Tanshinone IIA Ameliorates Myocardial Ischemia–Reperfusion Injury via Activating HDAC1 ‐Repressed Nrf2‐ xCT /Gpx4/ HO ‐1 Axis

ABSTRACT Myocardial ischemia/reperfusion injury (MIRI) brings secondary injury to heart tissues and involves complicated pathophysiological activities, such as cell death, oxidative stress, and inflammation. HDAC1 (Histone Deacetylase 1) has been documented to strengthen MIRI; our study intended to investigate the concrete regulatory mechanisms and functions of tanshinone IIA on HDAC1 in MIRI, which might provide experimental proofs for the adjuvant application of tanshinone IIA in the treatment of MIRI. Genecards and SwissTargetPrediction websites were utilized to download the myocardial infarction‐related and tanshinone IIA‐targeted genes respectively, and then the String website was applied to display protein–protein interaction (PPI) network. The Cytoscape software was subsequently used to select and display the PPI network of hub genes. AutoDockTools and PyMOL software were utilized to operate molecular docking and visualize the docking results between tanshinone IIA and HDAC1, and Oxygen–glucose deprivation/reoxygenation (OGD/R)‐treated myocardiocytes were used as the cell model of MIRI. The protein levels of HDAC1 and nuclear factor erythroid 2‐related factor 2 (Nrf2)‐regulated pathway were examined by western blot, and cell viability and apoptosis were evaluated by CCK8, Tunnel, and flow cytometry assays. The levels of lactate dehydrogenase, creatine kinase‐MB, malondialdehyde, reduced glutathione, and Fe2+ were assessed by corresponding kit, and MIRI rat models were constructed to verify the therapeutic effects of tanshinone IIA in vivo. Finally, hematoxylin and eosin staining and immunohistochemistry were used to display the pathological changes of MIRI heart tissues and the levels of 4‐hydroxynonenal respectively. HDAC1 was the possible target of tanshinone IIA and was involved in the myocardial infarction process. Tanshinone IIA could bind to amino acid residues of HDAC1 with high affinity. Besides, HDAC1 was elevated in OGD/R‐treated myocardiocytes, and tanshinone IIA pretreatment ameliorated myocardiocyte apoptosis, the release of inflammatory mediators, and ferroptosis under the following OGD/R treatment, which were abolished by HDAC1 upregulation. Besides, tanshinone IIA pretreatment suppressed HDAC1 expression and further activated the Nrf2‐xCT/Gpx4/HO‐1 axis in myocardiocytes with OGD/R operation. Functionally, tanshinone IIA pre‐injection ameliorated myocardial infarcted areas via activating the HDAC1‐suppressed Nrf2‐xCT/Gpx4/HO‐1 pathway in vivo. Tanshinone IIA could attenuate myocardial apoptosis, inflammatory response, and ferroptosis via activating the HDAC1‐repressed Nrf2‐xCT/Gpx4/HO‐1 axis, which promoted myocardial salvage in the MIRI process.