1. Tuder RM, Abman SH, Braun T, Capron F, Stevens T, Thistlethwaite PA, Haworth SG. Development and pathology of pulmonary hypertension. J Am Coll Cardiol. 2009;54:S3–S9. doi: 10.1016/j.jacc.2009.04.009
2. Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, Loyd JE. An imbalance between the excretion of thrombox- ane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. 1992;327:70–75. doi: 10.1056/NEJM199207093270202
3. Galie N, Manes A, Branzi A. The endothelin system in pulmonary ar- terial hypertension. Cardiovasc Res. 2004;61:227–237. doi: 10.1016/j. cardiores.2003.11.026
4. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier J-F, Chabot F, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173:1023–1030. doi: 10.1164/rccm.200510-1668OC
5. Nagaya N, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Nakanishi N, Yamagishi M, Kunieda T, Miyatake K. Serum uric acid levels cor- relate with the severity and the mortality of primary pulmonary hyper- tension. Am J Respir Crit Care Med. 1999;160:487–492. doi: 10.1164/ ajrccm.160.2.9812078
6. Savale L, Akagi S, Tu LY, Cumont A, Thuillet R, Phan C, Le Vely B, Berrebeh N, Huertas A, Jaïs X, et al. Serum and pulmonary uric acid in pulmonary arterial hypertension. Eur Respir J. 2021;58:2000332. doi: 10.1183/13993003.00332-2020
7. Voelkel MA, Wynne KM, Badesch DB, Groves BM, Voelkel NF. Hyperuricemia in severe pulmonary hypertension. Chest. 2000;117:19–24. doi: 10.1378/chest.117.1.19
8. Zharikov S, Krotova K, Hu H, Baylis C, Johnson RJ, Block ER, Patel J. Uric acid decreases no production and increases arginase activity in cultured pulmonary artery endothelial cells. Am J Physiol Cell Physiol. 2008;295:C1183–C1190. doi: 10.1152/ajpcell.00075.2008
9. Mishima M, Hamada T, Maharani N, Ikeda N, Onohara T, Notsu T, Ninomiya H, Miyazaki S, Mizuta E, Sugihara S, et al. Effects of uric acid on the no production of HUVECs and its restoration by urate lowering agents. Drug Res (Stuttg). 2016;66:270–274. doi: 10.1055/s-0035-1569405
10. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pul- monary hypertension. Circulation. 2004;109:159–165. doi: 10.1161/01. CIR.0000102381.57477.50
11. Spiekermann S, Schenk K, Hoeper MM. Increased xanthine oxidase activity in idiopathic pulmonary arterial hypertension. Eur Respir J. 2009;34:276. doi: 10.1183/09031936.00013309
12. Ghosh S, Gupta M, Xu W, Mavrakis DA, Janocha AJ, Comhair SAA, Haque MM, Stuehr DJ, Yu J, Polgar P, et al. Phosphorylation inactiva- tion of endothelial nitric oxide synthesis in pulmonary arterial hyperten- sion. Am J Physiol Lung Cell Mol Physiol. 2016;310:L1199–L1205. doi: 10.1152/ajplung.00092.2016
13. Monin L, Griffiths KL, Lam WY, Gopal R, Kang DD, Ahmed M, Rajamanickam A, Cruz-Lagunas A, Zúñiga J, Babu S, et al. Helminth- induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis. J Clin Invest. 2015;125:4699–4713. doi: 10.1172/JCI77378
14. Abe K, Toba M, Alzoubi A, Ito M, Fagan KA, Cool CD, Voelkel NF, McMurtry IF, Oka M. Formation of plexiform lesions in experimental se- vere pulmonary arterial hypertension. Circulation. 2010;121:2747–2754. doi: 10.1161/CIRCULATIONAHA.109.927681
15. Oka M, Ohnishi M, Takahashi H, Soma S, Hasunuma K, Sato K, Kira S. Altered vasoreactivity in lungs isolated from rats exposed to ni- tric oxide gas. Am J Physiol. 1996;271:L419–L424. doi: 10.1152/ajplu ng.1996.271.3.L419
16. Kuwabara Y, Tanaka-Ishikawa M, Abe K, Hirano M, Hirooka Y, Tsutsui H, Sunagawa K, Hirano K. Proteinase-activated receptor 1 antagonism ameliorates experimental pulmonary hypertension. Cardiovasc Res. 2019;115:1357–1368. doi: 10.1093/cvr/cvy284
17. Ming XF, Rajapakse AG, Carvas JM, Ruffieux J, Yang Z. Inhibition of S6K1 accounts partially for the anti-inflammatory effects of the argi- nase inhibitor L-norvaline. BMC Cardiovasc Disord. 2009;9:12. doi: 10.1186/1471-2261-9-12
18. Papp R, Nagaraj C, Zabini D, Nagy BM, Lengyel M, Skofic Maurer D, Sharma N, Egemnazarov B, Kovacs G, Kwapiszewska G, et al. Targeting TMEM16A to reverse vasoconstriction and remodelling in idiopathic pul- monary arterial hypertension. Eur Respir J. 2019;53:1800965.
