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• W2040962058 abstract "Invited EditorialOral BH4: A novel remedy for age-related skin microvascular impairment during heat stress or fool's elixir?Gary L. PierceGary L. PierceDepartment of Health and Human Physiology, The University of Iowa, Iowa City, IowaPublished Online:01 Oct 2013https://doi.org/10.1152/japplphysiol.00785.2013This is the final version - click for previous versionMoreSectionsPDF (90 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat 5,6,7,8-tetrahydrobiopterin (BH4) is a critical cofactor for the nitric oxide synthases (NOS) because it facilitates the electron transfer between the reductase and oxygenase domains of the NOS dimer and couples the reduction of molecular oxygen to the oxidation of l-arginine and synthesis of nitric oxide (NO). BH4 biosynthesis is regulated by the de novo pathway in which guanadine triphosphate (GTP) is converted to BH4 under the control of the rate-limiting enzyme GTP cyclohyrolase I (GTPCHI) and two intermediate enzymes pyruvoyl tetrahydrobiopterin synthase and sepiapterin reductase (SR). BH4 also is synthesized by a “salvage pathway,” whereby sepiapterin is converted to 7,8-dihydrobiopterin (BH2) via SR and subsequently reduced to BH4 by dihydrofolate reductase (DHFR) (Fig. 1). A large body of evidence implicates a reduction in vascular BH4 bioavailability as a central mechanism for the development of impaired NO-mediated microvascular function in a wide variety of conditions, including diabetes, hypertension, hypercholesterolemia, atherosclerosis, and aging (7). The aforementioned disorders also are associated with elevated vascular oxidative stress, and BH4 is particularly susceptible to oxidation by peroxynitrite (ONOO−), a reactive oxygen species byproduct of the NO and superoxide anion (O2·−) reaction (8) (Fig. 1). Oxidation of BH4 results in uncoupling of the NOS dimer, promoting transfer of electrons to molecular oxygen resulting in production of O2·− rather than NO. Consequently, supplementation of BH4 has been advanced for more than a decade as a novel remedy for restoring microvascular dysfunction in aged adults (9) and adults at risk for or with cardiovascular disease (CVD) (7).Fig. 1.Intracellular 5,6,7,8-tetrahydrobiopterin (BH4), synthesis, oxidation, and recycling in endothelial cells. GTP, guanidine triphosphate; GTPCHI, GTP cyclohydrolase I; PTPS, pyruvoyl tetrahydrobiopterin synthase; SR, sepiapterin reductase; DHFR, dihydrofolate reductase; ˙NO, nitric oxide; O2·−, superoxide anion radical; ONOO−, peroxynitrite; H202, hydrogen peroxide; BH3˙, trihydrobiopterin radical; DHF, dihydrofolate; 5MTHF, 5-methyltetrahydofolate; eNOS, endothelial nitric oxide synthase; Asc, ascorbate; Asc˙−, ascorbate radical.Download figureDownload PowerPointIn this issue of the Journal of Applied Physiology, Stanhewicz et al. (10) investigated the effects of acute oral administration of sapropterin dihydrochloride, an FDA-approved synthetic formulation of BH4, on cutaneous reflex vasodilation to hyperthermia (1°C increase in core body temperature) in older healthy adults. The authors report that a single oral therapeutic dose of sapropterin (10 mg/kg body wt) improved reflex skin vasodilation during whole body heat stress imposed by a water-perfused suit and that this was through an increase in tonic NO bioavailability. The authors previously reported that acute local perfusion of BH4 augments reflex vasodilation to hyperthermia through a NO-dependent mechanism (11). The current study extends these previous results by demonstrating that raising systemic BH4 levels through oral administration of a BH4 analog improved vasodilation to heat stress in older adults by augmenting NO-mediated dilation. That acute local perfusion of BH4 did not further augment vasodilation after the oral dose of sapropterin suggests that the 10 mg/kg oral dose was sufficient to improve tissue bioavailability of BH4 in the cutaneous microcirculation and improve reflex skin vasodilation to hyperthermia in older adults, although it cannot be completely ruled out that some of the beneficial effect of sapropterin is through antioxidant actions. Moreover, the single dose of sapropterin used appeared to fully restore reflex cutaneous vasodilation in the older adults to levels consistent with previously reported values in young subjects (11).The strengths of the study include the randomized, double-blind, placebo-controlled crossover design; use of coinfusion of l-NAME to “pharmaco-dissect” the contribution of NO to the BH4-mediated improvement in skin vasodilation; and the use of an FDA-approved drug that could