Aging of Platelet Nitric Oxide Signaling: Pathogenesis, Clinical Implications, and Therapeutics

 

 Buy Article Permissions and Reprints

Abstract

The nitric oxide (NO)/soluble guanylate cyclase (sGC) system is fundamental to endothelial control of vascular tone, but also plays a major role in the negative modulation of platelet aggregation. The phenomenon of platelet NO resistance, or decreased antiaggregatory response to NO, occurs increasingly with advanced age, as well as in the context of cardiovascular disease states such as heart failure, ischemic heart disease, and aortic valve disease. The central causes of NO resistance are “scavenging” of NO and dysfunction of sGC. In the current review, we discuss the roles of several modulators of NO synthesis and of the NO/sGC cascade on changes in platelet physiology with aging, together with potential therapeutic options to reduce associated thrombotic risk.

• References

• 1 Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288 (5789) 373-376
  CrossrefPubMedGoogle Scholar
• 2 Förstermann U. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch 2010; 459 (6) 923-939
  CrossrefPubMedGoogle Scholar
• 3 Pawloski JR, Hess DT, Stamler JS. Export by red blood cells of nitric oxide bioactivity. Nature 2001; 409 (6820) 622-626
  CrossrefPubMedGoogle Scholar
• 4 Vallance P, Leone A, Calver A, Collier J, Moncada S. Endogenous dimethylarginine as an inhibitor of nitric oxide synthesis. J Cardiovasc Pharmacol 1992; 20 (Suppl. 12) S60-S62
  CrossrefPubMedGoogle Scholar
• 5 Antoniades C, Shirodaria C, Leeson P , et al. Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: implications for endothelial function in human atherosclerosis. Eur Heart J 2009; 30 (9) 1142-1150
  CrossrefPubMedGoogle Scholar
• 6 Landmesser U, Dikalov S, Price SR , et al. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 2003; 111 (8) 1201-1209
  CrossrefPubMedGoogle Scholar
• 7 Xu J, Xie Z, Reece R, Pimental D, Zou MH. Uncoupling of endothelial nitric oxidase synthase by hypochlorous acid: role of NAD(P)H oxidase-derived superoxide and peroxynitrite. Arterioscler Thromb Vasc Biol 2006; 26 (12) 2688-2695
  CrossrefPubMedGoogle Scholar
• 8 Weber M, Lauer N, Mülsch A, Kojda G. The effect of peroxynitrite on the catalytic activity of soluble guanylyl cyclase. Free Radic Biol Med 2001; 31 (11) 1360-1367
  CrossrefPubMedGoogle Scholar
• 9 Ignarro LJ, Degnan JN, Baricos WH, Kadowitz PJ, Wolin MS. Activation of purified guanylate cyclase by nitric oxide requires heme. Comparison of heme-deficient, heme-reconstituted and heme-containing forms of soluble enzyme from bovine lung. Biochim Biophys Acta 1982; 718 (1) 49-59
  CrossrefPubMedGoogle Scholar
• 10 Mellion BT, Ignarro LJ, Myers CB , et al. Inhibition of human platelet aggregation by S-nitrosothiols. Heme-dependent activation of soluble guanylate cyclase and stimulation of cyclic GMP accumulation. Mol Pharmacol 1983; 23 (3) 653-664
  PubMedGoogle Scholar
• 11 Burgoyne JR, Prysyazhna O, Rudyk O, Eaton P. cGMP-dependent activation of protein kinase G precludes disulfide activation: implications for blood pressure control. Hypertension 2012; 60 (5) 1301-1308
  CrossrefPubMedGoogle Scholar
• 12 Rosenkranz AC, Dusting GJ, Ritchie RH. Endothelial dysfunction limits the antihypertrophic action of bradykinin in rat cardiomyocytes. J Mol Cell Cardiol 2000; 32 (6) 1119-1126
  CrossrefPubMedGoogle Scholar
• 13 Radomski MW, Palmer RMJ, Moncada S. The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. Br J Pharmacol 1987; 92 (3) 639-646
