{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T16:19:59Z","timestamp":1787501999683,"version":"build-2736575974"},"reference-count":36,"publisher":"American Physiological Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2008,11]]},"abstract":"<jats:p>\n                    Elevated levels of serum uric acid (UA) are commonly associated with primary pulmonary hypertension but have generally not been thought to have any causal role. Recent experimental studies, however, have suggested that UA may affect various vasoactive mediators. We therefore tested the hypothesis that UA might alter nitric oxide (NO) levels in pulmonary arterial endothelial cells (PAEC). In isolated porcine pulmonary artery segments (PAS), UA (7.5 mg\/dl) inhibits acetylcholine-induced vasodilation. The incubation of PAEC with UA caused a dose-dependent decrease in NO and cGMP production stimulated by bradykinin or Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -ionophore A23187. We explored cellular mechanisms by which UA might cause reduced NO production focusing on the effects of UA on the l-arginine-endothelial NO synthase (eNOS) and l-arginine-arginase pathways. Incubation of PAEC with different concentrations of UA (2.5\u201315 mg\/dl) for 24 h did not affect l-[\n                    <jats:sup>3<\/jats:sup>\n                    H]arginine uptake or activity\/expression of eNOS. However, PAEC incubated with UA (7.5 mg\/dl; 24 h) released more urea in culture media than control PAEC, suggesting that arginase activation might be involved in the UA effect. Kinetic analysis of arginase activity in PAEC lysates and rat liver and kidney homogenates demonstrated that UA activated arginase by increasing its affinity for l-arginine. An inhibitor of arginase ( S)-(2-boronoethyl)-l-cysteine prevented UA-induced reduction of A23187-stimulated cGMP production by PAEC and abolished UA-induced inhibition of acetylcholine-stimulated vasodilation in PAS. We conclude that UA-induced arginase activation is a potential mechanism for reduction of NO production in PAEC.\n                  <\/jats:p>","DOI":"10.1152\/ajpcell.00075.2008","type":"journal-article","created":{"date-parts":[[2008,9,10]],"date-time":"2008-09-10T21:44:17Z","timestamp":1221083057000},"page":"C1183-C1190","source":"Crossref","is-referenced-by-count":195,"title":["Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells"],"prefix":"10.1152","volume":"295","author":[{"given":"Sergey","family":"Zharikov","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina","family":"Krotova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanbo","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Baylis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward R.","family":"Block","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jawaharlal","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"crossref","unstructured":"Alderton W\n                      , Cooper C, Knowles R.\n                      Nitric oxide synthase: structure, function and inhibition.\n                      Biochem J\n                      357\n                      : 593\u2013615, 2001.","DOI":"10.1042\/bj3570593"},{"key":"R2","unstructured":"Aubert JD\n                      .\n                      Biochemical markers in the management of pulmonary hypertension.\n                      Swiss Med Wkly\n                      135\n                      : 43\u201349, 2005."},{"key":"R3","doi-asserted-by":"crossref","unstructured":"Bendayan D\n                      , Shitrit D, Ygla M, Huerta M, Fink G, Kramer M.\n                      Hyperuricemia as a prognostic factor in pulmonary arterial hypertension.\n                      Resp Med\n                      97\n                      : 130\u2013133, 2003.","DOI":"10.1053\/rmed.2003.1440"},{"key":"R4","doi-asserted-by":"crossref","unstructured":"Berkowitz D\n                      , White R, Li D, Minhas K, Cernetich A, Kim S, Burke S, Shoukas A, Nyhan D, Champion H, Hare J.\n                      Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels.\n                      Circulation\n                      108\n                      : 2000\u20132006, 2003.","DOI":"10.1161\/01.CIR.0000092948.04444.C7"},{"key":"R5","unstructured":"Block ER\n                      , Patel J, Sheridan N.\n                      Endotoxin protects against hyperoxic decrease in membrane fluidity in endothelial cells but not in fibroblasts.