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