Dexmedetomidine prevents cardiomyocytes from hypoxia/reoxygenation injury via modulating tetmethylcytosine dioxygenase 1-mediated DNA demethylation of Sirtuin1

Abstract

Myocardial hypoxia/reoxygenation (H/R) injury is a common pathological change in patients with acute myocardial infarction undergoing reperfusion therapy. Dexmedetomidine (DEX) has been found to substantially improve ischemia-mediated cell damage. Here, we focus on probing the role and mechanism of DEX in ameliorating myocardial H/R injury. Oxygen–glucose deprivation and reoxygenation (OGD/R) were applied to construct the H/R injury model in human myocardial cell lines. After different concentrations of DEX’s treatment, cell counting kit-8 (CCK-8) assay and BrdU assay were employed to test cell viability. The profiles of apoptosis-related proteins Bcl2, Bax, Bad and Caspase3, 8, 9 were determined by Western blot (WB). The expression of inflammatory factors interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α) was checked by reverse transcription-polymerase chain reaction (RT-PCR). By conducting WB, we examined the expression of NF-κB, Sirt1, Tet methylcytosine dioxygenase 1 (TET1) and DNA methylation-related proteins (DNA methyltransferase 1, DNMT1; DNA methyltransferase 3 alpha, DNMT3A; and DNA methyltransferase 3 beta, DNMT3B). Our data showed that OGD/R stimulation distinctly hampered the viability and elevated apoptosis and inflammatory factor expression in cardiomyocytes. DEX treatment notably impeded myocardial apoptosis and inflammation and enhanced cardiomyocyte viability. OGD/R enhanced total DNA methylation levels in cardiomyocytes, while DEX curbed DNA methylation. In terms of mechanism, inhibiting TET1 or Sirtuin1 (Sirt1) curbed the DEX-mediated myocardial protection. TET1 strengthened demethylation of the Sirt1 promoter and up-regulated Sirt1. DEX up-regulates Sirt1 by accelerating TET1 and mediating demethylation of the Sirt1 promoter and improves H/R-mediated myocardial injury.

Targeting ferroptosis as a promising therapeutic strategy to treat cardiomyopathy

“…EX527, a selective Sirt1 inhibitor reversed the protective effect of 10 against ferroptosis ( Zeng et al, 2023 ). This observation was corroborated by other study, which reported 10 upregulated miR-149 and downregulated HMGB1 to inhibit ferroptosis and improve SCM( Wang L. et al, 2022 ). Vitamin B6 (32) can suppress LPS-induced oxidative stress and LPO that lead to ferroptosis in vivo and in vitro through activating Nrf2.…”

“…5 attenuates IR-induced ICM through inhibiting ferroptosis by decreasing the production of LPO, increasing the Nrf2 and GPX4 protein, while decreasing the mRNA levels of Ptgs2 and Acsl4 , and the protein levels of ACSL4 ( Lin et al, 2021 ). Dexmedetomidine (6) , a highly selective alpha2-adrenoceptor agonist with sedative, analgesic, sympatholytic, and hemodynamic-stabilizing properties, posess the protective effect against I/R ( Xiao Z. et al, 2021 ; Chen Y. et al, 2021 ; Deng et al, 2022 ; Yang et al, 2022 ; Hu et al, 2023 ) and H/R ( Wu W. et al, 2022 ; Wang L. et al, 2022 ) induced cardiomyocyte injury. 6 attenuates ICM through inhibiting ferroptosis by activating AMPK/GSK-3β-dependant Nrf2/SLC7A11/GPX4 ( Wang et al, 2022d ).…”

STUB1 is acetylated by KAT5 and alleviates myocardial ischemia-reperfusion injury through LATS2-YAP-β-catenin axis

“…The in vitro MIRI model was established by oxygen-glucose deprivation/reoxygenation (OGD/R) as previously described 33 . In brief, AC16 and HL-1 cells were suspended in glucose- and serum-free DMEM, followed by culture in a hypoxic chamber (1% O 2 , 94% N 2 , and 5% CO 2 ) at 37 °C for 2, 4, 8, or 12 h. Afterward, the cells were maintained in DMEM containing 10% FBS under normal conditions (95% air and 5% CO 2 ) for 6 h for reoxygenation.…”

A review on regulation of DNA methylation during post-myocardial infarction

“…Moreover, a recent study has refined and expanded on these findings by exploring the link between DNA methylation and H/R injury. By increasing SIRT1 expression levels through DNMTi-mediated demethylation of the SIRT1 promoter, DEX can inhibit NF-κB activation and ameliorate H/R-triggered myocardial injury ( Wang et al, 2022 ). Given that Tet1-mediated DNA demethylation is critical to DEX’s mechanism of action in alleviating H/R injury, this approach represents a promising new pharmacological strategy based on DNA methylation for mitigating H/R injury after MI.…”