  CrossrefPubMedGoogle Scholar
• 14 Willoughby SR, Chirkova LP, Horowitz JD, Chirkov YY. Multiple agonist induction of aggregation: an approach to examine anti-aggregating effects in vitro. Platelets 1996; 7 (5-6) 329-333
  CrossrefPubMedGoogle Scholar
• 15 Erdmann J, Stark K, Esslinger UB , et al; CARDIoGRAM. Dysfunctional nitric oxide signalling increases risk of myocardial infarction. Nature 2013; 504 (7480) 432-436
  CrossrefPubMedGoogle Scholar
• 16 Chirkov YY, Horowitz JD. Impaired tissue responsiveness to organic nitrates and nitric oxide: a new therapeutic frontier?. Pharmacol Ther 2007; 116 (2) 287-305
  CrossrefPubMedGoogle Scholar
• 17 Thijssen DH, Black MA, Pyke KE , et al. Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol 2011; 300 (1) H2-H12
  CrossrefPubMedGoogle Scholar
• 18 Horowitz JD, Heresztyn T. An overview of plasma concentrations of asymmetric dimethylarginine (ADMA) in health and disease and in clinical studies: methodological considerations. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 851 (1-2) 42-50
  CrossrefPubMedGoogle Scholar
• 19 Rajendran S, Willoughby SR, Chan WP , et al. Polycystic ovary syndrome is associated with severe platelet and endothelial dysfunction in both obese and lean subjects. Atherosclerosis 2009; 204 (2) 509-514
  CrossrefPubMedGoogle Scholar
• 20 Chirkov YY, Chirkova LP, Horowitz JD. Nitroglycerin tolerance at the platelet level in patients with angina pectoris. Am J Cardiol 1997; 80 (2) 128-131
  CrossrefPubMedGoogle Scholar
• 21 Chirkov YY, Holmes AS, Chirkova LP, Horowitz JD. Nitrate resistance in platelets from patients with stable angina pectoris. Circulation 1999; 100 (2) 129-134
  CrossrefPubMedGoogle Scholar
• 22 Arnold WP, Mittal CK, Katsuki S, Murad F. Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci U S A 1977; 74 (8) 3203-3207
  CrossrefPubMedGoogle Scholar
• 23 Crane MS, Rossi AG, Megson IL. A potential role for extracellular nitric oxide generation in cGMP-independent inhibition of human platelet aggregation: biochemical and pharmacological considerations. Br J Pharmacol 2005; 144 (6) 849-859
  CrossrefPubMedGoogle Scholar
• 24 Sogo N, Magid KS, Shaw CA, Webb DJ, Megson IL. Inhibition of human platelet aggregation by nitric oxide donor drugs: relative contribution of cGMP-independent mechanisms. Biochem Biophys Res Commun 2000; 279 (2) 412-419
  CrossrefPubMedGoogle Scholar
• 25 Willoughby SR, Stewart S, Holmes AS, Chirkov YY, Horowitz JD. Platelet nitric oxide responsiveness: a novel prognostic marker in acute coronary syndromes. Arterioscler Thromb Vasc Biol 2005; 25 (12) 2661-2666
  CrossrefPubMedGoogle Scholar
• 26 Chan WP, Ngo DT, Sverdlov AL , et al. Premature aging of cardiovascular/platelet function in polycystic ovarian syndrome. Am J Med 2013; 126 (7) e1-e7
  PubMedGoogle Scholar
• 27 Yoo JH, Lee SC. Elevated levels of plasma homocyst(e)ine and asymmetric dimethylarginine in elderly patients with stroke. Atherosclerosis 2001; 158 (2) 425-430
  CrossrefPubMedGoogle Scholar
• 28 Achan V, Broadhead M, Malaki M , et al. Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscler Thromb Vasc Biol 2003; 23 (8) 1455-1459
  Google Scholar
• 29 Böger RH, Sullivan LM, Schwedhelm E , et al. Plasma asymmetric dimethylarginine and incidence of cardiovascular disease and death in the community. Circulation 2009; 119 (12) 1592-1600
  CrossrefPubMedGoogle Scholar
• 30 Siegerink B, Maas R, Vossen CY , et al. Asymmetric and symmetric dimethylarginine and risk of secondary cardiovascular disease events and mortality in patients with stable coronary heart disease: the KAROLA follow-up study. Clin Res Cardiol 2013; 102 (3) 193-202
