Liproxstatin-1 protects the mouse myocardium against ischemia/reperfusion injury by decreasing VDAC1 levels and restoring GPX4 levels

• Published in: Biochemical and biophysical research communications Vol. 520; no. 3; pp. 606 - 611
• Main Authors: Feng, Yansheng, Madungwe, Ngonidzashe B., Imam Aliagan, Abdulhafiz D., Tombo, Nathalie, Bopassa, Jean C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.12.2019
• Subjects: Animals; Antioxidants - metabolism; calcium; Calcium - metabolism; cardioprotective effect; Cardiotonic Agents - pharmacology; cell viability; Ferroptosis; Ferroptosis - drug effects; Heart - drug effects; Ischemia; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria, Heart - drug effects; Mitochondria, Heart - metabolism; Mitochondrial Membrane Transport Proteins - drug effects; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial Permeability Transition Pore; myocardial infarction; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - prevention & control; myocardium; Myocardium - metabolism; Myocardium - pathology; oligomerization; permeability; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Quinoxalines - pharmacology; Reactive oxygen species; Reactive Oxygen Species - metabolism; Reperfusion; reperfusion injury; Spiro Compounds - pharmacology; Voltage-Dependent Anion Channel 1 - metabolism; Voltage-Dependent Anion Channel 2 - metabolism; Voltage-Dependent Anion Channels - metabolism; Mitochondria; Reactive oxygen species; IP3R1; Reperfusion; Ischemia; GPX4; ROS; VDAC; Ferroptosis; I/R; mPTP; GRP75
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2019.10.006

Ferroptosis is a distinct iron-dependent mechanism of regulated cell death recognized in cancer and ischemia/reperfusion (I/R) injury of different organs. It has been reported that molecules such as liproxstatin-1 (Lip-1) inhibit ferroptosis and promote cell survival however, the mechanisms underlying this action are not clearly understood. We investigated the role and mechanism of Lip-1 in reducing cell death in the ischemic myocardium. Using an I/R model of isolated perfused mice hearts in which Lip-1 was given at the onset of reperfusion, we found that Lip-1 protects the heart by reducing myocardial infarct sizes and maintaining mitochondrial structural integrity and function. Further investigation revealed that Lip-1-induced cardioprotection is mediated by a reduction of VDAC1 levels and oligomerization, but not VDAC2/3. Lip-1 treatment also decreased mitochondrial reactive oxygen species production and rescued the reduction of the antioxidant GPX4 caused by I/R stress. Meanwhile, mitochondrial Ca2+ retention capacity needed to induce mitochondrial permeability transition pore opening did not change with Lip-1 treatment. Thus, we report that Lip-1 induces cardioprotective effects against I/R injury by reducing VDAC1 levels and restoring GPX4 levels. •Lip-1 protects the myocardium and mitochondria from ischemia/reperfusion injury.•Lip-1 reduces VDAC1 levels but not VDAC2/3.•Treatment rescues GPX4 levels and reduces mitochondrial ROS production.•Lip-1 does not impact Ca2+-induced mPTP opening.