Inhibition of HDAC6 Activity Alleviates Myocardial Ischemia/Reperfusion Injury in Diabetic Rats: Potential Role of Peroxiredoxin 1 Acetylation and Redox Regulation

Abstract

Patients with diabetes are more vulnerable to myocardial ischemia/reperfusion (MI/R) injury, which is associated with excessive reactive oxygen species (ROS) generation and decreased antioxidant defense. Histone deacetylase 6 (HDAC6), a regulator of the antioxidant protein peroxiredoxin 1 (Prdx1), is associated with several pathological conditions in the cardiovascular system. This study investigated whether tubastatin A (TubA), a highly selective HDAC6 inhibitor, could confer a protective effect by modulating Prdx1 acetylation in a rat model of MI/R and an in vitro model of hypoxia/reoxygenation (H/R). Here, we found that diabetic hearts with excessive HDAC6 activity and decreased acetylated-Prdx1 levels were more vulnerable to MI/R injury. TubA treatment robustly improved cardiac function, reduced cardiac infarction, attenuated ROS generation, and increased acetylated-Prdx1 levels in diabetic MI/R rats. These results were further confirmed by an in vitro study using H9c2 cells. Furthermore, a study using Prdx1 acetyl-silencing mutants (K197R) showed that TubA only slightly attenuated H/R-induced cell death and ROS generation in K197R-transfected H9c2 cells exposed to high glucose (HG), but these differences were not statistically significant. Taken together, these findings suggest that HDAC6 inhibition reduces ROS generation and confers a protective effect against MI/R or H/R injury by modulating Prdx1 acetylation at K197.

Investigating the potential effects of selective histone deacetylase 6 inhibitor ACY1215 on infarct size in rats with cardiac ischemia-reperfusion injury

“…The mechanisms in which ACY1215 reduced infarct size still remained unclear. It has been proposed that inhibition of HDAC6 activities led to a reduced infarct size by attenuation of reactive oxygen species and upregulation of peroxiredoxin 1 acetylation [23]. Additionally, ACY1215 might reduce infarct size by inhibiting the expression of HIF-1α based on the results of the present study.…”

“…In one study which was conducted by using an ex vivo IR model, the selective HDAC6 inhibitor tubastatin was reported to result in no benefit to limit infarct size [22]. However, in another study tubastatin administered for 7 days before ligation of coronary arteries showed a cardioprotective effect to reduce infarct size in rats with cardiac IR injury [23]. These inconsistent results of previous studies might be due to different protocols of drug administration and experimental IR models used in each study.…”

MiR-489 aggravates H2O2-induced apoptosis of cardiomyocytes via inhibiting IGF1

“…The oxidative stress response of cardiomyocytes may be regulated by lysine acetylation. In a rat myocardial I/R model, HDAC6 could deacetylate peroxiredoxin 1 and reduce its activity, increasing ROS production and exacerbating oxidative damage in cardiomyocytes [ 30 ].…”

Novel HDAC6 selective inhibitors with 4-aminopiperidine-1- carboxamide as the core structure enhanced growth inhibitory activity of bortezomib in MCF-7 cells

“…As a cytoplasmic enzyme, HDAC6 uniquely features two deacetylase domains, a dynein motor binding domain to enable HDAC6 to shuttle cargo along the microtubule and a zinc finger ubiquitin-binding domain at the C-terminus. Functionally, HDAC6 is able to remove the acetyl group from lysine residues mainly in non-histone substrates, including α-tubulin (7), Hsp90 (8), cortactin (9), and peroxiredoxin (10), and plays important roles in microtubule dynamics and chaperone activities. In contrast to the lethal effect of HDAC1-3 suppression, it has been reported that mice with HDAC6 knocked out are effectively normal (11).…”