  CrossrefPubMedGoogle Scholar
• 31 Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 2003; 23 (2) 168-175
  CrossrefPubMedGoogle Scholar
• 32 Halcox JP, Schenke WH, Zalos G , et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation 2002; 106 (6) 653-658
  CrossrefPubMedGoogle Scholar
• 33 Horowitz JD, De Caterina R, Heresztyn T , et al. ADMA and SDMA predict outcomes in patients with chronic atrial fibrillation: an ARISTOTLE substudy. Eur Heart J 2013; 34: 1040-1041
  PubMedGoogle Scholar
• 34 Chirkov YY, Holmes AS, Willoughby SR , et al. Stable angina and acute coronary syndromes are associated with nitric oxide resistance in platelets. J Am Coll Cardiol 2001; 37 (7) 1851-1857
  CrossrefPubMedGoogle Scholar
• 35 Chirkov YY, Holmes AS, Martelli JD, Horowitz JD. Effect of perindopril on platelet nitric oxide resistance in patients with chronic heart failure secondary to ischemic left ventricular dysfunction. Am J Cardiol 2004; 93 (11) 1438-1440 , A10
  CrossrefPubMedGoogle Scholar
• 36 Worthley MI, Holmes AS, Willoughby SR , et al. The deleterious effects of hyperglycemia on platelet function in diabetic patients with acute coronary syndromes mediation by superoxide production, resolution with intensive insulin administration. J Am Coll Cardiol 2007; 49 (3) 304-310
  CrossrefPubMedGoogle Scholar
• 37 Ngo DT, Sverdlov AL, Willoughby SR , et al. Determinants of occurrence of aortic sclerosis in an aging population. JACC Cardiovasc Imaging 2009; 2 (8) 919-927
  CrossrefPubMedGoogle Scholar
• 38 Chirkov YY, De Sciscio M, Sverdlov AL, Leslie S, Sage PR, Horowitz JD. Hydralazine does not ameliorate nitric oxide resistance in chronic heart failure. Cardiovasc Drugs Ther 2010; 24 (2) 131-137
  CrossrefPubMedGoogle Scholar
• 39 Suchard SJ, Boxer LA, Dixit VM. Activation of human neutrophils increases thrombospondin receptor expression. J Immunol 1991; 147 (2) 651-659
  PubMedGoogle Scholar
• 40 Jaffe EA, Ruggiero JT, Falcone DJ. Monocytes and macrophages synthesize and secrete thrombospondin. Blood 1985; 65 (1) 79-84
  PubMedGoogle Scholar
• 41 Kirsch T, Woywodt A, Klose J , et al. Endothelial-derived thrombospondin-1 promotes macrophage recruitment and apoptotic cell clearance. J Cell Mol Med 2010; 14 (7) 1922-1934
  CrossrefPubMedGoogle Scholar
• 42 Bauer EM, Qin Y, Miller TW , et al. Thrombospondin-1 supports blood pressure by limiting eNOS activation and endothelial-dependent vasorelaxation. Cardiovasc Res 2010; 88 (3) 471-481
  CrossrefPubMedGoogle Scholar
• 43 Isenberg JS, Qin Y, Maxhimer JB , et al. Thrombospondin-1 and CD47 regulate blood pressure and cardiac responses to vasoactive stress. Matrix Biol 2009; 28 (2) 110-119
  CrossrefPubMedGoogle Scholar
• 44 Csányi G, Yao M, Rodríguez AI , et al. Thrombospondin-1 regulates blood flow via CD47 receptor-mediated activation of NADPH oxidase 1. Arterioscler Thromb Vasc Biol 2012; 32 (12) 2966-2973
  CrossrefPubMedGoogle Scholar
• 45 Bauer PM, Bauer EM, Rogers NM , et al. Activated CD47 promotes pulmonary arterial hypertension through targeting caveolin-1. Cardiovasc Res 2012; 93 (4) 682-693
  CrossrefPubMedGoogle Scholar
• 46 Miller TW, Isenberg JS, Roberts DD. Thrombospondin-1 is an inhibitor of pharmacological activation of soluble guanylate cyclase. Br J Pharmacol 2010; 159 (7) 1542-1547
  CrossrefPubMedGoogle Scholar
• 47 Ramanathan S, Mazzalupo S, Boitano S, Montfort WR. Thrombospondin-1 and angiotensin II inhibit soluble guanylyl cyclase through an increase in intracellular calcium concentration. Biochemistry 2011; 50 (36) 7787-7799
