Abstract
Sepsis-associated organ dysfunction plays a critical role in its high mortality, mainly in connection with mitochondrial dysfunction. Whether the inhibition of mitochondrial fission is beneficial to sepsis-related organ dysfunction and underlying mechanisms are unknown. Cecal ligation and puncture induced sepsis in rats and dynamic related protein 1 knockout mice, lipopolysaccharide-treated vascular smooth muscle cells and cardiomyocytes, were used to explore the effects of inhibition of mitochondrial fission and specific mechanisms. Our study showed that mitochondrial fission inhibitor Mdivi-1 could antagonize sepsis-induced organ dysfunction including heart, vascular smooth muscle, liver, kidney, and intestinal functions, and prolonged animal survival. The further study showed that mitochondrial functions such as mitochondrial membrane potential, adenosine-triphosphate contents, reactive oxygen species, superoxide dismutase and malonaldehyde were recovered after Mdivi-1 administration via improving mitochondrial morphology. And sepsis-induced inflammation and apoptosis in heart and vascular smooth muscle were alleviated through inhibition of mitochondrial fission and mitochondrial function improvement. The parameter trends in lipopolysaccharide-stimulated cardiomyocytes and vascular smooth muscle cells were similar in vivo. Dynamic related protein 1 knockout preserved sepsis-induced organ dysfunction, and the animal survival was prolonged. Taken together, this finding provides a novel effective candidate therapy for severe sepsis/septic shock and other critical clinical diseases.
Highlights
Sepsis is a systemic inflammatory response syndrome caused by a dysregulated host response to infection, leading to septic shock and even death
The results showed that cardiac function was significantly impaired after sepsis, including both LVEF and LVFS
The results showed that the levels of TNT before sepsis were no different between dynamic related protein 1 (Drp1) KO and WT mice, and the levels of TNT after sepsis were increased both in Drp1 KO mice and WT mice, while the increase ratio of TNT level in Drp1 KO was lower than WT after sepsis (Figure 6A)
Summary
Sepsis is a systemic inflammatory response syndrome caused by a dysregulated host response to infection, leading to septic shock and even death. Mitochondria are the important organelle, which maintains a dynamic process of continuous division and fusion This dynamic process is vital for sustaining the normal structure and function of mitochondria, while the imbalance of mitochondrial fission and fusion is crucial for inducing mitochondrial dysfunction (Balog et al, 2016). Our previous studies found that mitochondria showed over-fission in cardiac muscle and vascular smooth muscle which induced mitochondrial dysfunction following hemorrhagic shock. Cecal ligation and puncture (CLP)induced sepsis in SD rats and Drp knockout Drp KO mice and lipopolysaccharide (LPS)-treated vascular smooth muscle cells (VSMCs) and cardiomyocytes were applied, the protective effects of inhibition of mitochondrial fission on organ function following sepsis and the underlying mechanisms were explored
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