Targeted deletion of NF-κB p50 diminishes the cardioprotection of histone deacetylase inhibition

Abstract

We have recently demonstrated that the inhibition of histone deacetylases (HDAC) protects the heart against ischemia-reperfusion (I/R) injury. The mechanism by which HDAC inhibition confers myocardial protection remains unknown. The purpose of this study is to investigate whether the disruption of NF-kappaB p50 would eliminate the protective effects of HDAC inhibition. Wild-type and NF-kappaB p50-deficient mice were treated with trichostatin A (TSA; 0.1 mg/kg ip), a potent inhibitor of HDACs. Twenty-four hours later, the hearts were perfused in Langendorff model and subjected to 30 min of ischemia and 30 min of reperfusion. Inhibition of HDACs by TSA in wild-type mice produced marked improvements in left ventricular end-diastolic pressure, left ventricular rate pressure product, and the reduction of infarct size compared with non-TSA-treated group. TSA-induced cardioprotection in wild-type animals was absent with genetic deletion of NF-kappaB p50 subunit. Notably, Western blot displayed a significant increase in nuclear NF-kappaB p50 and the immunoprecipitation demonstrated a remarkable acetylation of NF-kappaB p50 at lysine residues following HDAC inhibition. EMSA exhibited a subsequent increase in NF-kappaB DNA binding activity. Luciferase assay demonstrated an activation of NF-kappaB by HDAC inhibition. The pretreatment of H9c2 cardiomyoblasts with TSA (50 nmol/l) decreased cell necrosis and increased in cell viability in simulated ischemia. The resistance of H9c2 cardiomyoblasts to simulated ischemia by HDAC inhibition was eliminated by genetic knockdown of NF-kappaB p50 with transfection of NF-kappaB p50 short interfering RNA but not scrambled short interfering RNA. These results suggest that NF-kappaB p50 acetylation and activation play a pivotal role in HDAC inhibition-induced cardioprotection.

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

“…HDAC4 is expressed in the heart, stem cells, the endothelium, and vascular smooth muscle cells (1,4,12,19,21). Cardioprotective effects of HDAC inhibition against injury have been well identified (45,47,48). Our recent observation demonstrates that HDAC inhibition enhanced myocardial repair in vivo through stimulation of endogenous regeneration (46), which is in line with our observation that HDAC inhibition facilitated the embryonic stem cells' differentiation into cardiac lineages and enhanced resistance to oxidant stress (4).…”

Stimulation of glucagon-like peptide-1 receptor through exendin-4 preserves myocardial performance and prevents cardiac remodeling in infarcted myocardium

“…It is also likely that sufficient PO 2 in the perfusate contributes to the increase in coronary effluents. We have observed previously that the cardiac-protective effect is associated with the increase in coronary effluent as well as increased angiogenesis (40,42). Future studies also need to define whether GLP-1R activation stimulates vascular growth in the infarcted myocardium.…”

“…The methodology of Langendorff's perfused heart preparation and measurement of left ventricular (LV) function has been described previously in detail (40,42). Briefly, mice were anesthetized with a lethal ip injection of pentobarbital sodium (120 mg/kg).…”

Scriptaid, a Novel Histone Deacetylase Inhibitor, Protects Against Traumatic Brain Injury via Modulation of PTEN and AKT Pathway

“…The epigenetic influence of HDIs on gene expression make them a useful new class of pharmacological agents that could ameliorate various disease conditions. For example, HDIs also promote neuronal survival in ischemic injury, [14][15][16][17] multiple sclerosis [18,19], and Alzheimer's and Huntington's disease models [20][21][22][23][24]. These multiple roles of HDIs can be attributed to alterations in the expression of different gene sets by increasing acetylation of chromatin.…”