19. Lang M, Kojonazarov B, Tian X, Kalymbetov A, Weissmann N, Grimminger F, Kretschmer A, Stasch J-P, Seeger W, Ghofrani HA, et al.The soluble guanylate cyclase stimulator riociguat ameliorates pulmo- nary hypertension induced by hypoxia and SU5416 in rats. PLoS One. 2012;7:e43433. doi: 10.1371/journal.pone.0043433
20. Wu XW, Muzny DM, Lee CC, Caskey CT. Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol. 1992;34:78–84. doi: 10.1007/BF00163854
21. Mazzali M, Hughes J, Kim YG, Jefferson A, Kang DH, Gordon KL, Lan YL, Kivlighn S, Johnson RJ. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension. 2001;38:1101–1106. doi: 10.1161/hy1101.092839
22. Chen CC, Hsu YJ, Lee TM. Impact of elevated uric acid on ventricu- lar remodeling in infarcted rats with experimental hyperuricemia. Am J Physiol Heart Circ Physiol. 2011;301:H1107–H1117. doi: 10.1152/ajphe art.01071.2010
23. Kawamorita Y, Shiraishi T, Tamura Y, Kumagai T, Shibata S, Fujigaki Y, Hosoyamada M, Nakagawa T, Uchida S. Renoprotective effect of topiroxostat via antioxidant activity in puromycin aminonucleoside ne- phrosis rats. Physiol Rep. 2017;5:e13358. doi: 10.14814/phy2.13358
24. da Silva Gonçalves Bós D, Van Der Bruggen CEE, Kurakula K, Sun X-Q, Casali KR, Casali AG, Rol N, Szulcek R, dos Remedios C, Guignabert C, et al. Contribution of impaired parasympathetic activity to right ven- tricular dysfunction and pulmonary vascular remodeling in pulmonary arterial hypertension. Circulation. 2018;137:910–924. doi: 10.1161/ CIRCULATIONAHA.117.027451
25. Kono A, Maughan WL, Sunagawa K, Hamilton K, Sagawa K, Weisfeldt ML. The use of left ventricular end-ejection pressure and peak pres- sure in the estimation of the end-systolic pressure-volume relationship. Circulation. 1984;70:1057–1065. doi: 10.1161/01.CIR.70.6.1057
26. Toba M, Alzoubi A, O’Neill KD, Gairhe S, Matsumoto Y, Oshima K, Abe K, Oka M, McMurtry IF. Temporal hemodynamic and histological progres- sion in Sugen5416/hypoxia/normoxia-exposed pulmonary arterial hy- pertensive rats. Am J Physiol Heart Circ Physiol. 2014;306:H243–H250. doi: 10.1152/ajpheart.00728.2013
27. Jung C, Grün K, Betge S, Pernow J, Kelm M, Muessig J, Masyuk M, Kuethe F, Ndongson-Dongmo B, Bauer R, et al. Arginase inhibition re- verses monocrotaline-induced pulmonary hypertension. Int J Mol Sci. 2017;18:1609. doi: 10.3390/ijms18081609
28. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide syn- thase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995;333:214–221. doi: 10.1056/NEJM199507273330403
29. Kaneko K, Aoyagi Y, Fukuuchi T, Inazawa K, Yamaoka N. Total purine and purine base content of common foodstuffs for facilitating nutritional therapy for gout and hyperuricemia. Biol Pharm Bull. 2014;37:709–721.
30. Ohata K, Kamijo-Ikemori A, Sugaya T, Hibi C, Nakamura T, Murase T, Oikawa T, Hoshino S, Katayama K, Asano J, et al. Renoprotective effect of the xanthine oxidoreductase inhibitor topiroxostat under de- creased angiotensin II type 1a receptor expression. Eur J Pharmacol. 2017;815:88–97. doi: 10.1016/j.ejphar.2017.09.005
31. Abe K, Shinoda M, Tanaka M, Kuwabara Y, Yoshida K, Hirooka Y, McMurtry IF, Oka M, Sunagawa K. Haemodynamic unloading re- verses occlusive vascular lesions in severe pulmonary hypertension. Cardiovasc Res. 2016;111:16–25. doi: 10.1093/cvr/cvw070
32. Ohtsubo T, Rovira II, Starost MF, Liu C, Finkel T. Xanthine oxidore- ductase is an endogenous regulator of cyclooxygenase-2. Circ Res. 2004;95:1118–1124. doi: 10.1161/01.RES.0000149571.96304.36
33. Taniguchi T, Ashizawa N, Matsumoto K, Iwanaga T, Saitoh K. Uricosuric agents decrease the plasma urate level in rats by concomitant treat- ment with topiroxostat, a novel xanthine oxidoreductase inhibitor. J Pharm Pharmacol. 2016;68:76–83. doi: 10.1111/jphp.12490
34. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophys- iology, and pharmacology. Pharmacol Rev. 1991;43:109–142.
