Abstract
Enhancement of mitochondrial physiological function prevents sepsis-induced dysfunction. The present study aimed to elucidate the mechanism by which hydrogen (H2) affects mitochondrial function in a wild-type (WT) and homozygous nuclear factor erythroid 2-related factor 2 (Nrf2) knockout (KO, Nrf2−/−) murine model of sepsis. In myocardial tissues with severe sepsis, H2 gas treatment reduced mitochondrial dysfunction, whereas zinc protoporphyrin (ZnPPIX) negated these beneficial effects. H2 treatment upregulated the protein expression of mitofusin-2 (Mfn2), peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), and protein heme oxygenase-1 (HO-1) in WT mice with severe sepsis but not in their Nrf2−/− counterparts, and this upregulation was inhibited in the presence of ZnPPIX. In conclusion, the mechanism by which H2 limits organ damage in mice with severe sepsis involves HO-1, whereas the mechanism that limits severe sepsis-related mitochondrial dysfunction involves both HO-1 and Nrf2.
Highlights
Systemic inflammation in response to infection can lead to sepsis, which, when severe, is characterized by multipleorgan dysfunction syndrome [1]
We detected no significant differences in the Respiratory Control Ratio (RCR) in a comparison of the KO + cecal ligation and puncture (CLP) + H2 group with the CLP and KO + CLP groups (Figure 1(a))
We detected no significant differences in the Adenosine Triphosphate (ATP) level and Membrane Potential (MMP) in the KO + CLP + H2 group compared with that in the CLP and KO + CLP groups
Summary
Systemic inflammation in response to infection can lead to sepsis, which, when severe, is characterized by multipleorgan dysfunction syndrome [1]. E pathophysiology of sepsis and septic shock is strongly associated with the cardiovascular system, in which cardiac function plays a fundamental role. Previous studies have reported the role of various factors in cardiac injury during sepsis, and the protein heme oxygenase-1 (HO-1), a rate-limiting microsomal enzyme in the catabolism of heme into carbon monoxide, free iron, and biliverdin, limited septic injury by suppressing interleukin-1β and nuclear factor-κB expression during the initial development of sepsis [6]. Nuclear factor erythroid 2-related factor 2 (Nrf2) is increasingly recognized as an important regulator of basal and induced expression of a range of antioxidant response element-dependent genes [8, 9]. The binding of Nrf to a DNA promoter under conditions of oxidative stress induced the transcription of antioxidant genes and subsequent translation of proteins, including HO-1 [11]
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