Mitochondrial antioxidant SkQ1 decreases inflammation following hemorrhagic shock by protecting myocardial mitochondria

Abstract

Background: Hemorrhagic shock (HS) is a type of hypovolemic shock characterized by hemodynamic instability, tissue hypoperfusion and cellular hypoxia. In pathophysiology, the gradual accumulation of reactive oxygen species (ROS) damages the mitochondria, leading to irreversible cell damage and the release of endogenous damage-associated molecular patterns (DAMPs) including mitochondrial DAMPs (MTDs), eventually triggering the inflammatory response. The novel mitochondria-targeted antioxidant SkQ1 (Visomitin) effectively eliminate excessive intracellular ROS and exhibits anti-inflammatory effects; however, the specific role of SkQ1 in HS has not yet been explicated.Methods and results: A 40% fixed-blood-loss HS rat model was established in this study. Transmission electron microscopy showed that after HS, the myocardial mitochondrial ultrastructure was damaged and the mtDNA release in circulation was increased and the differentially expressed genes were significantly enriched in mitochondrial and ROS-related pathways. Mitochondria-targeted antioxidant SkQ1 attenuated the increased ROS induced by HS in myocardial tissues and by oxygen-glucose deprivation (OGD) in cardiomyocytes. Ultrastructurally, SkQ1 protected the myocardial mitochondrial structure and reduced the release of the peripheral blood mtDNA after HS. RNA-seq transcriptome analysis showed that 56.5% of the inflammation-related genes, which altered after HS, could be significantly reversed after SkQ1 treatment. Moreover, ELISA indicated that SkQ1 significantly reversed the HS-induced increases in the TNF-α, IL-6, and MCP-1 protein levels in rat peripheral blood.Conclusion: HS causes damage to the rat myocardial mitochondrial structure, increases mtDNA release and ROS contents, activates the mitochondrial and ROS-related pathways, and induces systemic inflammatory response. The mitochondrial antioxidant SkQ1 can improve rat myocardial mitochondria ultrastructure, reduce mtDNA and ROS contents, and decrease inflammation by protecting myocardial mitochondria, thereby playing a novel protective role in HS.

The role of mtDAMPs in the trauma-induced systemic inflammatory response syndrome

“…Recent research by our team has also identified myocardial mitochondrial structure disruption in the rat model of hemorrhagic shock (HS), resulting in increased mtDNA release and ROS contents, which in turn activates the systemic inflammatory response ( 131 ). More importantly, we found the mitochondrial antioxidant SkQ1 can protect myocardial mitochondria, improve the ultrastructure of rat myocardial mitochondria, reduce mtDNA release and the ROS content, and thus reduce inflammation ( 14 ). Cardiopulmonary bypass, surgical trauma, and ischemia–reperfusion injury stimulate a systemic inflammatory response in cardiac surgery.…”

“…Similar to bacterial DNA, mtDNA contains unmethylated CpG repeats that are recognized by the immune system as non-self. Post-traumatic mitochondrial damage causes mtDNA released outside the mitochondria ( 10 , 14 , 15 ). A recent study in a trauma cohort from Briggs GD showed that the size of mtDNA in the circulation post-trauma is a mixture of “larger forms” and low molecular weight mtDNA, and it was the low-molecular-weight version of cell-free mtDNA that is associated with inflammation and poor clinical outcomes post-trauma ( 16 ).…”

Recent Advances in Our Understanding of Age-Related Macular Degeneration: Mitochondrial Dysfunction, Redox Signaling, and the Complement System

“…SkQ1, also known as visomitin, is a mitochondrialtargeted antioxidant tested against various conditions, including hemorrhagic shock, toxic shock, and Alzheimer's disease, with promising results [464][465][466]. In the eye, SkQ1 has been studied as an effective drug in vitro, countering ocular surface inflammation and improving corneal epithelial wound healing by enhancing cell proliferation and migration [467].…”

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“…More recently, a group in China independently reported the ability of SkQ1 to protect against a severe hemorrhagic shock (HS) in rats [ 133 ]. Again, SkQ1 not only prevented organ damage but also reversed the HS-induced increases in blood levels of pro-inflammatory cytokines IL-6 and TNF-α.…”

“…More recently, a group in China independently reported the ability of SkQ1 to protect against a severe hemorrhagic shock (HS) in rats [133]. Again, SkQ1 not only prevented Mice were placed at −20 • C for 1 h and then returned to room temperature.…”