The histone deacetylase inhibitor SAHA exerts a protective effect against myocardial ischemia/reperfusion injury by inhibiting sodium-calcium exchanger

Calcium overload performs a crucial function in the pathogenesis of myocardial ischemia-reperfusion (I/ R) damage, which contributes to mitochondrial impairment and apoptosis of cardiomyocytes. Sub-eroylanilide hydroxamic acid (SAHA), a small molecule histone deacetylases inhibitor with modulatory capacity on Na+-Ca2+ exchanger (NCX), is proven to have protective potential towards cardiac remod-eling and injury, but the mechanism remains unclear. Hence, Hence, our present research explored the modulation of NCX-Ca2+-CaMKII by SAHA in myocardial I/R damage. Our outcomes indicate that in vitro hypoxia and reoxygenation models of myocardial cells, SAHA treatment inhibited the increase in expression of NCX1, intracellular Ca2+ concentration, expression of CaMKII and self-phosphorylated CaMKII, and cell apoptosis. In addition, SAHA treatment improved myocardial cell mitochondrial swelling inhibited mitochondrial membrane potential diminution and the openness of the mitochondrial permeability transition pore, and protected against mitochondrial dysfunction following I/R injury. In vivo, SAHA treatment alleviated the decrease in FS% and EF%, the increase in the myocardial infarct area, and myocardial enzyme levels caused by I/R injury, while also reducing myocardial cell apoptosis, and inhibiting mitochondrial fission and mitochondrial membrane rupture. These results indicated that SAHA treatment alleviated myocardial cell apoptosis as well as mitochondrial dysfunction resulting from myocardial I/R impairment, and contributed to myocardial function recovery by inhibiting the NCX-Ca2+- CaMKII pathway. These findings offered additional theoretical support to explore the mechanism of SAHA as a therapeutic agent in cardiac I/R damage and develop new treatment strategies. (c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

Calcium overload plays a crucial role in the pathogenesis of myocardial ischemia-reperfusion (I/R) damage, leading to mitochondrial impairment and apoptosis of cardiomyocytes. Sub-eroylanilide hydroxamic acid (SAHA), a histone deacetylases inhibitor with modulatory capacity on Na+-Ca2+ exchanger (NCX), has been shown to have protective potential against cardiac remodeling and injury. The present research explored the modulation of NCX-Ca2+-CaMKII by SAHA in myocardial I/R damage. The results indicated that SAHA treatment alleviated myocardial cell apoptosis and mitochondrial dysfunction resulting from myocardial I/R impairment, and contributed to myocardial function recovery by inhibiting the NCX-Ca2+- CaMKII pathway.