Histone Deacetylase Inhibition Blunts Ischemia/Reperfusion Injury by Inducing Cardiomyocyte Autophagy

Abstract

Background Reperfusion accounts for a substantial fraction of the myocardial injury occurring with ischemic heart disease. Yet, no standard therapies are available targeting reperfusion injury. Here, we tested the hypothesis that SAHA, a histone deacetylase (HDAC) inhibitor FDA-approved for cancer treatment, will blunt reperfusion injury. Methods and Results Twenty-one rabbits were randomized into 3 groups: a) vehicle control, b) SAHA pretreatment (one day prior and at surgery), and c) SAHA treatment at the time of reperfusion only. Each arm was subjected to ischemia/reperfusion surgery (I/R, 30min coronary ligation, 24h reperfusion). Additionally cultured neonatal and adult rat ventricular cardiomyocytes were subjected to simulated I/R (sI/R) to probe mechanism. SAHA reduced infarct (those reduction inhibitor, SAHA, infarct size in a large animal model, even when delivered in the clinically relevant context of reperfusion. The cardioprotective effects of SAHA during I/R occur, at least in part, through induction of autophagic flux. assayed in both rabbit myocardium and in mice harboring an RFP-GFP-LC3 transgene. In cultured myocytes subjected to sI/R, SAHA pretreatment reduced cell death by 40%. This eduction in cell death correlated with increased autophagic activity in SAHA-treated cells. RNAi-mediated knockdown of ATG7 and ATG5, essential autophagy proteins, abolished SAHA's cardioprotective effects. Conclusions The FDS-approved anti-cancer HDAC inhibitor, SAHA, reduces myocardial infarct size in a large animal model, even when delivered in the clinically relevant context of reperfusion. The cardioprotective effects of SAHA during I/R occur, at least in part, through induction of autophagic flux.

Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy

“…5 E and F). Interestingly, and in contrast to recent reports (23,24), left ventricular mass was unchanged (Fig. 5G).…”

“…The therapeutic potential of HDAC inhibition has also been explored for different cancers and the HDAC inhibitor, SAHA, is FDA-approved to treat cutaneous T-cell lymphoma. Importantly, it was recently shown that SAHA induces autophagy in cardiomyocytes (24), but the underlying mechanism was not determined. The effects of modulating HDAC activity likely are a function of the specific disease, cell type, and dosing protocols used, and should be completely understood to expand the therapeutic reach of HDAC inhibition.…”

“…heart disease (23)(24)(25)(26)(27). HDACs are enzymes that remove acetyl groups from lysine residues on histones and cytoplasmic proteins, but can also affect gene expression, protein function, and cell signaling (28).…”

Induction and Assessment of Ischemia-reperfusion Injury in Langendorff-perfused Rat Hearts

“…After an ischemic insult, the developed pressure is reduced and the end diastolic pressure elevates ( Figure 1B). When the rats are administered a known preconditioning agent such as the class I and IIb HDAC inhibitor SAHA (vorinostat) 18 prior to excising the heart, the reduction in developed pressure and the elevation of end diastolic pressure associated with ischemia reperfusion injury are attenuated ( Figure 1C). Other measures of left ventricular function, such as the rate of pressure generation (dP/dt max ), the rate of pressure relaxation (-dP/dt max ), and the rate pressure product (RPP) can be directly obtained or calculated from the software output (Figure 2).…”

A class of their own: exploring the nondeacetylase roles of class IIa HDACs in cardiovascular disease

“…Class I and class IIa HDAC inhibitors have shown promise in ameliorating the effects of adverse tissue remodeling post-MI. Several comprehensive in vivo studies have shown that pan-HDAC inhibitors such as suberoylanilide acid, TSA, and valproic acid not only reduce infarct scar area but also improve cardiac function after an MI (22,49,72,76).…”