ACSL4, COX2), inflammation (interleukin-1β, interleukin-6, tumor necrosis factor-α), oxidative stress (4-hydroxynonenal), apoptosis (Bax, Bcl-2, caspase-3), reduced histological injury, and ameliorates endothelial dysfunction (CD31) in the posttransplant DCD hearts. CONCLUSIONS: Normothermic EVHP combined with Lip-1 treatment can be a promising DCD heart preservation strategy, which can alleviate myocardial IRI, ameliorate endothelial dysfunction, and improve posttransplant cardiac function for DCD hearts via inhibiting myocardial ferroptosis.