Ischemia/reperfusion injury and cardioprotective mechanisms: Role of mitochondria and reactive oxygen species

Figure 1 Flowchart depicting the variations of pH, ROS and mPTP opening during ischaemia and reperfusion phases in the control hearts, and in hearts protected by preconditioning or postconditioning. A: In the control hearts reactive oxygen species (ROS) production slightly increases during the initial part of ischaemia until the O₂ is exhausted. Then sharply increases in reperfusion. Formation of mitochondrial permeability transition pores (mPTP) had been limited during ischaemia by the low pH despite increased cellular levels of ROS, Ca²⁺ and Pi overload. But as pH returns to its baseline level and ROS formation increases prolonged opening occurs. The limited damages occurring during ischaemia are exacerbated by the prolonged mPTP opening which mediates irreversible cell damages in reperfusion. The opening effect, besides Ca²⁺ overload, is also due to indirect effects, such as phospholipase A2 (PLA2) and calpain activations and consequent arachidonic acid release after membrane phospholipids degradation. A part membrane depolarisation also inorganic phosphate (Pi), lower levels of nitric oxide (NO) contribute to mPTP opening. Other factors which regulate pore formation are Bcl-2–associated X protein (Bax)/Bcl-2-associated death promoter (Bad), B-cell lymphoma 2 (Bcl-2) and glycogen synthase kinase 3 β (GSK-3β). Pore opening leads to cell-death through the release of pro-apoptotic factors as cytochrome c (Cyt c) and via ROS-induced ROS release (RIRR); B: The pre/postconditioned hearts are characterized by delayed pH recovery, ROS signalling and activation of protective pathways (e.g. Reperfusion Injury Salvage Kinases (RISK)/Survivor Activating Factor Enhancement (SAFE). These conditions contribute to reduce mPTP opening and consequent cell death limitation. The details of the protective signalling (RISK/SAFE) can be seen in Figure 2 and Figure 3. For further explanations see the text.