HDAC1 localizes to the mitochondria of cardiac myocytes and contributes to early cardiac reperfusion injury

Abstract

Rationale Recent evidence indicates that histone deacetylase enzymes (HDACs) contribute to ischemia re-perfusion (I/R) injury, and pan-HDAC inhibitors have been shown to be cardioprotective when administered either before an ischemic insult or during reperfusion. We have shown previously that selective inhibition of class I HDACs provides superior cardioprotection when compared to pan-HDAC inhibition in a pretreatment model, but selective class I HDAC inhibition has not been tested during reperfusion, and specific targets of class I HDACs in I/R injury have not been identified. Objective We hypothesized that selective inhibition of class I HDACs with the drug MS-275 (entinostat) during reperfusion would improve recovery from I/R injury in the first hour of reperfusion. Methods and results Hearts from male Sprague-Dawley rats were subjected to ex vivo I/R injury ± MS-275 class I HDAC inhibition during reperfusion alone. MS-275 significantly attenuated I/R injury, as indicated by improved LV function and tissue viability at the end of reperfusion. Unexpectedly, we observed that HDAC1 is present in the mitochondria of cardiac myocytes, but not fibroblasts or endothelial cells. We then designed mitochondria-restricted and mitochondria-excluded HDAC inhibitors, and tested both in our ex vivo I/R model. The selective inhibition of mitochondrial HDAC1 attenuated I/R injury to the same extent as MS-275, whereas the mitochondrial-excluded inhibitor did not. Further assays demonstrated that these effects are attributable to a decrease in SDHA activity and subsequent metabolic ROS production in reperfusion. Conclusions We demonstrate for the first time that HDAC1 is present within the mitochondria of cardiac myocytes, and mitochondrial HDAC1 contributes significantly to I/R injury within the first hour of reperfusion.

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“…Recently, it has been shown that protein acetylation can alter the metabolism of the cell (Zhao et al, 2010), which can be achieved by post-translational modification of non-histone cytoplasmic and mitochondrial proteins (Anderson and Hirschey, 2012;Kim et al, 2006). In fact, several HDACs have been localized in the cytoplasm and mitochondria (Bakin and Jung, 2004;Drazic et al, 2016;Herr et al, 2018). On a functional level, it has been shown that treatment with HDAC inhibitors causes a rapid increase in mitochondrial activity, arguing against regulation at the level of the chromatin (Becker et al, 2018).…”

Epigenetics in Cardiac Fibrosis

“…In the heart, many proteins involved in metabolism, intra- and extracellular signaling, gene regulation, cell–cell communication and contraction have been shown to be acetylated, although little is known regarding if or how this post-translational modification alters the function of the target proteins 137 , 138 , 139 . Consistent with this, nongenomic, non-nuclear roles for canonical epigenetic regulators such as HDAC1 and HDAC2 in the heart are beginning to emerge 131 , 140 .…”

Imbalance of Lysine Acetylation Contributes to the Pathogenesis of Parkinson’s Disease

“…Recently, lymphoid enhancer-binding factor 1 (LEF1) and T cell-specific transcription factor 1 (TCF1) were identified as novel KDACs that are not related to the abovementioned types of KDACs [ 34 ]. Zn 2+ -dependent HDACs are primarily distributed in the nucleus or cytoplasm, although HDAC1 and HDAC7 are also found in mitochondria in some types of cells or under certain conditions [ 35 , 36 ]. In contrast, some SIRTs, including SIRT3-5, are restricted to the mitochondria, indicating their unique and crucial roles in mitochondria.…”