Histone Deacetylase Inhibition Attenuates Cardiomyocyte Hypoxia-Reoxygenation Injury

Author(s): 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.

Journal Name: Current Molecular Medicine

Volume 18 , Issue 10 , 2018

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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.

Keywords: Histone deacetylase, histone deacetylase inhibitors, hypoxia-reoxygenation, ischemia-reperfusion injury, cardiac injury.

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Article Details

VOLUME: 18
ISSUE: 10
Year: 2018
Page: [711 - 718]
Pages: 8
DOI: 10.2174/1566524019666190208102729
Price: $58

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