Handbook of Vitamin C Research

344Alin StirbanMechanisms of ascorbate-mediated improvement of endothelial function, as well asthe clinical and experimental evidence, along with actual treatment and dietaryrecommendations are briefly reviewed.Endothelial dysfunction (ED) is an early and reversible sign of atherosclerosis [1],represents a good predictor for cardiovascular risk [2] and its improvement was postulated toprevent atherosclerosis. ED accompanies states related to high cardiovascular (CV) risk, suchas smoking [3], dyslipidemia [4], arterial hypertension [5], obesity [6],hyperhomocysteinemia [7], coronary artery disease [8], congestive heart failure [9] and type1 [10] and type 2 [11] diabetes mellitus. Several attempts have been made to improve ED inhigh-risk populations like treatment with vitamin C [12] and E [13], L-arginine [14],tetrahydrobiopterin [15], sildenafil [16], folic acid [17], benfotiamine [18], etc [19]. Theinterest for vitamin C is easy to understand since it represents an inexpensive treatment, hasmodest side-effects and is commonly substituted by over-the counter products.Mechanisms of Endothelium-Mediated VasodilatationNitric oxide (NO) plays a major role in mediating the effects of endothelium. NO ismainly produced within endothelial cells together with L-citrulline from the substrate L-arginine by the enzyme endothelial NO-synthase (eNOS). Tetrahydrobiopterin is an essentialcofactor for eNOS [20] and its depletion alters eNOS function, which instead of producingNO, reduces molecular oxygen to superoxide anions, thus acting pro-oxidant [21].NO induces relaxation of vascular smooth muscle cells (VSMC) by enhancing theactivity of the enzyme guanylyl cyclase, which catalyzes the production of cyclic guanosin-5-monophosphate (cGMP) leading to a decrease of intracellular calcium concentration,relaxation of VSMC and vasodilatation [22]. The concentration of cGMP is also regulated bythe activity of the enzyme phosphodiesterase type 5, which is responsible for its degradation[23].Mechanisms of Vitamin C Improving EDVitamin C has been suggested to reverse ED by several mechanisms: it serves as a potentantioxidant, it directly enhances the activity of eNOS, the acyl CoA oxidase system andcounteracts the action of proinflammatory lipids [24].Oxidative stress reduces the availability of NO mainly by 3 mechanisms. First, nitricoxide reacts with reactive oxygen species resulting in the formation of peroxynitrite – apowerful oxidant with toxic potential [25] - second, oxidized low density lipoprotein (LDL)can react directly with and inactivate nitric oxide [26] and third, oxidative stress increasesformation of advanced glycation end products (AGE) which can inactivate NO themselves[27]. All these mechanisms reduce the bioavailability of NO for vascular effects. OxidizedLDL can also decrease NO effectiveness by lowering its production (it lowers the uptake ofL-arginine and impairs the signal transduction, as well as the agonist receptor dependent