Energy metabolism regulated by HDAC inhibitor attenuates cardiac injury in hemorrhagic rat model

Abstract

A disturbance of energy metabolism reduces cardiac function in acute severe hemorrhagic patients. Alternatively, adequate energy supply reduces heart failure and increases survival. However, the approach to regulating energy metabolism conductive to vital organs is limited, and the underlying molecular mechanism remains unknown. This study assesses the ability of histone deacetylase inhibitors (HDACIs) to preserve cardiac energy metabolism during lethal hemorrhagic injury. In the lethally hemorrhagic rat and hypoxic myocardial cells, energy metabolism and heart function were well maintained following HDACI treatment, as evident by continuous ATP production with normal cardiac contraction. Valproic acid (VPA) regulated the energy metabolism of hemorrhagic heart by reducing lactate synthesis and protecting the mitochondrial ultrastructure and respiration, which were attributable to the inhibition of lactate dehydrogenase A activity and the increased myeloid cell leukemia-1 (mcl-1) gene expression, ultimately facilitating ATP production and consumption. MCL-1, the key target of VPA, mediated this cardioprotective effect under acute severe hemorrhage conditions. Our results suggest that HDACIs promote cardioprotection by improving energy metabolism during hemorrhagic injury and could therefore be an effective strategy to counteract this process in the clinical setting.

HDAC inhibitor valproic acid protects heart function through Foxm1 pathway after acute myocardial infarction

“…Our results are consistent with a previous brain injury study showing that VPA inhibits the TNF-NF-κB activity and modulates immune response [47]. Other functions of VPA include anti-apoptotic and improved energy metabolism, which are also consistent with previous studies in hemorrhagic [48].…”

Research Progress in Regulatory Mechanism of Valproic Acid on Inflammatory Responses to Burns and Trauma

“…A variety of immune cells (e.g., endothelial cells, macrophages, and neutrophils) and immune molecules participate in this process to remove pathogens and ultimately promote wound healing (Larouche et al, 2018; Salibian et al, 2016). Valproic acid (VPA) is a histone deacetylase inhibitor (HDACi) that has been shown to protect organs in the course of disease and treatment, thereby increasing survival rates in animal models of hemorrhagic shock or lethal burn injury (Kuai et al, 2016; Liu et al, 2022; Tang et al, 2018; Wakam et al, 2021). HDACi can effectively reduce tissue and organ damage secondary to ischemia and hypoxia, and it also has certain efficacy in alleviating the inflammatory response caused by ischemia and hypoxia, thereby improving survival in rat models of burn shock (Toppi et al, 2019).…”

Influence of Vitamin E on the Haemodynamic Effects of Intragastric Chromium Intake and Lipid Peroxidation in Experimental Rats

“…In addition, the occurrence of cardiovascular pathologies is most often closely associated with mitochondrial dysfunction of cardiomyocytes; the main cause of this dysfunction is related to oxidative stress and the initiation of an inflammatory process accompanying reduced adenosine triphosphatase (ATPase) activity and irreversible protein modification with the formation of carbonyl protein, an oxidative damage marker. [8,9,10].…”

“…It is known that the toxic effect of chromium is associated with the stimulation of free radical processes, as well as the formation of intermediate products during the reduction of hexavalent chromium, which have a high reactivity [20]. These reactive chromium intermediates are capable of generating reactive oxygen species (ROS) [6], which cause oxidation of protein and lipid macromolecules with damage to organs and systems [14,22], and exhibit neuro-, hepato-, nephro-, cardio-, gene-and immunotoxicity and carcinogenicity [9,13,16].…”