Necroptosis is one of a regulated programmed death mode,
fibrosis is closely related with cell death. It has been reported that inhibition of necroptosis can play the protective role in cardiac
ischemia and
reperfusion injury,
stroke and other diseases, but the mechanisms of
aldehyde dehydrogenases 2 (ALDH2) against high
glucose induced neonatal rat ventricular primary cardiomyocytes
fibrosis and necroptosis had not been elucidated clearly. This study was to observe the effect of ALDH2 on high
glucose (HG) induced myocardial
fibrosis and necroptosis in primary rat cardiomyocytes model. In contrast to normal
glucose group, in HG group, with the decreases of ALDH2 activity,
mRNA and
protein levels, the cardiomyocytes viability was decreased,
reactive oxygen species (ROS), the
inflammation factors -
tumor necrosis factor-α (TNF-α),
interleukin-6 (IL-6), interleukin-1β (IL-1β) levels,
collagen I (col I) and col III
mRNA expressions and tissue inhibitors of
matrix metalloproteinase 4 (TIMP4)
protein expression were increased, while
matrix metalloproteinase 14 (MMP14)
protein level, the ratio of MMP14/TIMP4 were decreased, and the necroptosis key factors - the receptor interacting
protein 1 (RIP1), RIP3 and mixed lineage
kinase domain-like
protein (MLKL) at
mRNA and
protein expressions were increased, the
inflammasome core
proteins - NLRP3 and ASC
protein expressions were also increased, the apoptosis rate and
necrosis rate were also increased. When the cardiomyocytes were treated with Alda-1 (the ALDH2 agonist) in HG intervention, the cell viability, ALDH2 activity,
mRNA and
protein levels, MMP14
protein level, the ratio of MMP14/TIMP4 were higher, ROS and TNF-α,
IL-6, IL-1β levels, RIP1, RIP3, MLKL, NLRP3 and ASC expressions, col I and col III, TIMP4 expressions, the apoptosis rate and
necrosis rate were lower than in HG group.
Daidzin, the antagonist of ALDH2 abolished the role of Alda-1. In summary, ALDH2 maybe is a key regulator in high
glucose induced cardiomyocytes injury. Activation of ALDH2 prevented the happening of
fibrosis, apoptosis and necroptosis in high
glucose induced primary cardiomyocytes injury model, the protective effects were related to the inhibiting of oxidative stress and
inflammation, changing of MMP14 and TIMP4, then inhibiting the happening of
fibrosis, apoptosis and necroptosis. These findings advance our understanding of the intensive mechanisms of ALDH2's cardioprotection, and provide the targeted basis for clinical diabetes treatment.