Valproic acid attenuates sepsis-induced myocardial dysfunction in rats by accelerating autophagy through the PTEN/AKT/mTOR pathway
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 SpragueāDawley rats (180ā200āÆg) were acquired from the Animal Center of Xinjiang Medical University (Urumqi, China). The animals were housed in an environment with a constant temperature of 24āÆĀ°C and a 12āÆh lightādark cycle. During treatment, the rats were randomly assigned to five groups: the sham group, the cecum ligation and puncture (CLP) group, the CLPāÆ+āÆVPA (50āÆmg/kg) group, the CLPāÆ+āÆVPA (100āÆmg/kg) group, and the CLPāÆ+āÆVPA (200āÆmg/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 4āÆdays. However, 100āÆmg and 200āÆmg 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.
References (53)
- et al.
Sepsis-associated in-hospital cardiac arrest: epidemiology, pathophysiology, and potential therapies
J. Crit. Care
(2017) - et al.
Cecal ligation and puncture: the gold standard model for polymicrobial sepsis?
Trends Microbiol.
(2011) - et al.
Increased TFAM binding to mtDNA damage hot spots is associated with mtDNA loss in aged rat heart
Free Radic. Biol. Med.
(2018) - et al.
Complement and sepsis-induced heart dysfunction
Mol. Immunol.
(2017) - et al.
The role of mitochondria in sepsis-induced cardiomyopathy
Biochim. Biophys. Acta Mol. basis Dis.
(2019) Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: analytical and biological challenges
Anal. Biochem.
(2017)- et al.
The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration
Cell. Signal.
(2014) - et al.
Alamandine attenuates sepsis-associated cardiac dysfunction via inhibiting MAPKs signaling pathways
Life Sci.
(2018) - et al.
Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice
Life Sci.
(2019) - et al.
The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy
Biochem. Biophys. Res. Commun.
(2017)