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Chronic Treatment with Tetrahydrobiopterin Reverses Endothelial Dysfunction and Oxidative Stress in Hypercholesterolemia
  1. Francesco Cosentino (f_cosentino{at}hotmail.com)
  1. Cardiology, La Sapienza University, Rome, Italy
    1. David Hürlimann (davidh{at}greenmail.ch)
    1. University Hospital Zürich, Cardiology, Switzerland
      1. Chiara delli Gatti
      1. University Hospital Zürich, Cardiology, Switzerland
        1. Remy Chenevard (rchenevard{at}bluewin.ch)
        1. University Hospital Zürich, Cardiology, Switzerland
          1. Nenad Blau
          1. University Children's Hospital Zürich, Switzerland
            1. Nicholas John Alp (nicholas.alp{at}well.ox.ac.uk)
            1. Departement of Cardiovascular Medicine, Oxford University, United Kingdom
              1. Keith M Channon (keith.channon{at}cardiov.ox.ac.uk)
              1. Departement of Cardiovascular Medicine, Oxford University, United Kingdom
                1. Masato Eto
                1. University Hospital Zürich, Cardiology, Switzerland
                  1. Peter Lerch
                  1. ZLB Behring AG, Bern, Switzerland
                    1. Frank Enseleit (frank.enseleit{at}usz.ch)
                    1. University Hospital Zürich, Cardiology, Switzerland
                      1. Frank Ruschitzka (frankruschitzka{at}yahoo.com)
                      1. University Hospital Zürich, Cardiology, Switzerland
                        1. Massimo Volpe
                        1. Cardiology, La Sapienza University, Rome, Italy
                          1. Thomas F Lüscher (cardiotfl{at}gmx.ch)
                          1. University Hospital Zürich, Cardiology, Switzerland
                            1. Georg Noll (georg.noll{at}usz.ch)
                            1. University Hospital Zürich, Cardiology, Switzerland

                              Abstract

                              Objectives Reduced availability of tetrahydrobiopterin (BH4), an essential cofactor of NO synthase (NOS), decreases NO production and increases ROS. Both mechanisms contribute to atherosclerotic vascular disease. Although acute supplementation of BH4 improves endothelial dysfunction, the effect of chronic BH4 in humans is unknown. We investigated the effect of chronic BH4 supplementation on endothelial function and oxidative stress in hypercholesterolemia.

                              Design Randomized double-blind placebo controlled.

                              Setting University Hospital

                              Patients 22 hypercholesterolemic patients (LDL>4.5mmol/L) were randomized to 4-weeks of oral BH4 (400 mg bid) or placebo. Age-matched healthy volunteers served as controls.

                              Main outcome measures Endothelium-dependent and iVindependent vasodilation was assessed by venous occlusion plethysmography. To elucidate the mechanisms of BH4 effect, NO release and superoxide anion (O2-) production were measured in human aortic endothelial cells exposed to native LDL (100 mg cholesterol/dL).

                              Results BH4 plasma levels were significantly increased by oral supplementation. NO-mediated vasodilation to acetylcholine was reduced in patients compared with controls and restored by BH4. No effect of BH4 on endothelium-independent vasodilation was observed. Furthermore, 8-F2fnisoprostane plasma levels, a marker of vascular oxidative stress, were reduced by BH4. In LDL-treated endothelial cells, BH4 levels and NO release were reduced and O2- production increased compared to control cells. Exogenous BH4 normalized NO and O2-production.

                              Conclusions In hypercholesterolemia, endothelial dysfunction and oxidative stress can be reversed by chronic oral treatment with BH4. Thus, BH4 availability is essential for maintaining NO synthesis and low O2- production by eNOS in vivo, and may provide a rational therapeutic approach to prevent cardiovascular disease.

                              • NO
                              • cholesterol
                              • endothelium
                              • free radicals
                              • tetrahydrobiopterin

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