Elsevier

Life Sciences

Volume 232, 1 September 2019, 116613
Life Sciences

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

https://doi.org/10.1016/j.lfs.2019.116613Get rights and content

Abstract

Aims

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.

Main methods

A sepsis model was established via the cecum ligation and puncture of male Spragueā€“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.

Key findings

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.

Significance

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.

Introduction

Sepsis is a complex systemic disease that involves life-threatening organ dysfunction caused by the body's uncontrolled response to infection [1]. The high incidence of sepsis, high mortality due to sepsis, and high hospitalization costs for sepsis are increasingly eliciting attention [[2], [3], [4], [5]]. Sepsis-induced myocardial dysfunction (SIMD) is an overall but reversible dysfunction of the heart caused by sepsis and is an important cause of sepsis death in intensive care units [[6], [7], [8], [9]]. However, no targeted treatment is currently available for SIMD, and its exact mechanism remains unclear [6,10]. An in-depth study of the pathogenesis and treatment of SIMD has important research significance to reduce high mortality due to sepsis.

The pathogenesis of SIMD is complex; it involves inflammatory mediator dysfunction, mitochondrial dysfunction, oxidative stress, calcium regulation disorder, autonomic nervous system disorders, and endothelial dysfunction [11,12]. Autophagy is a vital catabolic process in cells [13]. It is responsible for the degradation of biological macromolecules, aging and damaged organelles, and the reuse of degradation products [13]. A previous study found that autophagy can protect cardiomyocytes by degrading misfolded proteins and damaged organelles in cardiomyocytes, maintaining intracellular homeostasis, and ensuring energy supply to cardiomyocytes [[14], [15], [16]]. Therefore, the development of drugs related to the important targets of autophagy and its related pathways has important research significance for the prevention and treatment of SIMD. Histone acetylation modification is an important mechanism of epigenetic regulation. Previous studies have shown that histone deacetylase (HDAC) inhibitor plays a protective role in sepsis, but the underlying mechanisms remain unclear [[17], [18], [19], [20], [21]]. Prior research has also found that valproic acid (VPA), a class I HDAC inhibitor, can induce autophagy [22]. Therefore, we speculate that VPA may attenuate SIMD via autophagy.

Hence, this study investigated whether the HDAC inhibitor VPA can attenuate SIMD. We found that VPA can ameliorate SIMD by enhancing the autophagy level of the myocardium to reduce myocardial inflammation, mitochondrial damage, and oxidative stress in sepsis animal models.

Section snippets

Sepsis animal model

Male Spragueā€“Dawley rats (180ā€“200ā€Æg) were acquired from the Animal Center of Xinjiang Medical University (Urumqi, China). The animals were housed in an environment with a constant temperature of 24ā€ÆĀ°C and a 12ā€Æh lightā€“dark cycle. During treatment, the rats were randomly assigned to five groups: the sham group, the cecum ligation and puncture (CLP) group, the CLPā€Æ+ā€ÆVPA (50ā€Æmg/kg) group, the CLPā€Æ+ā€ÆVPA (100ā€Æmg/kg) group, and the CLPā€Æ+ā€ÆVPA (200ā€Æmg/kg) group. A sepsis model was established via CLP

VPA attenuates mortality rate and myocardial damage in septic rats

SIMD is an overall but reversible dysfunction of the heart caused by sepsis; it is an important cause of sepsis death [11,12,28]. VPA was used to study the effects on sepsis-induced myocardial dysfunction in rats. The data showed that septic rats exhibited high mortality, and approximately 70% of the rats died within 4ā€Ædays. However, 100ā€Æmg and 200ā€Æmg VPA treatment significantly reduced the 4-day mortality in septic rats (Fig. 1A). Cardiac function parameters, such as left ventricular structure

Discussion

The current interventions that target autophagy in the treatment of SIMD remain lacking. The major findings of the current study showed that VPA, a first class HDAC inhibitor, can attenuate SIMD by promoting autophagy to improve mitochondrial function, reduce oxidative damage, and decrease excessive immune response. Moreover, the current study showed that VPA can inhibit the AKT signaling pathway, further inhibit p-mTOR, and consequently, increased autophagic levels and excessive immune

Conclusion

The salient finding of the present study is that VPA attenuates SIMD by promoting autophagy to improve mitochondrial function, reduce oxidative damage, and decrease excessive immune response. Moreover, this study demonstrated that VPA induces autophagy by inhibiting HDAC1- and HDAC3-mediated PTEN expression in the myocardial tissues of septic rats. These results preliminarily indicated that VPA may be used for the intervention and treatment of SIMD.

Author contributions

Conception and design: Xiaohui Shi and Dong Xiao. Acquisition of data: Xiaohui Shi and Yan Liu. Analysis and interpretation of data: Xiaohui Shi and Daquan Zhang. Writing, review, and revision of the manuscript: Xiaohui Shi, Daquan Zhang, and Dong Xiao.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

The authors declare that they have no competing interests.

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