have genuine clinical/translational impact. The latter is important because there are no established pharmacological remedies to prevent impaired cutaneous blood flow during heat stress in older adults who are particularly susceptible to hyperthermia-induced injury. However, as with all good studies, the current study raises many new questions that remain to be answered. For example, what is the minimal effective dose of sapropterin required to show the same effect as the 10 mg/g use in this study? The current study design experimentally clamped body temp after a 1°C rise from baseline. Do the beneficial effects of sapropterin on reflex skin vasodilation observed with mild hyperthermia persist with more severe hyperthermia. The study used a single acute dose of sapropterin followed by experimental measurements at 2- to 3-h postingestion. How long does the beneficial effect on cutaneous blood flow last beyond 3 h? Finally, as the authors point out, the current study was in healthy older adults without risk factors for CVD and not on any vasoactive medications. A recent study demonstrated that 2–6 wk of oral sapropterin had no effect on vascular endothelial function in older adults with advanced atherosclerosis (4). Therefore, it remains to be determined whether oral sapropterin would be effective in improving skin vasodilation during hyperthermia in older adults at risk for or with clinical CVD.One major issue that remains largely unresolved is how exogenously administered BH4 is transported from the circulation and into endothelial cells. There is currently no known cellular transporter or receptor for BH4 and plasma concentrations of BH4 do not correlate well with vascular concentrations (1). One hypothesis is that exogenously administered BH4 is oxidized rapidly to BH2 upon entering circulation (4), diffuses into the cell as BH2, and then is recycled back to BH4 via the “salvage” pathway enzyme DHFR (Fig. 1). Indeed, siRNA knockdown or pharmacological inhibition of DHFR with methotrexate in endothelial cells results in a rapid decrease in intracellular BH4 and an increase in BH2 with concomitant eNOS uncoupling (3). Therefore, these data support the idea that DHFR likely plays a significant role in the regulation of vascular BH4 bioavailability.Sapopterin's clinical indication is for the treatment of BH4-deficient hyperphenylalaninemia, a rare defect in BH4 synthesis that renders phenylalanine hydroxylase unable to metabolize phenylalanine to tyrosine. The benefits of sapropterin are that it has a good safety profile, is associated with minimal side effects, and is shelf stable (e.g., does not get oxidized easily). However, major limitations for widespread use of sapropterin in studies with “off-label” vascular endpoints is that the drug is currently made by only one manufacturer in the world and is very expensive, making feasibility of chronic intervention studies with microvascular function as a primary outcome challenging.In light of these limitations there is a growing interest in alternative therapeutic approaches to increase intracellular BH4 bioavailability by protecting BH4 from oxidation and/or stimulating de novo BH4 synthesis. For example, intravenous administration of 5-methyltetrahydrofolate (5MTHF), the biologically active form of folic acid, improves NOS coupling-associated endothelial function in older adults with atherosclerosis through the ONOO− scavenging effects of 5MTHF or increased BH4 recycling during conversion of folate to 5MTHF (Fig. 1) (2). Similarly, acute local perfusion of ascorbic acid improves reflex skin vasodilation during heat stress in older adults (6), however it is currently unknown whether oral ascorbic acid preparations or other antioxidants can improve cutaneous vasodilation during hyperthermia with aging. Finally, GTPCHI, the rate-limiting enzyme for BH4 biosynthesis, can be modulated by numerous pharmacological and physiological stimuli. HMG CoA reductase inhibitors (statins) (5) and laminar shear stress (e.g., in vitro exercise blood flow mimetic) (12) increase GTPCHI mRNA and activity in endothelial cells, respectively, thus augmenting de novo synthesis of BH4 and NOS coupling (Fig. 1). Taken together, these studies suggest that alternative strategies to preserve or increase vascular BH4 bioavailability in aged humans deserve further investigation.In summary, acute oral administration of sapropterin, an FDA-approved BH4 analog, is effective in fully restoring the reflex skin vasodilatory response to hyperthermia in older adults largely through a NO-dependent mechanism. However, before sapropterin is labeled the next “elixir” for prevention of hyperthermia-related skin microvascular dysfunction in older adults, randomized controlled trials of sapropterin or other synthetic BH4 analogs are essential to determine whether preserving intracellular BH4 bioavailability ultimately reduces heat-related morbidity and mortality in the aged population.