Histone Deacetylase Inhibition Attenuates Cardiomyocyte Hypoxia-Reoxygenation Injury

Title:Histone Deacetylase Inhibition Attenuates Cardiomyocyte Hypoxia-Reoxygenation Injury

Volume: 18 Issue: 10

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 and Hasan B. Alam

Affiliation:

• Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan,United States

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

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.

Cite this article as:

Williams M. Aaron , He Wei , Li Yongqing *, Bhatti F. Umar , Nikolian C. Vahagn , Chang Panpan , Chang Zhigang , Halaweish Ihab , Liu Baoling , Cheng Xin and Alam B. Hasan , Histone Deacetylase Inhibition Attenuates Cardiomyocyte Hypoxia-Reoxygenation Injury, Current Molecular Medicine 2018; 18 (10) . https://dx.doi.org/10.2174/1566524019666190208102729