4.5 AP39
In addition, a H2S donor targeting mitochondria (AP39) has been synthesized by scientists. 10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5yl)phenoxy)decyl (AP39) can reduce intracellular oxidative stress and pro-inflammatory factor gene expression, maintain cell vitality, ensure mitochondrial energy and DNA integrity, and play an anti-inflammatory and antioxidant cytoprotection[75]. In mouse heart transplantation experiments, studies have found that adding AP39 to organ preservation solution can significantly improve cell viability, reduce cold ischemia-reperfusion injury, and tissue fibrosis[76]. In mouse pancreatic transplantation experiments, AP39 can significantly reduce ROS production and improve pancreatic island function[77]. These studies undoubtedly demonstrate the significant potential of AP39 in preventing and treating I/R injury in organ transplantation. As an H2S donor, in addition to protecting cells, AP39 can induce vascular relaxation by stimulating NO signaling and activating KATP channels (Kchannels)[78]. The development of AP39 shows that the development of specific target donors of hydrogen sulfide in subcellular organelles has great potential in future biological research.
The mechanism of ischemia-reperfusion
According to the progression of diseases, ischemia-reperfusion injury can be divided into two stages: ischemia and reperfusion. It is generally believed that the degree of cell dysfunction, injury, and necrosis is related to the severity and duration of ischemia. Therefore, the main idea for treating I/R is to restore blood flow to the ischemic site as soon as possible[13]. However, the sensitivity of different organs to ischemic manifestations also varies, such as the brain, heart, and other organs with poor tolerance to ischemia and hypoxia, and differences in organ tolerance can also affect the degree of cell damage. In addition, although the recovery of reperfusion can provide oxygen and nutrients to cells, it will further strengthen the damage after ischemia, activate cell death and immune response, etc[12]. On the other hand, inflammatory mediators will also be transported to the distal organs with the recovery of reperfusion, which is also the reason for multi organ failure in the later stage of I/R[79-81]. I/R is a dynamic process with significant differences in organs, so a deeper understanding of its molecular mechanisms can help us find better treatment methods.
Calcium overload
When ischemia occurs, ATP in cells is rapidly depleted, ATP synthesis decreases, sodium pump activity decreases, intracellular Na+ content increases, and sodium calcium exchange proteins are activated, leading to reverse transport of Na+ to the extracellular space and an increase in intracellular Ca2+[82, 83]. On the other hand, due to hypoxia and anaerobic metabolism, the production of H+ increases, and the pH of extracellular fluid and cytoplasm decreases. When tissue perfusion resumes, the pH of extracellular fluid increases, but the pH of cytoplasm is still very low. In order to reduce the accumulation of H+ in cells, H+-Na+ exchange protein and Na+-Ca2+ exchange protein are activated, increasing calcium overload[82]. When the body is in a state of stress, the release of a large amount of catecholamines activates protein kinase C(PKC) through a signaling pathway, promotes H+-Na+ exchange, and also increases intracellular Ca2+. Due to the massive accumulation of Ca2+, the damage of endoplasmic reticulum and mitochondria intensifies. With the complete opening of the mitochondrial mPT pore(mitochondrial permeability transition pore), it will have a more negative impact on cells[84].
Figure 3