  CrossrefPubMedGoogle Scholar
• 48 Ridnour LA, Windhausen AN, Isenberg JS , et al. Nitric oxide regulates matrix metalloproteinase-9 activity by guanylyl-cyclase-dependent and -independent pathways. Proc Natl Acad Sci U S A 2007; 104 (43) 16898-16903
  CrossrefPubMedGoogle Scholar
• 49 Isenberg JS, Romeo MJ, Yu C , et al. Thrombospondin-1 stimulates platelet aggregation by blocking the antithrombotic activity of nitric oxide/cGMP signaling. Blood 2008; 111 (2) 613-623
  CrossrefPubMedGoogle Scholar
• 50 Isenberg JS, Ridnour LA, Perruccio EM, Espey MG, Wink DA, Roberts DD. Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner. Proc Natl Acad Sci U S A 2005; 102 (37) 13141-13146
  CrossrefPubMedGoogle Scholar
• 51 Isenberg JS, Wink DA, Roberts DD. Thrombospondin-1 antagonizes nitric oxide-stimulated vascular smooth muscle cell responses. Cardiovasc Res 2006; 71 (4) 785-793
  CrossrefPubMedGoogle Scholar
• 52 Nishiyama A, Matsui M, Iwata S , et al. Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein 1 as a negative regulator of thioredoxin function and expression. J Biol Chem 1999; 274 (31) 21645-21650
  CrossrefPubMedGoogle Scholar
• 53 Patwari P, Higgins LJ, Chutkow WA, Yoshioka J, Lee RT. The interaction of thioredoxin with Txnip. Evidence for formation of a mixed disulfide by disulfide exchange. J Biol Chem 2006; 281 (31) 21884-21891
  CrossrefPubMedGoogle Scholar
• 54 Schulze PC, Liu H, Choe E , et al. Nitric oxide-dependent suppression of thioredoxin-interacting protein expression enhances thioredoxin activity. Arterioscler Thromb Vasc Biol 2006; 26 (12) 2666-2672
  CrossrefPubMedGoogle Scholar
• 55 Shaked M, Ketzinel-Gilad M, Ariav Y, Cerasi E, Kaiser N, Leibowitz G. Insulin counteracts glucotoxic effects by suppressing thioredoxin-interacting protein production in INS-1E beta cells and in Psammomys obesus pancreatic islets. Diabetologia 2009; 52 (4) 636-644
  CrossrefPubMedGoogle Scholar
• 56 Forrester MT, Seth D, Hausladen A , et al. Thioredoxin-interacting protein (Txnip) is a feedback regulator of S-nitrosylation. J Biol Chem 2009; 284 (52) 36160-36166
  CrossrefPubMedGoogle Scholar
• 57 Brandwein HJ, Lewicki JA, Murad F. Reversible inactivation of guanylate cyclase by mixed disulfide formation. J Biol Chem 1981; 256 (6) 2958-2962
  PubMedGoogle Scholar
• 58 Maron BA, Zhang YY, Handy DE , et al. Aldosterone increases oxidant stress to impair guanylyl cyclase activity by cysteinyl thiol oxidation in vascular smooth muscle cells. J Biol Chem 2009; 284 (12) 7665-7672
  CrossrefPubMedGoogle Scholar
• 59 Chen J, Saxena G, Mungrue IN, Lusis AJ, Shalev A. Thioredoxin-interacting protein: a critical link between glucose toxicity and beta-cell apoptosis. Diabetes 2008; 57 (4) 938-944
  CrossrefPubMedGoogle Scholar
• 60 Minn AH, Hafele C, Shalev A. Thioredoxin-interacting protein is stimulated by glucose through a carbohydrate response element and induces beta-cell apoptosis. Endocrinology 2005; 146 (5) 2397-2405
  CrossrefPubMedGoogle Scholar
• 61 Saxena G, Chen J, Shalev A. Intracellular shuttling and mitochondrial function of thioredoxin-interacting protein. J Biol Chem 2010; 285 (6) 3997-4005
  CrossrefPubMedGoogle Scholar
• 62 Ogata FT, Batista WL, Sartori A , et al. Nitrosative/oxidative stress conditions regulate thioredoxin-interacting protein (TXNIP) expression and thioredoxin-1 (TRX-1) nuclear localization. PLoS ONE 2013; 8 (12) e84588
  CrossrefPubMedGoogle Scholar
