Vitamin C revisited

Abstract

This narrative review summarizes the role of vitamin C in mitigating oxidative injury-induced microcirculatory impairment and associated organ failure in ischemia/reperfusion or sepsis. Preclinical studies show that high-dose vitamin C can prevent or restore microcirculatory flow impairment by inhibiting activation of nicotinamide adenine dinucleotide phosphate-oxidase and inducible nitric oxide synthase, augmenting tetrahydrobiopterin, preventing uncoupling of oxidative phosphorylation, and decreasing the formation of superoxide and peroxynitrite, and by directly scavenging superoxide. Vitamin C can additionally restore vascular responsiveness to vasoconstrictors, preserve endothelial barrier by maintaining cyclic guanylate phosphatase and occludin phosphorylation and preventing apoptosis. Finally, high-dose vitamin C can augment antibacterial defense. These protective effects against overwhelming oxidative stress due to ischemia/reperfusion, sepsis or burn seems to mitigate organ injury and dysfunction, and promote recovery after cardiac revascularization and in critically ill patients, in the latter partially in combination with other antioxidants. Of note, several questions remain to be solved, including optimal dose, timing and combination of vitamin C with other antioxidants. The combination obviously offers a synergistic effect and seems reasonable during sustained critical illness. High-dose vitamin C, however, provides a cheap, strong and multifaceted antioxidant, especially robust for resuscitation of the circulation. Vitamin C given as early as possible after the injurious event, or before if feasible, seems most effective. The latter could be considered at the start of cardiac surgery, organ transplant or major gastrointestinal surgery. Preoperative supplementation should consider the inhibiting effect of vitamin C on ischemic preconditioning. In critically ill patients, future research should focus on the use of short-term high-dose intravenous vitamin C as a resuscitation drug, to intervene as early as possible in the oxidant cascade in order to optimize macrocirculation and microcirculation and limit cellular injury.

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 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 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.