Ers organ perfusion and oxygenation. In the absence of BH4, eNOS becomes uncoupled, producing superoxide (O2? rather than nitric oxide (NO) [15]. O2?and NO yield peroxynitrite, the most damaging ROS.Figure 1 Ischemia/reperfusion-induced and sepsis-induced endothelial dysfunction is initiated by increased amounts of reactive oxygen species. 1. Ascorbate reduces the production of superoxide (O2?, hydrogen peroxide and peroxynitrite (OONO? by inhibiting the Jak2/Stat1/IRF1 signaling pathway, which leads to subunit p47phox GW0742MedChemExpress GW610742 expression of nicotinamide adenine dinucleotide phosphate oxidase (NADPH-ox) and thus to O2?formation. 2. Ascorbate protects against oxidative stress induced pathological vasoconstriction and loss of endothelial barrier by PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28461585 inhibiting tetrahydrobiopterin (BH4) oxidation, the cofactor of endothelial nitric oxide synthase (eNOS), thereby preventing endothelial nitric oxide (eNO) depletion and eNOS uncoupling. 3. Ascorbate inhibits inducible nitric oxide synthase (iNOS) mRNA and iNOS expression, preventing abundant production of nitric oxide (NO) that generates OONO?in the presence of O2? 4. Ascorbate protects against vascular leakage by inhibiting protein phosphatase 2A (PP2A) activation, which dephosphorylates occludin. Phosphorylated occludin is crucial for maintenance of tight junctions. 5. Ascorbate inhibits myocardial apoptosis by preventing Bax activation, which decreases the ability of BCl-2 to inhibit cytochrome-C release from the mitochondria into the cytoplasm and subsequent caspase-3 activation, which initiates apoptosis. The combination with vitamin E is synergistic. 6. Ascorbate inhibits microcirculatory flow impairment by inhibiting tumor necrosis factor-induced intracellular adhesion molecule (ICAM) expression, which triggers leukocyte stickiness and sludging. cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate; I/R, ischemia/reperfusion; sGC, soluble guanylate cyclase.Oudemans-van Straaten et al. Critical Care 2014, 18:460 http://ccforum.com/content/18/1/Page 3 ofRole of vitamin C: in vitro studies The underlying mechanisms for the effect of ascorbate on these pathways have been demonstrated in in vitro studies with cultured endothelial cells. Endothelial cells can accumulate ascorbate to millimolar levels [16] and represent an appropriate model to study the effects of high-dose vitamin C. In vitro studies are presented focusing on protective effects of vitamin C (ascorbate) in ischemia/reperfusion and sepsis.Endothelial dysfunctionprotects against vascular leakage by inhibiting protein phosphatase 2A activation [24]. Furthermore, oxidants and LPS increase apoptosis, impairing the endothelial barrier. LPS decreases Bcl-2 (which inhibits apoptosis) and increases Bax (which suppresses the ability of Bcl2 to block apoptosis). Ascorbate inhibited apoptosis [25] and protected endothelial progenitor cells [26]. Simultaneous administration with vitamin E had a synergistic effect on the prevention of apoptosis.Impairment of microcirculatory flowAscorbate decreases oxidative stress in endothelial cells by reducing the production of O2? hydrogen peroxide and peroxynitrite. Mechanisms include prevention of NOX activation, decreased inducible nitric oxide synthase (iNOS) expression and increased NO bioavailability (Figure 1) [16-18]. NOX is the major source of ROS in endothelial and myocardial cells [1,19]. Activation of NOX leads to the formation of intracellular O2? A.