• 63 Bedford MT, Richard S. Arginine methylation an emerging regulator of protein function. Mol Cell 2005; 18 (3) 263-272
  CrossrefPubMedGoogle Scholar
• 64 Ago T, Matsushima S, Kuroda J, Zablocki D, Kitazono T, Sadoshima J. The NADPH oxidase Nox4 and aging in the heart. Aging (Albany, NY Online) 2010; 2 (12) 1012-1016
  PubMedGoogle Scholar
• 65 Lin KY, Ito A, Asagami T , et al. Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 2002; 106 (8) 987-992
  CrossrefPubMedGoogle Scholar
• 66 Kielstein JT, Salpeter SR, Bode-Boeger SM, Cooke JP, Fliser D. Symmetric dimethylarginine (SDMA) as endogenous marker of renal function—a meta-analysis. Nephrol Dial Transplant 2006; 21 (9) 2446-2451
  CrossrefPubMedGoogle Scholar
• 67 Kittel A, Maas R, König J , et al. In vivo evidence that Agxt2 can regulate plasma levels of dimethylarginines in mice. Biochem Biophys Res Commun 2013; 430 (1) 84-89
  CrossrefPubMedGoogle Scholar
• 68 Schepers E, Glorieux G, Dhondt A, Leybaert L, Vanholder R. Role of symmetric dimethylarginine in vascular damage by increasing ROS via store-operated calcium influx in monocytes. Nephrol Dial Transplant 2009; 24 (5) 1429-1435
  CrossrefPubMedGoogle Scholar
• 69 Schepers E, Barreto DV, Liabeuf S , et al; European Uremic Toxin Work Group (EUTox). Symmetric dimethylarginine as a proinflammatory agent in chronic kidney disease. Clin J Am Soc Nephrol 2011; 6 (10) 2374-2383
  CrossrefPubMedGoogle Scholar
• 70 Rajendran S, Chirkov YY. Platelet hyperaggregability: impaired responsiveness to nitric oxide (“platelet NO resistance”) as a therapeutic target. Cardiovasc Drugs Ther 2008; 22 (3) 193-203
  CrossrefPubMedGoogle Scholar
• 71 Yamashita T, Sekiguchi A, Iwasaki YK , et al. Recruitment of immune cells across atrial endocardium in human atrial fibrillation. Circ J 2010; 74 (2) 262-270
  CrossrefPubMedGoogle Scholar
• 72 Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J. Inflammation and angiotensin II. Int J Biochem Cell Biol 2003; 35 (6) 881-900
  CrossrefPubMedGoogle Scholar
• 73 Kutter D, Devaquet P, Vanderstocken G, Paulus JM, Marchal V, Gothot A. Consequences of total and subtotal myeloperoxidase deficiency: risk or benefit?. Acta Haematol 2000; 104 (1) 10-15
  CrossrefPubMedGoogle Scholar
• 74 van der Veen BS, de Winther MP, Heeringa P. Myeloperoxidase: molecular mechanisms of action and their relevance to human health and disease. Antioxid Redox Signal 2009; 11 (11) 2899-2937
  CrossrefPubMedGoogle Scholar
• 75 Leopold JA, Loscalzo J. Oxidative risk for atherothrombotic cardiovascular disease. Free Radic Biol Med 2009; 47 (12) 1673-1706
  CrossrefPubMedGoogle Scholar
• 76 Cook NL, Viola HM, Sharov VS, Hool LC, Schöneich C, Davies MJ. Myeloperoxidase-derived oxidants inhibit sarco/endoplasmic reticulum Ca2+-ATPase activity and perturb Ca2+ homeostasis in human coronary artery endothelial cells. Free Radic Biol Med 2012; 52 (5) 951-961
  CrossrefPubMedGoogle Scholar
• 77 Rudolph TK, Rudolph V, Witte A , et al. Liberation of vessel adherent myeloperoxidase by enoxaparin improves endothelial function. Int J Cardiol 2010; 140 (1) 42-47
  CrossrefPubMedGoogle Scholar
• 78 Rudolph V, Andrié RP, Rudolph TK , et al. Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation. Nat Med 2010; 16 (4) 470-474
  CrossrefPubMedGoogle Scholar
• 79 Eiserich JP, Baldus S, Brennan ML , et al. Myeloperoxidase, a leukocyte-derived vascular NO oxidase. Science 2002; 296 (5577) 2391-2394
  CrossrefPubMedGoogle Scholar
• 80 Eiserich JP, Hristova M, Cross CE , et al. Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 1998; 391 (6665) 393-397
