Inhibition of ATM/Chk2 Pathway Ameliorates Hypoxia-induced Myocardium Injury
Abstract
Background: Acute myocardial infarction (AMI) is a kind of acute myocardial ischemic disease based on atherosclerosis that has high global morbidity and mortality. Recent work suggests the possible presence of DNA damage response (DDR) in AMI. However, the evidence is insufficient, and it remains elusive whether DDR can be used as a therapeutic target of AMI. Methods: The inductions of DDR were confirmed in rat myocardial ischemia model and cell model. Then, the specific inhibitor or siRNA target Chk1, ATM and Chk2 were used in H9C2 and NRVMs to assess their protective effect under hypoxia. Results: The induction of phosphorylation of H2A.X was observed in a rat model, suggesting that DDR occurs in myocardial tissues. DDR was also induced in vitro in H9C2 and NRVMs hypoxia models by the upregulation of p-H2A.X, p-Chk1, and p-Chk2. Then, we used UCN-01, a specific Chk1 inhibitor, to block Chk1 phosphorylation and find it has no effect on p-H2A.X expression, MTT, LDH, and cell apoptosis after 6h hypoxia. However, KU-55933, an ATM inhibitor, reversed the hypoxia-induced phosphorylation of ATM, H2A.X, and Chk2, and it also reduced apoptosis of H9C2 and NRVMs. Conclusion: Our results suggested that DDR occurs during myocardial ischemia in vivo and oxygen depletion injury in vitro. Inhibition of the ATM/Chk2 pathway might play a cytoprotective role in guarding against myocardial cell injury.
Keywords
AMI, DDR, ATM inhibition, KU-55933
DOI
10.12783/dtbh/mshh2017/13422
10.12783/dtbh/mshh2017/13422
Refbacks
- There are currently no refbacks.