35. Kanabrocki EL, Third JL, Ryan MD, Nemchausky BA, Shirazi P, Scheving LE, McVormick JB, Hermida RC, Bremner WF, Hoppensteadt DA, et al. Circadian relationship of serum uric acid and nitric oxide. JAMA. 2000;283:2240–2241. doi: 10.1001/jama.283.17.2235
36. Tanaka M, Abe K, Oka M, Saku K, Yoshida K, Ishikawa T, McMurtry IF, Sunagawa K, Hoka S, Tsutsui H. Inhibition of nitric oxide synthase unmasks vigorous vasoconstriction in established pulmonary arterial hypertension. Physiol Rep. 2017;5:e13537. doi: 10.14814/phy2.13537
37. Kuebler WM, Nicolls MR, Olschewski A, Abe K, Rabinovitch M, Stewart D, Chan SY, Morrell NW, Archer SL, Spiekerkoetter E. A pro-con debate: current controversies in PAH pathogenesis at the American Thoracic Society International Conference in 2017. Am J Physiol Lung Cell Mol Physiol. 2018;315:L502–L516. doi: 10.1152/ajplung.00150.2018
38. Huang F, Zhang H, Wu M, Yang H, Kudo M, Peters CJ, Woodruff PG, Solberg OD, Donne ML, Huang X, et al. Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction. Proc Natl Acad Sci USA. 2012;109:16354–16359. doi: 10.1073/pnas.1214596109
39. Yin W, Zhou QL, OuYang SX, Chen Y, Gong YT, Liang YM. Uric acid reg- ulates NLRP3/IL-1beta signaling pathway and further induces vascular endothelial cells injury in early CKD through ROS activation and K(+) efflux. BMC Nephrol. 2019;20:319.
40. Cero FT, Hillestad V, Sjaastad I, Yndestad A, Aukrust P, Ranheim T, Lunde IG, Olsen MB, Lien E, Zhang L, et al. Absence of the inflam- masome adaptor ASC reduces hypoxia-induced pulmonary hyperten- sion in mice. Am J Physiol Lung Cell Mol Physiol. 2015;309:L378–L387. doi: 10.1152/ajplung.00342.2014
41. Tang B, Chen GX, Liang MY, Yao JP, Wu ZK. Ellagic acid prevents monocrotaline-induced pulmonary artery hypertension via inhibiting NLRP3 inflammasome activation in rats. Int J Cardiol. 2015;180:134–141. doi: 10.1016/j.ijcard.2014.11.161
42. Hille R, Nishino T. Xanthine oxidase and xanthine dehydrogenase. FASEB J. 1995;9:995–1003. doi: 10.1096/fasebj.9.11.7649415
43. Tsutsui H, Kinugawa S, Matsushima S. Oxidative stress and heart failure. Am J Physiol Heart Circ Physiol. 2011;301:H2181–H2190. doi: 10.1152/ajpheart.00554.2011
44. Hoshikawa Y, Ono S, Suzuki S, Tanita T, Chida M, Song C, Noda M, Tabata T, Voelkel NF, Fujimura S. Generation of oxidative stress contrib- utes to the development of pulmonary hypertension induced by hypoxia. J Appl Physiol. 2001;90:1299–1306. doi: 10.1152/jappl.2001.90.4.1299
45. Jankov RP, Kantores C, Pan J, Belik J. Contribution of xanthine oxidase- derived superoxide to chronic hypoxic pulmonary hypertension in neo- natal rats. Am J Physiol Lung Cell Mol Physiol. 2008;294:L233–L245. doi: 10.1152/ajplung.00166.2007
46. Zuckerbraun BS, Shiva S, Ifedigbo E, Mathier MA, Mollen KP, Rao J, Bauer PM, Choi JJW, Curtis E, Choi AMK, et al. Nitrite potently inhibits hypoxic and inflammatory pulmonary arterial hypertension and smooth muscle proliferation via xanthine oxidoreductase-dependent nitric oxide generation. Circulation. 2010;121:98–109. doi: 10.1161/CIRCULATIO NAHA.109.891077
47. de Yong JW, van der Meer P, Nieukoop AS, Huizer T, Stroeve RJ, Bos E. Xanthine oxidoreductase activity in perfused hearts of various species, includ- ing humans. Circ Res. 1990;67:770–773. doi: 10.1161/01.RES.67.3.770