Weidinger 2015 Antioxid Redox Signal

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Weidinger A, Müllebner A, Paier-Pourani J, Banerjee A*, Miller I, Lauterböck L, Duvigneau JC, Skulachev VP, Redl H, Kozlov AV (2015) Vicious inducible nitric oxide synthase-mitochondrial reactive oxygen species cycle accelerates inflammatory response and causes liver injury in rats. Antioxid Redox Signal 22:572-86.

» PMID: 25365698

Weidinger A, Muellebner A, Paier-Pourani J, Banerjee A, Miller I, Lauterboeck L, Duvigneau JC, Skulachev VP, Redl H, Kozlov AV (2015) Antioxid Redox Signal

Abstract: Increasing evidences suggest that, apart from activation of guanylyl cyclase, intracellular nitric oxide (NO) signaling is associated with an interaction between NO and reactive oxygen species (ROS) to modulate physiological or pathophysiological processes. The aim of this study was to understand the contribution of mitochondrial ROS (mtROS) to NO-mediated signaling in hepatocytes on inflammation.

In rats treated with lipopolysaccharide (LPS), mitochondria-targeted antioxidants (mtAOX) (mitoTEMPO and SkQ1) reduced inducible nitric oxide synthase (iNOS) gene expression in liver, NO levels in blood and plasma, and markers of organ damage (lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase). In cultured hepatocytes, treated with inflammatory mediators, generated ex vivo by incubation of white blood cells with LPS, we observed an increase in NO and mtROS levels. l-NG-monomethyl arginine citrate, a NOS inhibitor, decreased both NO and mtROS levels. mtAOX reduced mtROS, cytoplasmic ROS levels, and expression of iNOS and interleukin (IL)-6. These data suggest that NO, generated by iNOS, elevates mtROS, which, in turn, diffuse into the cytoplasm and upregulate iNOS and IL-6.

Here, for the first time, we show that intracellular signaling pathways mediated by NO and ROS are linked to each other via mtROS and form an iNOS-mtROS feed-forward loop which aggravates liver failure on acute inflammation.

Our results provide a mechanistic explanation of how NO and mtROS cooperate to conduct inflammatory intracellular signals. We anticipate our results to be the missing mechanistic link between acute systemic inflammation and liver failure.


O2k-Network Lab: RU Moscow Skulachev VP, AT Vienna Kozlov AV


Labels: MiParea: Respiration 

Stress:Oxidative stress;RONS  Organism: Rat  Tissue;cell: Liver  Preparation: Homogenate 


Coupling state: LEAK, OXPHOS, ET  Pathway: N, S  HRR: Oxygraph-2k 


Clarification

  • Banerjee A refers to Banerjee Asmita (Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Vienna, Austria) and not Banerjee Anindita