Dexmedetomidine Inhibits Ferroptosis to Alleviate Hypoxia/Reoxygenation-Induced Cardiomyocyte Injury by Regulating the HDAC2/FPN Pathway.

Purpose: Myocardial ischemia/reperfusion injury (MIRI) is closely associated with ferroptosis. Dexmedetomidine (Dex) has good therapeutic effects on MIRI. This study investigates whether dexmedetomidine (Dex) regulates ferroptosis during MIRI by affecting ferroportin1 (FPN) levels and elucidates the underlying mechanisms.

Methods: A murine MIRI model was established using male C57BL/6 J mice subjected to 30 min of left anterior descending coronary artery ligation followed by 48 h of reperfusion. In vitro, cardiomyocyte hypoxia/reoxygenation (H/R) models were created with 16 h of hypoxia and 8 h of reoxygenation. Triphenyltetrazolium chloride (TTC) staining was employed to determine infarct size. The pathological changes in myocardial tissues were assessed using hematoxylin-eosin (HE) staining. Lipid reactive oxygen species (ROS) level was detected using BODIPY™ 581/591 C11, and ferrous iron (Fe) and malondialdehyde (MDA) levels were measured using the kits. Cardiomyocyte viability was examined using cell counting kit-8 (CCK8) assay. The histone H3 lysine 27 acetylation (H3K27Ac) level in the FPN promoter region was determined using DNA pulldown assay. Chromatin immunoprecipitation (ChIP) assay was used to investigate the relationship between histone deacetylase 2 (HDAC2) and FPN promoter.

Results: Dex alleviated ferroptosis in cardiomyocytes by upregulating FPN levels, which mitigated H/R-induced oxidative damage. FPN knockdown abolished the protective effects of Dex, confirming its dependence on FPN expression. Additionally, HDAC2 knockdown alleviated I/R-induced myocardial injury and ferroptosis in mice. Moreover, H/R-induced HDAC2 upregulation transcriptionally inhibited FPN expression by reducing the H3K27Ac level in the FPN promoter region, but Dex therapy restored this impact via inhibition of HDAC2. As expected, HDAC2 overexpression partially reversed the inhibitory effect of Dex on H/R-mediated cardiomyocyte ferroptosis.

Conclusion: Dex alleviated H/R-mediated cardiomyocyte ferroptosis through regulating the HDAC2/FPN axis. Our findings lend theoretical support to the use of Dex in MIRI therapy.