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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 and Hasan B. Alam   Pages 1 - 8 ( 8 )

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.

Affiliation:

Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan



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