Folic acid supplementation improves microvascular function in older adults through nitric oxide-dependent mechanisms
Tóm tắt
Older adults have reduced vascular endothelial function, evidenced by attenuated nitric oxide (NO)-dependent cutaneous vasodilatation. Folic acid and its metabolite, 5-methyltetrahydrofolate (5-MTHF), are reported to improve vessel function. We hypothesized that (i) local 5-MTHF administration and (ii) chronic folic acid supplementation would improve cutaneous microvascular function in ageing through NO-dependent mechanisms. There were two separate studies in which there were 11 young (Y: 22±1 years) and 11 older (O: 71±3 years) participants. In both studies, two intradermal microdialysis fibres were placed in the forearm skin for local delivery of lactated Ringer's solution with or without 5 mM 5-MTHF. Red cell flux was measured by laser-Doppler flowmetry. Cutaneous vascular conductance [CVC=red cell flux/mean arterial pressure] was normalized as percentage maximum CVC (%CVCmax) (28 mM sodium nitroprusside, local temperature 43°C). In study 1 after CVC plateaued during local heating, 20 mM NG-nitro-L-arginine methyl ester (L-NAME) was perfused at each site to quantify NO-dependent vasodilatation. The local heating plateau (%CVCmax: O=82±3 vs Y=96±1, P=0.002) and NO-dependent vasodilatation (%CVCmax: O=26±6% vs Y=49±5, P=0.03) were attenuated in older participants. 5-MTHF augmented the overall (%CVCmax=91±2, P=0.03) and NO-dependent (%CVCmax=43±9%, P=0.04) vasodilatation in older but not young participants. In study 2 the participants ingested folic acid (5 mg/day) or placebo for 6 weeks in a randomized, double-blind, crossover design. A rise in oral temperature of 1°C was induced using a water-perfused suit, body temperature was held and 20 mM L-NAME was perfused at each site. Older participants had attenuated reflex (%CVCmax: O=31±8 vs Y=44±5, P=0.001) and NO-dependent (%CVCmax: O=9±2 vs Y=21±2, P=0.003) vasodilatation. Folic acid increased CVC (%CVCmax=47±5%, P=0.001) and NO-dependent vasodilatation (20±3%, P=0.003) in the older but not the young participants. Both local perfusion of 5-MTHF and supplementation with folic acid increase vasodilatation in ageing individuals through NO-dependent mechanisms.
Từ khóa
Tài liệu tham khảo
Holowatz, 2003, Nitric oxide and attenuated reflex cutaneous vasodilation in aged skin, Am. J. Physiol. Heart Circ. Physiol., 284, H1662, 10.1152/ajpheart.00871.2002
Kenney, 1997, Decreased active vasodilator sensitivity in aged skin, Am J. Physiol., 272, H1609
Minson, 2002, Decreased nitric oxide- and axon reflex-mediated cutaneous vasodilation with age during local heating, J. Appl. Physiol., 93, 1644, 10.1152/japplphysiol.00229.2002
Stanhewicz, 2012, Local tetrahydrobiopterin administration augments reflex cutaneous vasodilation through nitric oxide-dependent mechanisms in aged human skin, J. Appl. Physiol., 112, 791, 10.1152/japplphysiol.01257.2011
Delp, 2008, Ageing diminishes endothelium-dependent vasodilatation and tetrahydrobiopterin content in rat skeletal muscle arterioles, J. Physiol., 586, 1161, 10.1113/jphysiol.2007.147686
Holowatz, 2006, L-Arginine supplementation or arginase inhibition augments reflex cutaneous vasodilatation in aged human skin, J. Physiol., 574, 573, 10.1113/jphysiol.2006.108993
Holowatz, 2006, 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, 10.1152/ajpheart.00648.2006
Lu, 1999, Oxidative damage elicited by imbalance of free radical scavenging enzymes is associated with large-scale mtDNA deletions in aging human skin, Mutat. Res., 423, 11, 10.1016/S0027-5107(98)00220-6
Crabtree, 2011, Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease, Nitric Oxide, 25, 81, 10.1016/j.niox.2011.04.004
Werner, 2011, Tetrahydrobiopterin: biochemistry and pathophysiology, Biochem. J., 438, 397, 10.1042/BJ20110293
Vasquez-Vivar, 1998, Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors, Proc. Natl. Acad. Sci. U.S.A., 95, 9220, 10.1073/pnas.95.16.9220
Sugiyama, 2009, Tetrahydrobiopterin recycling, a key determinant of endothelial nitric-oxide synthase-dependent signaling pathways in cultured vascular endothelial cells, J. Biol. Chem., 284, 12691, 10.1074/jbc.M809295200
Stanhewicz, 2013, Oral sapropterin acutely augments reflex vasodilation in aged human skin through nitric oxide-dependent mechanisms, J. Appl. Physiol., 115, 972, 10.1152/japplphysiol.00481.2013