  CrossrefPubMedGoogle Scholar
• 81 Ash DE. Structure and function of arginases. J Nutr 2004; 134 (10, Suppl) 2760S-2764S , discussion 2765S–2767S
  PubMedGoogle Scholar
• 82 Kim JH, Bugaj LJ, Oh YJ , et al. Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats. J Appl Physiol (1985) 2009; 107 (4) 1249-1257
  CrossrefPubMedGoogle Scholar
• 83 Shin WS, Berkowitz DE, Ryoo SW. Increased arginase II activity contributes to endothelial dysfunction through endothelial nitric oxide synthase uncoupling in aged mice. Exp Mol Med 2012; 44 (10) 594-602
  CrossrefPubMedGoogle Scholar
• 84 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22 (8) 983-988
  CrossrefPubMedGoogle Scholar
• 85 Hart RG, Halperin JL, Pearce LA , et al; Stroke Prevention in Atrial Fibrillation Investigators. Lessons from the Stroke Prevention in Atrial Fibrillation trials. Ann Intern Med 2003; 138 (10) 831-838
  CrossrefPubMedGoogle Scholar
• 86 Ball J, Carrington MJ, McMurray JJ, Stewart S. Atrial fibrillation: profile and burden of an evolving epidemic in the 21st century. Int J Cardiol 2013; 167 (5) 1807-1824
  CrossrefPubMedGoogle Scholar
• 87 Joakimsen O, Bonaa KH, Stensland-Bugge E, Jacobsen BK. Age and sex differences in the distribution and ultrasound morphology of carotid atherosclerosis: the Tromsø Study. Arterioscler Thromb Vasc Biol 1999; 19 (12) 3007-3013
  CrossrefPubMedGoogle Scholar
• 88 Eveborn GW, Schirmer H, Heggelund G, Lunde P, Rasmussen K. The evolving epidemiology of valvular aortic stenosis. the Tromsø study. Heart 2013; 99 (6) 396-400
  CrossrefPubMedGoogle Scholar
• 89 Kannel WB, Dawber TR, McGee DL. Perspectives on systolic hypertension. The Framingham study. Circulation 1980; 61 (6) 1179-1182
  CrossrefPubMedGoogle Scholar
• 90 Gerhard M, Roddy MA, Creager SJ, Creager MA. Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans. Hypertension 1996; 27 (4) 849-853
  CrossrefPubMedGoogle Scholar
• 91 Taddei S, Virdis A, Mattei P , et al. Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation 1995; 91 (7) 1981-1987
  CrossrefPubMedGoogle Scholar
• 92 Hart EC, Wallin BG, Barnes JN, Joyner MJ, Charkoudian N. Sympathetic nerve activity and peripheral vasodilator capacity in young and older men. Am J Physiol Heart Circ Physiol 2014; 306 (6) H904-H909
  CrossrefPubMedGoogle Scholar
• 93 Casey DP, Walker BG, Ranadive SM, Taylor JL, Joyner MJ. Contribution of nitric oxide in the contraction-induced rapid vasodilation in young and older adults. J Appl Physiol (1985) 2013; 115 (4) 446-455
  CrossrefPubMedGoogle Scholar
• 94 Goubareva I, Gkaliagkousi E, Shah A, Queen L, Ritter J, Ferro A. Age decreases nitric oxide synthesis and responsiveness in human platelets and increases formation of monocyte-platelet aggregates. Cardiovasc Res 2007; 75 (4) 793-802
  CrossrefPubMedGoogle Scholar
• 95 Cai H, Yuan Z, Fei Q, Zhao J. Investigation of thrombospondin-1 and transforming growth factor-β expression in the heart of aging mice. Exp Ther Med 2012; 3 (3) 433-436
  PubMedGoogle Scholar
• 96 Frazier EP, Isenberg JS, Shiva S , et al. Age-dependent regulation of skeletal muscle mitochondria by the thrombospondin-1 receptor CD47. Matrix Biol 2011; 30 (2) 154-161
  CrossrefPubMedGoogle Scholar
• 97 Sverdlov AL, Chan WP, Procter NE, Chirkov YY, Ngo DT, Horowitz JD. Reciprocal regulation of NO signaling and TXNIP expression in humans: impact of aging and ramipril therapy. Int J Cardiol 2013; 168 (5) 4624-4630
  CrossrefPubMedGoogle Scholar