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author(s).AUTHOR CONTRIBUTIONSAuthor contributions: G.L.P. conception and design of research; G.L.P. prepared figures; G.L.P. drafted manuscript; G.L.P. edited and revised manuscript; G.L.P. approved final version of manuscript.REFERENCES1. Antoniades C, Shirodaria C, Crabtree M, Rinze R, Alp N, Cunnington C, Diesch J, Tousoulis D, Stefanadis C, Leeson P, Ratnatunga C, Pillai R, Channon KM. Altered plasma versus vascular biopterins in human atherosclerosis reveal relationships between endothelial nitric oxide synthase coupling, endothelial function, and inflammation. Circulation 116: 2851–2859, 2007.Crossref | PubMed | ISI | Google Scholar2. Antoniades C, Shirodaria C, Warrick N, Cai S, de Bono J, Lee J, Leeson P, Neubauer S, Ratnatunga C, Pillai R, Refsum H, Channon KM. 5-Methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation 114: 1193–1201, 2006.Crossref | PubMed | ISI | Google Scholar3. Crabtree MJ, Tatham AL, Hale AB, Alp NJ, Channon KM. Critical role for tetrahydrobiopterin recycling by dihydrofolate reductase in regulation of endothelial nitric-oxide synthase coupling: relative importance of the de novo biopterin synthesis versus salvage pathways. J Biol Chem 284: 28128–28136, 2009.Crossref | PubMed | ISI | Google Scholar4. Cunnington C, Van Assche T, Shirodaria C, Kylintireas I, Lindsay AC, Lee JM, Antoniades C, Margaritis M, Lee R, Cerrato R, Crabtree MJ, Francis JM, Sayeed R, Ratnatunga C, Pillai R, Choudhury RP, Neubauer S, Channon KM. Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease. Circulation 125: 1356–1366, 2012.Crossref | PubMed | ISI | Google Scholar5. Hattori Y, Nakanishi N, Akimoto K, Yoshida M, Kasai K. HMG-CoA reductase inhibitor increases GTP cyclohydrolase I mRNA and tetrahydrobiopterin in vascular endothelial cells. Arterioscler Thromb Vasc Biol 23: 176–182, 2003.Crossref | PubMed | ISI | Google Scholar6. Holowatz LA, Thompson CS, Kenney WL. Acute ascorbate supplementation alone or combined with arginase inhibition augments reflex cutaneous vasodilation in aged human skin. Am J Physiol Heart Circ Physiol 291: H2965–H2970, 2006.Link | ISI | Google Scholar7. Katusic ZS, d'Uscio LV, Nath KA. Vascular protection by tetrahydrobiopterin: progress and therapeutic prospects. Trends Pharmacol Sci 30: 48–54, 2009.Crossref | PubMed | ISI | Google Scholar8. Milstien S, Katusic Z. Oxidation of tetrahydrobiopterin by peroxynitrite: implications for vascular endothelial function. Biochem Biophys Res Commun 263: 681–684, 1999.Crossref | PubMed | ISI | Google Scholar9. Pierce GL, Larocca TJ. Reduced vascular tetrahydrobiopterin (BH4) and endothelial function with ageing: is it time for a chronic BH4 supplementation trial in middle-aged and older adults? J Physiol 586: 2673–2674, 2008.Crossref | ISI | Google Scholar10. Stanhewicz AE, Alexander LA, Kenney WL. Oral sapropterin acutely augments reflex vasodilation in aged human skin through nitric oxide-dependent mechanisms. J Appl Physiol; doi:10.1152/japplphysiol.00481.2013.Link | ISI | Google Scholar11. Stanhewicz AE, Bruning RS, Smith CJ, Kenney WL, Holowatz LA. Local tetrahydrobiopterin administration augments reflex cutaneous vasodilation through nitric oxide-dependent mechanisms in aged human skin. J Appl Physiol 112: 791–797, 2012.Link | ISI | Google Scholar12. Widder JD, Chen W, Li L, Dikalov S, Thony B, Hatakeyama K, Harrison DG. Regulation of tetrahydrobiopterin biosynthesis by shear stress. Circ Res 101: 830–838, 2007.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: G. L. Pierce, 225 S. Grand Ave, 412 FH, The Univ. of Iowa, Iowa City, IA 52242 (e-mail: [email protected]edu). Download PDF Back to Top Next FiguresReferencesRelatedInformationCited ByOral sapropterin acutely augments reflex vasodilation in aged human skin through nitric oxide-dependent mechanismsAnna E. Stanhewicz, Lacy M. Alexander, and W. Larry Kenney1 October 2013 | Journal of Applied Physiology, Vol. 115, No. 7 More from this issue > Volume 115Issue 7October 2013Pages 951-953 Copyright & PermissionsCopyright © 2013 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00785.2013PubMed23845981History Received 9 July 2013 Accepted 9 July 2013 Published online 1 October 2013 Published in print 1 October 2013 Metrics" @default.
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