\n                      Lab Invest\n                      54\n                      : 146\u2013153, 1986."},{"key":"R6","unstructured":"Chen CH\n                      , Chen HA, Wang HP, Liao HT, Chou CT, Huang DF.\n                      Pulmonary arterial hypertension in autoimmune diseases: an analysis of 19 cases from a medical center in northern Taiwan.\n                      J Microbiol Immunol Infect\n                      39\n                      : 162\u2013168, 2006."},{"key":"R7","doi-asserted-by":"crossref","unstructured":"Chicoine L\n                      , Paffett M, Young T, Nelin L.\n                      Arginase inhibition increases nitric oxide production in bovine pulmonary arterial endothelial cells.\n                      Am J Physiol Lung Cell Mol Physiol\n                      287\n                      : L60\u2013L68, 2004.","DOI":"10.1152\/ajplung.00194.2003"},{"key":"R8","doi-asserted-by":"crossref","unstructured":"Corraliza IM\n                      , Campo ML, Soler G, Modolell M.\n                      Determination of arginase activity in macrophages: a micromethod.\n                      J Immunol Methods\n                      174\n                      : 231\u2013235, 1994.","DOI":"10.1016\/0022-1759(94)90027-2"},{"key":"R9","doi-asserted-by":"crossref","unstructured":"Duan X\n                      , Ling F.\n                      Is uric acid itself a player or a bystander in the pathophysiology of chronic heart failure?\n                      Med Hypotheses\n                      70\n                      : 578\u2013581, 2008.","DOI":"10.1016\/j.mehy.2007.06.018"},{"key":"R10","doi-asserted-by":"crossref","unstructured":"Hoeper MM\n                      , Hohlfeld JM, Fabel H.\n                      Hyperuricemia in patients with right or left heart failure.\n                      Eur Respir J\n                      13\n                      : 682\u2013685, 1999.","DOI":"10.1183\/09031936.99.13368299"},{"key":"R11","doi-asserted-by":"crossref","unstructured":"Hu H\n                      , Xin M, Belayev L, Zhang J, Block ER, Patel JM.\n                      Autoinhibitory domain fragment of endothelial NOS enhances pulmonary artery vasorelaxation by the NO-cGMP pathway.\n                      Am J Physiol Lung Cell Mol Physiol\n                      286\n                      : L1066\u2013L1074, 2004.","DOI":"10.1152\/ajplung.00378.2003"},{"key":"R12","doi-asserted-by":"crossref","unstructured":"Itoh Y\n                      , Hai Ma F, Hoshi H, Oka M, Noda K, Ukai Y, Kojima H, Nagano T, Toda N.\n                      Determination and bioimaging method for nitric oxide in biological specimens by diaminofluorescein fluorometry.\n                      Anal Biochem\n                      287\n                      : 203\u2013209, 2000.","DOI":"10.1006\/abio.2000.4859"},{"key":"R13","doi-asserted-by":"crossref","unstructured":"Kang DH\n                      , Park S, Lee I, Johnson RJ.\n                      Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells.\n                      J Am Soc Nephrol\n                      16\n                      : 3553\u20133562, 2005.","DOI":"10.1681\/ASN.2005050572"},{"key":"R14","doi-asserted-by":"crossref","unstructured":"Khosla U\n                      , Zharikov S, Finch J, Nakagawa T, Roncal C, Mu W, Krotova K, Block ER, Prabhakar S, Johnson RJ.\n                      Hyperuricemia induces endothelial dysfunction.\n                      Kidney Int\n                      67\n                      : 1739\u20131742, 2005.","DOI":"10.1111\/j.1523-1755.2005.00273.x"},{"key":"R15","doi-asserted-by":"crossref","unstructured":"Krotova K\n                      , Hu H, Xia SL, Belayev Patel JM L, Block EM, Zharikov S.\n                      Peptides modified by myristoylation activate eNOS in endothelial cells through Akt phosphorylation.\n                      Br J Pharmacol\n                      148\n                      : 732\u2013740, 2006.","DOI":"10.1038\/sj.bjp.0706777"},{"key":"R16","doi-asserted-by":"crossref","unstructured":"Kuzkaya N\n                      , Weissmann N, Harrison D, Dikalov S.\n                      Interactions of peroxynitrite with uric acid in the presence of ascorbate and thiols: implications for uncoupling endothelial nitric oxide synthase.\n                      Biochem Parmacol\n                      70\n                      : 343\u2013354, 2005.","DOI":"10.1016\/j.bcp.2005.05.009"},{"key":"R17","doi-asserted-by":"crossref","unstructured":"Li H\n                      , Meininger C, Hawker J, Haynes T, Kepka-Lenhart D, Mistry S, Morris S, Wu G.