• 98 Nishinaka Y, Nishiyama A, Masutani H , et al. Loss of thioredoxin-binding protein-2/vitamin D3 up-regulated protein 1 in human T-cell leukemia virus type I-dependent T-cell transformation: implications for adult T-cell leukemia leukemogenesis. Cancer Res 2004; 64 (4) 1287-1292
  CrossrefPubMedGoogle Scholar
• 99 Jung KA, Kwak MK. The Nrf2 system as a potential target for the development of indirect antioxidants. Molecules 2010; 15 (10) 7266-7291
  CrossrefPubMedGoogle Scholar
• 100 He X, Ma Q. Redox regulation by nuclear factor erythroid 2-related factor 2: gatekeeping for the basal and diabetes-induced expression of thioredoxin-interacting protein. Mol Pharmacol 2012; 82 (5) 887-897
  CrossrefPubMedGoogle Scholar
• 101 von Leitner EC, Klinke A, Atzler D , et al. Pathogenic cycle between the endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine and the leukocyte-derived hemoprotein myeloperoxidase. Circulation 2011; 124 (24) 2735-2745
  CrossrefPubMedGoogle Scholar
• 102 Lip GY, Brechin CM, Lane DA. The global burden of atrial fibrillation and stroke: a systematic review of the epidemiology of atrial fibrillation in regions outside North America and Europe. Chest 2012; 142 (6) 1489-1498
  CrossrefPubMedGoogle Scholar
• 103 Berkowitz DE, White R, Li D , et al. Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation 2003; 108 (16) 2000-2006
  CrossrefPubMedGoogle Scholar
• 104 Santhanam L, Lim HK, Lim HK , et al. Inducible NO synthase dependent S-nitrosylation and activation of arginase1 contribute to age-related endothelial dysfunction. Circ Res 2007; 101 (7) 692-702
  CrossrefPubMedGoogle Scholar
• 105 Holowatz LA, Santhanam L, Webb A, Berkowitz DE, Kenney WL. Oral atorvastatin therapy restores cutaneous microvascular function by decreasing arginase activity in hypercholesterolaemic humans. J Physiol 2011; 589 (Pt 8) 2093-2103
  CrossrefPubMedGoogle Scholar
• 106 Steppan J, Nyhan D, Berkowitz DE. Development of novel arginase inhibitors for therapy of endothelial dysfunction. Front Immunol 2013; 4: 278
  PubMedGoogle Scholar
• 107 Yamawaki H, Pan S, Lee RT, Berk BC. Fluid shear stress inhibits vascular inflammation by decreasing thioredoxin-interacting protein in endothelial cells. J Clin Invest 2005; 115 (3) 733-738
  CrossrefPubMedGoogle Scholar
• 108 Willoughby SR, Rajendran S, Chan WP , et al. Ramipril sensitizes platelets to nitric oxide: implications for therapy in high-risk patients. J Am Coll Cardiol 2012; 60 (10) 887-894
  CrossrefPubMedGoogle Scholar
• 109 Anderson TJ, Elstein E, Haber H, Charbonneau F. Comparative study of ACE-inhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study). J Am Coll Cardiol 2000; 35 (1) 60-66
  PubMedGoogle Scholar
• 110 Hornig B, Landmesser U, Kohler C , et al. Comparative effect of ace inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutase. Circulation 2001; 103 (6) 799-805
  CrossrefPubMedGoogle Scholar
• 111 Ceriello A, Assaloni R, Da Ros R , et al. Effect of atorvastatin and irbesartan, alone and in combination, on postprandial endothelial dysfunction, oxidative stress, and inflammation in type 2 diabetic patients. Circulation 2005; 111 (19) 2518-2524
  CrossrefPubMedGoogle Scholar
• 112 Landmesser U, Bahlmann F, Mueller M , et al. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 2005; 111 (18) 2356-2363
  CrossrefPubMedGoogle Scholar
• 113 Oguz A, Uzunlulu M. Short term fluvastatin treatment lowers serum asymmetric dimethylarginine levels in patients with metabolic syndrome. Int Heart J 2008; 49 (3) 303-311
  CrossrefPubMedGoogle Scholar
