Acidic pH Environment Alters Cell Death and Regulates AIF Translocation in Endothelial Cells
Abstract
Cardiac transplantations are the golden standard treatment for end-stage heart failure but issues like ischemia-reperfusion injury (IRI) and graft rejection persist. Prolonged ischemia induces anaerobic metabolism, lactic acid accumulation, and intracellular acidosis. IRI is associated with programmed cell death, of which necroptosis is significant. We have shown that in hypoxia-reoxygenation, targeting necroptosis prevents murine microvascular endothelial cell (MVEC) death through cyclophilin D inhibition in vitro and apoptosis-inducing factor (AIF) is implicated in DNA damage. Here, we investigated AIF and the impact of acidic pH on cell death. Acidic pH conditions altered MVEC necroptosis to an apoptosis-like pattern. AIF nuclear translocation and DNA fragmentation increased. Endonuclease G did not translocate into the nucleus, suggesting other nucleases may be involved in DNA fragmentation. PARP-1 regulates AIF translocation and DNA fragmentation. Clarifying the mechanisms underlying ischemia and the acidic cellular environment may lead to therapeutic strategies preventing IRI and cardiac transplant graft rejection.