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Valproic acid attenuates sepsis-induced myocardial dysfunction in rats by accelerating autophagy through the PTEN/AKT/mTOR pathway

Shi, Xiaohui, Liu, Yan, Zhang, Daquan, Xiao, Dong
Life sciences 2019 v.232 pp. 116613
Western blotting, acetylation, adenosine triphosphate, autophagy, blood serum, cecum, chromatin, echocardiography, eosin, genes, histone deacetylase, histones, inflammation, laboratory animals, males, mitochondria, mitochondrial DNA, models, myocardium, oxidative stress, precipitin tests, protective effect, quantitative polymerase chain reaction, rats, reverse transcriptase polymerase chain reaction, sepsis (infection), staining, transmission electron microscopy, valproic acid
Sepsis is a leading cause of death and disability worldwide. Autophagy may play a protective role in sepsis-induced myocardial dysfunction (SIMD). The present study investigated whether valproic acid (VPA), a class I histone deacetylase (HDAC) inhibitor, can attenuate SIMD by accelerating autophagy.A sepsis model was established via the cecum ligation and puncture of male Sprague–Dawley rats. Cardiac injuries were measured using serum markers, echocardiographic cardiac parameters, and hematoxylin and eosin staining. Cardiac mitochondria injuries were detected with transmission electron microscopy, adenosine triphosphate (ATP) and cardiac mitochondrial DNA (mtDNA) contents. Cardiac oxidative levels were measured using redox markers in the cardiac homogenate. Real-time polymerase chain reaction (RT-PCR) and Western blot were performed to detect the expression levels of relative genes and proteins. HDAC binding to the phosphatase and tensin homolog deleted on chromosome ten (PTEN) promoters and histone acetylation levels of the PTEN promoters were analyzed via chromatin immunoprecipitation and quantitative RT-PCR.VPA can ameliorate SIMD by enhancing the autophagy level of the myocardium to reduce mitochondrial damage, oxidative stress, and myocardial inflammation in septic rats. Moreover, this study demonstrated that VPA induces autophagy by inhibiting HDAC1- and HDAC3-mediated PTEN expression in the myocardial tissues of septic rats.This study found that VPA attenuates SIMD through myocardial autophagy acceleration by increasing PTEN expression and inhibiting the AKT/mTOR pathway. These findings preliminarily suggest that VPA may be a potential approach for the intervention and treatment of SIMD.