\n                      Regulatory role of arginase I and II in nitric oxide, polyamine, and proline synthesis in endothelial cells.\n                      Am J Physiol Endocrinol Metab\n                      280\n                      : E75\u2013E82, 2001.","DOI":"10.1152\/ajpendo.2001.280.1.E75"},{"key":"R18","doi-asserted-by":"crossref","unstructured":"Li H\n                      , Meininger C, Kelly K, Hawker J, Morris S, Wu G.\n                      Activities of arginase I and II are limiting for endothelial cell proliferation.\n                      Am J Physiol Regul Integr Comp Physiol\n                      282\n                      : R64\u2013R69, 2002.","DOI":"10.1152\/ajpregu.2002.282.1.R64"},{"key":"R19","doi-asserted-by":"crossref","unstructured":"Lim HK\n                      , Ryoo S, Benjo A, Shuleri K, Miriel V, Baraban E, Camara A, Soucy K, Nyhan D, Shoukas A, Berkowitz DE.\n                      Mitochondrial arginase II constrains endothelial NOS-3 activity.\n                      Am J Physiol Heart Circ Physiol\n                      293\n                      : H3317\u2013H3324, 2007.","DOI":"10.1152\/ajpheart.00700.2007"},{"key":"R20","doi-asserted-by":"crossref","unstructured":"Michel T\n                      , Feron O.\n                      Nitric oxide synthase: which, where, how and why?\n                      J Clin Invest\n                      100\n                      : 2146\u20132152, 1997.","DOI":"10.1172\/JCI119750"},{"key":"R21","doi-asserted-by":"crossref","unstructured":"Morris S\n                      .\n                      Recent advances in arginine metabolism.\n                      Curr Opin Clin Nutr Metab Care\n                      7\n                      : 45\u201351, 2004.","DOI":"10.1097\/00075197-200401000-00009"},{"key":"R22","doi-asserted-by":"crossref","unstructured":"Murad F\n                      .\n                      The nitric oxide-cyclic GMP signal transduction system for intracellular and intercellular communication.\n                      Resent Prog Horm Res\n                      49\n                      : 239\u2013248, 1994.","DOI":"10.1016\/B978-0-12-571149-4.50016-7"},{"key":"R23","doi-asserted-by":"crossref","unstructured":"Nagaya N\n                      , Uematsu M, Satoh T, Kyotani S, Sakamaki F, Nakanishi N, Yamagishi M, Kunieda T, Miyatake K.\n                      Serum uric acid levels correlate with the severity and the mortality of primary pulmonary hypertension.\n                      Am J Respir Crit Care Med\n                      160\n                      : 487\u2013492, 1999.","DOI":"10.1164\/ajrccm.160.2.9812078"},{"key":"R24","doi-asserted-by":"crossref","unstructured":"Nakagawa T\n                      , Hu H, Zharikov S, Tuttle K, Short R, Glushakova O, Ouyang X, Feig D, Block ER, Herrera-Acosta J, Patel JM, Johnson RJ.\n                      A causal role for uric acid in fructose-induced metabolic syndrome.\n                      Am J Physiol Renal Physiol\n                      290\n                      : F625\u2013F631, 2006.","DOI":"10.1152\/ajprenal.00140.2005"},{"key":"R25","doi-asserted-by":"crossref","unstructured":"Nishida K\n                      , Abiko T, Ishihara M, Tomokawa M.\n                      Arterial-injury-induced smooth muscle cell proliferation in rats is accompanied by increase in polyamine synthesis and level.\n                      Atheriosclerosis\n                      83\n                      : 119\u2013125, 1990.","DOI":"10.1016\/0021-9150(90)90157-E"},{"key":"R26","doi-asserted-by":"crossref","unstructured":"Palmer R\n                      , Ashton D, Moncada S.\n                      Vascular endothelial cells synthasize nitric oxide from\n                      l\n                      -arginine.\n                      Nature\n                      333\n                      : 664\u2013666, 1988.","DOI":"10.1038\/333664a0"},{"key":"R27","doi-asserted-by":"crossref","unstructured":"Patel JM\n                      , Zhang J, Block ER.\n                      Nitric-oxide-induced inhibition of lung endothelial cell nitric oxide synthase via interaction with allosteric thiols: role of thioredoxin in regulation of catalityc activity.\n                      Am J Respir Cell Mol Biol\n                      15\n                      : 410\u2013419, 1996.","DOI":"10.1165\/ajrcmb.15.3.8810647"},{"key":"R28","doi-asserted-by":"crossref","unstructured":"Ryoo S\n                      , Lemmon C, Soucy K, Gupta G, White A, Nyhan D, Shoukas A, Romer L, Berkowitz D.