Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.
Department of Medicine, MacKay Medical College, New Taipei City, 252, Taiwan.
BMC Pharmacol Toxicol. 2020 Mar 12;21(1):21. doi: 10.1186/s40360-020-0400-0.
Despite the fact that histone deacetylase (HDAC) inhibitors have been tested to treat various cardiovascular diseases, the effects of selective HDAC6 inhibitor ACY1215 on infarct size during cardiac ischemia-reperfusion (IR) injury still remain unknown. In the present study we aimed to investigate the effects of ACY1215 on infarct size in rats with cardiac IR injury, as well as to examine the association between HDAC6 inhibitors and the gene expression of hypoxia inducible factor-1α (HIF-1α), a key regulator of cellular responses to hypoxia.
By using computational analysis of high-throughput expression profiling dataset, the association between HDAC inhibitors (pan-HDAC inhibitors panobinostat and vorinostat, and HDAC6 inhibitor ISOX) and their effects on HIF-1α gene-expression were evaluated. The male Wistar rats treated with ligation of left coronary artery followed by reperfusion were used as a cardiac IR model. ACY1215 (50 mg/kg), pan-HDAC inhibitor MPT0E028 (25 mg/kg), and vehicle were intraperitoneally injected within 5 min before reperfusion. The infarct size in rat myocardium was determined by 2,3,5-triphenyltetrazolium chloride staining. The serum levels of transforming growth factor-β (TGF-β) and C-reactive protein (CRP) were also determined.
The high-throughput gene expression assay showed that treatment of ISOX was associated with a more decreased gene expression of HIF-1α than that of panobinostat and vorinostat. Compared to control rats, ACY1215-treated rats had a smaller infarct size (49.75 ± 9.36% vs. 19.22 ± 1.70%, p < 0.05), while MPT0E028-treated rats had a similar infarct size to control rats. ACY-1215- and MPT0E028-treated rats had a trend in decreased serum TGF-β levels, but not statistically significant. ACY1215-treated rats also had higher serum CRP levels compared to control rats (641.6 μg/mL vs. 961.37 ± 64.94 μg/mL, p < 0.05).
Our research indicated that HDAC6 inhibition by ACY1215 might reduce infarct size in rats with cardiac IR injury possibly through modulating HIF-1α expression. TGF-β and CRP should be useful biomarkers to monitor the use of ACY1215 in cardiac IR injury.
尽管组蛋白去乙酰化酶（HDAC）抑制剂已被尝试用于治疗各种心血管疾病，但选择性 HDAC6 抑制剂 ACY1215 对心肌缺血再灌注（IR）损伤时梗死面积的影响仍不清楚。在本研究中，我们旨在研究 ACY1215 对心肌 IR 损伤大鼠梗死面积的影响，并探讨 HDAC6 抑制剂与缺氧诱导因子-1α（HIF-1α）基因表达之间的关系，HIF-1α 是细胞对缺氧反应的关键调节因子。
通过高通量表达谱数据集的计算分析，评估了 HDAC 抑制剂（pan-HDAC 抑制剂 panobinostat 和 vorinostat 以及 HDAC6 抑制剂 ISOX）与 HIF-1α 基因表达之间的关联。雄性 Wistar 大鼠结扎左冠状动脉后再灌注，作为心肌 IR 模型。ACY1215（50mg/kg）、pan-HDAC 抑制剂 MPT0E028（25mg/kg）和载体在再灌注前 5 分钟内腹腔注射。通过 2,3,5-三苯基氯化四氮唑染色测定大鼠心肌梗死面积。还测定了血清转化生长因子-β（TGF-β）和 C 反应蛋白（CRP）的水平。
高通量基因表达测定显示，ISOX 处理与 HIF-1α 基因表达的下调更相关，而 panobinostat 和 vorinostat 则不然。与对照组大鼠相比，ACY1215 治疗组大鼠的梗死面积较小（49.75±9.36% vs. 19.22±1.70%，p<0.05），而 MPT0E028 治疗组大鼠的梗死面积与对照组大鼠相似。ACY-1215 和 MPT0E028 治疗组大鼠血清 TGF-β 水平呈下降趋势，但无统计学意义。ACY1215 治疗组大鼠的血清 CRP 水平也高于对照组大鼠（641.6μg/ml 比 961.37±64.94μg/ml，p<0.05）。
我们的研究表明，ACY1215 通过调节 HIF-1α 表达可能减少心肌 IR 损伤大鼠的梗死面积。TGF-β 和 CRP 可能是监测 ACY1215 在心肌 IR 损伤中应用的有用生物标志物。