Alian, 2012, The effects of folic acid on markers of endothelial function in patients with type 1 diabetes mellitus, Medicinski Arhiv, 66, 12, 10.5455/medarh.2012.66.12-15
Doshi, 2001, Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide? Arterioscler, Thromb. Vasc. Biol., 21, 1196, 10.1161/hq0701.092000
Verhaar, 1998, 5-methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia, Circulation, 97, 237, 10.1161/01.CIR.97.3.237
Stroes, 2000, Folic acid reverts dysfunction of endothelial nitric oxide synthase, Circ. Res., 86, 1129, 10.1161/01.RES.86.11.1129
Antoniades, 2006, 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, 10.1161/CIRCULATIONAHA.106.612325
Bruning, 2012, Endothelial nitric oxide synthase mediates cutaneous vasodilation during local heating and is attenuated in middle-aged human skin, J. Appl. Physiol., 112, 2019, 10.1152/japplphysiol.01354.2011
Minson, 2001, Nitric oxide and neurally mediated regulation of skin blood flow during local heating, J. Appl. Physiol., 91, 1619, 10.1152/jappl.2001.91.4.1619
Johnson, 1986, Effect of local warming on forearm reactive hyperaemia, Clin. Physiol., 6, 337, 10.1111/j.1475-097X.1986.tb00239.x
Doshi, 2002, Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering, Circulation, 105, 22, 10.1161/hc0102.101388
Bellamy, 1999, Oral folate enhances endothelial function in hyperhomocysteinaemic subjects, Eur. J. Clin. Invest., 29, 659, 10.1046/j.1365-2362.1999.00527.x
Chao, 1999, Effect of short-term vitamin (folic acid, vitamins B6 and B12) administration on endothelial dysfunction induced by post-methionine load hyperhomocysteinemia, Am. J. Cardiol., 84, 1359, 10.1016/S0002-9149(99)00575-5
Loew, 1987, [Plasma kinetics and elimination of folic acid], Klin. Wochenschr., 65, 520, 10.1007/BF01721039
Willems, 2004, Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease, Br. J. Pharmacol., 141, 825, 10.1038/sj.bjp.0705446
Stern, 2011, A comparison of folic acid pharmacokinetics in obese and nonobese women of childbearing age, Therapeut. Drug Monit., 33, 336, 10.1097/FTD.0b013e318219407a
Aoki, 1997, Circadian variation in skin blood flow responses to passive heat stress, Physiol. Behav., 63, 1, 10.1016/S0031-9384(97)00348-X
Stanhewicz, 2013, Oral sapropterin acutely augments reflex vasodilation in aged human skin through nitric oxide-dependent mechanisms, J. Appl. Physiol., 15, 972, 10.1152/japplphysiol.00481.2013
Holowatz, 2008, The human cutaneous circulation as a model of generalized microvascular function, J. Appl. Physiol., 105, 370, 10.1152/japplphysiol.00858.2007
Rg, 2003, Individuals at increased coronary heart disease risk are characterized by an impaired microvascular function in skin, Eur. J. Clin. Invest., 33, 536, 10.1046/j.1365-2362.2003.01179.x
Abularrage, 2005, Evaluation of the microcirculation in vascular disease, J. Vasc. Surg., 42, 574, 10.1016/j.jvs.2005.05.019
McCord, 2006, Prostanoids contribute to cutaneous active vasodilation in humans, Am. J. Physiology. Regul. Integr. Comp. Physiol., 291, R596, 10.1152/ajpregu.00710.2005
Wong, 2004, H1 but not H2 histamine receptor activation contributes to the rise in skin blood flow during whole body heating in humans, J. Physiol., 560, 941, 10.1113/jphysiol.2004.071779
Bennett, 2003, Evidence for a role for vasoactive intestinal peptide in active vasodilatation in the cutaneous vasculature of humans, J. Physiol., 552, 223, 10.1113/jphysiol.2003.042135
Holowatz, 2009, Ketorolac alters blood flow during normothermia but not during hyperthermia in middle-aged human skin, J. Appl. Physiol., 107, 1121, 10.1152/japplphysiol.00750.2009
Stanhewicz, 2012, Local tetrahydrobiopterin administration augments reflex cutaneous vasodilation through nitric oxide-dependent mechanisms in aged human skin, J. Appl. Physiol., 112, 791, 10.1152/japplphysiol.01257.2011
Holowatz, 2011, Oral atorvastatin therapy restores cutaneous microvascular function by decreasing arginase activity in hypercholesterolaemic humans, J. Physiol., 589, 2093, 10.1113/jphysiol.2010.203935
Bruning, 2013, Aspirin and clopidogrel alter core temperature and skin blood flow during heat stress, Med. Sci. Sports Exerc., 45, 674, 10.1249/MSS.0b013e31827981dc
Lekakis, 2004, Oral folic acid enhances endothelial function in patients with hypercholesterolaemia receiving statins, Eur. J. Cardiovasc. Prevent. Rehab., 11, 416