• 114 Xia W, Yin Z, Li J, Song Y, Qu X. Effects of rosuvastatin on asymmetric dimethylarginine levels and early atrial fibrillation recurrence after electrical cardioversion. Pacing Clin Electrophysiol 2009; 32 (12) 1562-1566
  CrossrefPubMedGoogle Scholar
• 115 Stepien JM, Prideaux RM, Willoughby SR, Chirkov YY, Horowitz JD. Pilot study examining the effect of cholesterol lowering on platelet nitric oxide responsiveness and arterial stiffness in subjects with isolated mild hypercholesterolaemia. Clin Exp Pharmacol Physiol 2003; 30 (7) 507-512
  CrossrefPubMedGoogle Scholar
• 116 Strey CH, Young JM, Lainchbury JH , et al. Short-term statin treatment improves endothelial function and neurohormonal imbalance in normocholesterolaemic patients with non-ischaemic heart failure. Heart 2006; 92 (11) 1603-1609
  CrossrefPubMedGoogle Scholar
• 117 Ashrafian H, Horowitz JD, Frenneaux MP. Perhexiline. Cardiovasc Drug Rev 2007; 25 (1) 76-97
  CrossrefPubMedGoogle Scholar
• 118 Willoughby SR, Stewart S, Chirkov YY, Kennedy JA, Holmes AS, Horowitz JD. Beneficial clinical effects of perhexiline in patients with stable angina pectoris and acute coronary syndromes are associated with potentiation of platelet responsiveness to nitric oxide. Eur Heart J 2002; 23 (24) 1946-1954
  CrossrefPubMedGoogle Scholar
• 119 Chirkov YY, Naujalis JI, Sage RE, Horowitz JD. Antiplatelet effects of nitroglycerin in healthy subjects and in patients with stable angina pectoris. J Cardiovasc Pharmacol 1993; 21 (3) 384-389
  CrossrefPubMedGoogle Scholar
• 120 Armstrong PW, Armstrong JA, Marks GS. Pharmacokinetic-hemodynamic studies of intravenous nitroglycerin in congestive cardiac failure. Circulation 1980; 62 (1) 160-166
  CrossrefPubMedGoogle Scholar
• 121 Ghofrani HA, Galiè N, Grimminger F , et al; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013; 369 (4) 330-340
  CrossrefPubMedGoogle Scholar
• 122 Ghofrani HA, D'Armini AM, Grimminger F , et al; CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013; 369 (4) 319-329
  CrossrefPubMedGoogle Scholar
• 123 Dautov RF, Ngo DT, Licari G , et al. The nitric oxide redox sibling nitroxyl partially circumvents impairment of platelet nitric oxide responsiveness. Nitric Oxide 2013; 35: 72-78
  CrossrefPubMedGoogle Scholar
• 124 Cosby K, Partovi KS, Crawford JH , et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 2003; 9 (12) 1498-1505
  CrossrefPubMedGoogle Scholar
• 125 Bueno M, Wang J, Mora AL, Gladwin MT. Nitrite signaling in pulmonary hypertension: mechanisms of bioactivation, signaling, and therapeutics. Antioxid Redox Signal 2013; 18 (14) 1797-1809
  CrossrefPubMedGoogle Scholar
• 126 Rassaf T, Totzeck M, Hendgen-Cotta UB, Shiva S, Heusch G, Kelm M. Circulating nitrite contributes to cardioprotection by remote ischemic preconditioning. Circ Res 2014; 114 (10) 1601-1610
  CrossrefPubMedGoogle Scholar
• 127 Dautov RF, Stafford I, Liu S, Cullen H, Madhani M, Chirkov YY, Horowitz JD. Hypoxic potentiation of nitrite effects in human vessels and platelets. Nitric Oxide 2014; 40C: 36-44
  PubMedGoogle Scholar
• 128 Siddiqi N, Neil C, Bruce M , et al; NIAMI investigators. Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI). Eur Heart J 2014; 35 (19) 1255-1262
  CrossrefPubMedGoogle Scholar
• 129 Galiè N, Ghofrani HA, Torbicki A , et al; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353 (20) 2148-2157
  CrossrefPubMedGoogle Scholar
• 130 Webb DJ, Muirhead GJ, Wulff M, Sutton JA, Levi R, Dinsmore WW. Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina. J Am Coll Cardiol 2000; 36 (1) 25-31
  CrossrefPubMedGoogle Scholar