Investigating the potential effects of selective histone deacetylase 6 inhibitor ACY1215 on infarct size in rats with cardiac ischemia-reperfusion injury

Abstract

Background: 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 ischemiareperfusion (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. Methods: 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 geneexpression 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. Results: 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, ACY1215treated 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). Conclusions: 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.

Role of Selective Histone Deacetylase 6 Inhibitor ACY-1215 in Cancer and Other Human Diseases

“…In glucocorticoid-induced osteoporosis, ACY-1215 reverses dexamethasone-induced inhibition of osteoblast proliferation and differentiation ( Wang et al, 2020 ). In rats with cardiac ischemia-reperfusion injury, ACY-1215 might reduce infarct size through modulating hypoxia inducible factor-1α expression ( Lin et al, 2020 ). Although this part of the study did not have a more in-depth mechanism discussion, it also provided a new treatment idea for the diseases.…”

Histone deacetylase 6 as a novel promising target to treat cardiovascular disease

“…So far, specific HDAC6 inhibitors have been found to treat cardiovascular disease, including ACY-1215, ACY-241, tubacin, tubastatin A, and nextrastat A [1,15,18,55,66,75]. Recently, Lin et al [34] indicated that ACY1215 can regulate the expression of HIF-1α to reduce infarct size after cardiac IR injury. At the same time, Boucherat et al [51] found that the proliferation and migration of PAH PASMCs could be affected by the pharmacology of HDAC6, tubastatin A, ACY-775, ACY-241, or siHDAC6, which increased the resistance to apoptosis.…”

“…Overall, HDAC6 can catalyze histone deacetylation, enable nucleosome compaction, and inhibit gene transcription and translation. In addition, HDAC6 can act on nonhistone substrates in the cytoplasm, such as α‐tubulin [29], β‐catenin [30], tau protein [31], heat shock protein (HSP)−90 [32], peroxiredoxin (Prdx) [33], and cortactin [34]. Thus, HDAC6 has far‐reaching biological functions [35].…”

Targeting Epigenetics and Non-coding RNAs in Myocardial Infarction: From Mechanisms to Therapeutics

“…Presently, experiments concerning the functional role of lncRNAs were performed under experimental animal models or by in vitro assays. Some studies revealed the active role of lncRNAs in cell autophagy (Liang et al, 2020;Zhang and He, 2020;Li J. et al, 2021), apoptosis (Zhu et al, 2018;Gong et al, 2019;Zhang D. et al, 2019, Zhang M. et al, 2019Zhou et al, 2019;Huang L. et al, 2020;Liao et al, 2020;Lv et al, 2020;Yan et al, 2020;Zhang Y. et al, 2020;Zhou et al, 2020;Liu et al, 2021;Zhu et al, 2021a, 1), cardiac fibrosis (Wang X. et al, 2018, 30;Huang et al, 2019;Sun F. et al, 2019;Zhang JC. et al, 2019, 21;Lang et al, 2021;Zhang H. et al, 2021, 155-5), cardiac remodelling Zhang B.f. et al, 2020), inflammation, and angiogenesis (Chen ZL.…”