\n                      Oxidized low-density lipoprotein-dependent endothelial arginase II activation contributes to impaired nitric oxide signaling.\n                      Circ Res\n                      99\n                      : 951\u2013960, 2006.","DOI":"10.1161\/01.RES.0000247034.24662.b4"},{"key":"R29","doi-asserted-by":"crossref","unstructured":"Teng R\n                      , Ye Y, Parks D, Beckman J.\n                      Urate produced during hypoxia protects heart proteins from peroxynitrite-mediated protein nitration.\n                      Free Radic Biol Med\n                      33\n                      : 1243\u20131249, 2002.","DOI":"10.1016\/S0891-5849(02)01020-1"},{"key":"R30","doi-asserted-by":"crossref","unstructured":"Topal G\n                      , Brunet A, Walch L, Boucher JL, David-Dufilho M.\n                      Mitochondrial arginase II modulates nitric-oxide synthesis through nonfreely exchangeable\n                      l\n                      -arginine pools in human endothelial cells.\n                      J Pharmacol Exp Ther\n                      318\n                      : 1368\u20131374, 2006.","DOI":"10.1124\/jpet.106.103747"},{"key":"R31","doi-asserted-by":"crossref","unstructured":"Voelkel M\n                      , Wynne K, Badesch D, Groves B, Voelkel N.\n                      Hyperuricemia in severe pulmonary hypertension.\n                      Chest\n                      117\n                      : 19\u201324, 2000.","DOI":"10.1378\/chest.117.1.19"},{"key":"R32","doi-asserted-by":"crossref","unstructured":"Wei LH\n                      , Wu G, Morris SM, Ignarro LJ.\n                      Elevated arginase I expression in rat aortic smooth muscle cells increases cell proliferation.\n                      Proc Natl Acad Sci USA\n                      98\n                      : 9260\u20139264, 2001.","DOI":"10.1073\/pnas.161294898"},{"key":"R33","doi-asserted-by":"crossref","unstructured":"Wensel R\n                      , Opitz CF, Anker SD, Winkler J, Hoffken G, Kleber FX, Sharma R, Hummel M, Hetzer R, Ewert R.\n                      Assessment of survival in patients with primary pulmonary hypertension. Importance of cardiopulmonary exercise testing.\n                      Circulation\n                      106\n                      : 319\u2013324, 2002.","DOI":"10.1161\/01.CIR.0000022687.18568.2A"},{"key":"R34","doi-asserted-by":"crossref","unstructured":"Wu X\n                      , Muzny D, Lee C, Caskey C.\n                      Two independent mutational events in the loss of urate oxidase during hominoid evolution.\n                      J Mol Evol\n                      34\n                      : 78\u201384, 1992.","DOI":"10.1007\/BF00163854"},{"key":"R35","doi-asserted-by":"crossref","unstructured":"Wu X\n                      , Morris S.\n                      Arginine metabolism: nitric oxide and beyond.\n                      Biochem J\n                      336\n                      : 1\u201317, 1998.","DOI":"10.1042\/bj3360001"},{"key":"R36","doi-asserted-by":"crossref","unstructured":"Zharikov S\n                      , Krotova K, Belayev L, Block ER.\n                      Pertussis toxin activates\n                      l\n                      -arginine uptake in pulmonary endothelial cells through downregulation of PKC-\u03b1 activity.\n                      Am J Physiol Lung Cell Mol Physiol\n                      286\n                      : L974\u2013L983, 2004.","DOI":"10.1152\/ajplung.00236.2003"}],"container-title":["American Journal of Physiology-Cell Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.physiology.org\/doi\/pdf\/10.1152\/ajpcell.00075.2008","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T13:27:20Z","timestamp":1718630840000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.physiology.org\/doi\/10.1152\/ajpcell.00075.2008"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,11]]},"references-count":36,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2008,11]]}},"alternative-id":["10.1152\/ajpcell.00075.2008"],"URL":"https:\/\/doi.org\/10.1152\/ajpcell.00075.2008","relation":{},"ISSN":["0363-6143","1522-1563"],"issn-type":[{"value":"0363-6143","type":"print"},{"value":"1522-1563","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,11]]}}}