Histone deacetylase inhibition attenuates cardiomyocyte hypoxia-reoxygenation injury

Aaron M. Williams, Wei He, Yongqing Li, Umar F. Bhatti, Vahagn C. Nikolian, Panpan Chang, Zhigang Chang, Ihab Halaweish, Baoling Liu, Xin Cheng, Hasan B. Alam

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background: Cardiac reperfusion injury can have devastating consequences. Histone deacetylase (HDAC) inhibitors are potent cytoprotective agents, but their role in the prevention of cardiac injury remains ill-defined. Objective: We sought to determine the therapeutic potential of HDAC inhibitors in an in vitro model of cardiomyocyte hypoxia-reoxygenation (H/R). Method: H9c2 cardiomyocytes were subjected to H/R and treated with various classspecific and pan-HDAC inhibitors in equal concentrations (5µM). Biological activity of inhibitors was determined, as a proxy for concentration adequacy, by Western blot for acetylated histone H3 and α-tubulin. Cell viability and cytotoxicity were measured by methyl thiazolyl tetrazolium and lactate dehydrogenase assays, respectively. Mechanistic studies were performed to better define the effects of the most effective agent, Tubastatin-A (Tub-A), on the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway effectors, and on the degree of autophagy. Results: All inhibitors acetylated well-known target proteins (histone H3 and α-tubulin), suggesting that concentrations were adequate to induce a biological effect. Improved cell viability and decreased cell cytotoxicity were noted in cardiomyocytes exposed to Tub-A, whereas the cytoprotective effects of other HDAC inhibitors were inconsistent. Pro-survival mediators in the PI3K/mTOR pathway were up-regulated and the degree of autophagy was significantly attenuated in cells that were treated with Tub-A. Conclusion: HDAC inhibitors improve cell viability in a model of cardiomyocyte H/R, with Class IIb inhibition (Tub-A) demonstrating superior cellular-level potency and effectiveness. This effect is, at least in part, related to an increased expression of prosurvival mediators and a decreased degree of autophagy.

Original languageEnglish (US)
Pages (from-to)711-718
Number of pages8
JournalCurrent Molecular Medicine
Volume18
Issue number10
DOIs
StatePublished - 2018
Externally publishedYes

Keywords

  • Cardiac injury
  • Histone deacetylase
  • Histone deacetylase inhibitors
  • Hypoxia-reoxygenation
  • Ischemia-reperfusion injury

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology

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