{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:23:31Z","timestamp":1791296611512,"version":"4.1.0"},"reference-count":72,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2004,6,8]]},"abstract":"<jats:p>\n                    The pathogenic mechanisms by which physical exercise influences atherosclerotic lesion formation remain poorly understood. Because vigorous physical training increases oxidative stress, this study tested the hypothesis that graduated and moderate physical exercise together with metabolic intervention (\n                    <jats:sc>l<\/jats:sc>\n                    -arginine and antioxidants) may contribute to increased vascular protection. Exercise training in mice was induced by graduated swimming. In hypercholesterolemic male mice on an atherogenic high-cholesterol diet, graduated and moderate exercise lowered plasma cholesterol and decreased atherosclerotic lesions compared with sedentary control mice. Antioxidants (1.0% vitamin E added to the chow and 0.05% vitamin C added to the drinking water) and\n                    <jats:sc>l<\/jats:sc>\n                    -arginine (6% in drinking water) supplementation to exercising hypercholesterolemic mice further and synergistically reduced atherosclerosis compared with untreated exercised mice. Arterial oxidation-specific epitopes and systemic oxidative stress were reduced by metabolic intervention. Graduated chronic exercise elicited an increase in production of nitric oxide through increased endothelial nitric oxide synthase expression and ameliorated scavenger activities. Thus, metabolic intervention with\n                    <jats:sc>l<\/jats:sc>\n                    -arginine and antioxidants together with graduated and moderate exercise training reduce atherosclerotic lesion formation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0402734101","type":"journal-article","created":{"date-parts":[[2004,5,28]],"date-time":"2004-05-28T20:14:08Z","timestamp":1085775248000},"page":"8797-8802","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":92,"title":["Long-term combined beneficial effects of physical training and metabolic treatment on atherosclerosis in hypercholesterolemic mice"],"prefix":"10.1073","volume":"101","author":[{"given":"Claudio","family":"Napoli","sequence":"first","affiliation":[{"name":"Departments of General Pathology, Medicine, Clinical Pathology, and Human Pathology, University of Naples, 80131 Naples, Italy; Excellence Research Center on Cardiovascular Diseases, Second University of Naples, Naples 80134, Italy; Division of Anesthesiology, and Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Department of Pharmacological Sciences, University of Salerno, Salerno 84084, Italy; and Division of Hypertension, Mayo Clinic Foundation,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Williams-Ignarro","sequence":"additional","affiliation":[{"name":"Departments of General Pathology, Medicine, Clinical Pathology, and Human Pathology, University of Naples, 80131 Naples, Italy; Excellence Research Center on Cardiovascular Diseases, Second University of Naples, Naples 80134, Italy; Division of Anesthesiology, and Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Department of Pharmacological Sciences, University of Salerno, Salerno 84084, Italy; and Division of Hypertension, Mayo Clinic Foundation,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filomena","family":"de Nigris","sequence":"additional","affiliation":[{"name":"Departments of General Pathology, Medicine, Clinical Pathology, and Human Pathology, University of Naples, 80131 Naples, Italy; Excellence Research Center on Cardiovascular Diseases, Second University of Naples, Naples 80134, Italy; Division of Anesthesiology, and Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Department of Pharmacological Sciences, University of Salerno, Salerno 84084, Italy; and Division of Hypertension, Mayo Clinic Foundation,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilach O.","family":"Lerman","sequence":"additional","affiliation":[{"name":"Departments of General Pathology, Medicine, Clinical Pathology, and Human Pathology, University of Naples, 80131 Naples, Italy; Excellence Research Center on Cardiovascular Diseases, Second University of Naples, Naples 80134, Italy; Division of Anesthesiology, and Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Department of Pharmacological Sciences, University of Salerno, Salerno 84084, Italy; and Division of Hypertension, Mayo Clinic Foundation,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loredana","family":"Rossi","sequence":"additional","affiliation":[{"name":"Departments of General Pathology, Medicine, Clinical Pathology, and Human Pathology, University of Naples, 80131 Naples, Italy; Excellence Research Center on Cardiovascular Diseases, Second University of Naples, Naples 80134, Italy; Division of Anesthesiology, and Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Department of Pharmacological Sciences, University of Salerno, Salerno 84084, Italy; and Division of Hypertension, Mayo Clinic Foundation,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Guarino","sequence":"additional","affiliation":[{"name":"Departments of General Pathology, Medicine, Clinical Pathology, and Human Pathology, University of Naples, 80131 Naples, Italy; Excellence Research Center on Cardiovascular Diseases, Second University of Naples, Naples 80134, Italy; Division of Anesthesiology, and Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Department of Pharmacological Sciences, University of Salerno, Salerno 84084, Italy; and Division of Hypertension, Mayo Clinic Foundation,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gelsomina","family":"Mansueto","sequence":"additional","affiliation":[{"name":"Departments of General Pathology, Medicine, Clinical Pathology, and Human Pathology, University of Naples, 80131 Naples, Italy; Excellence Research Center on Cardiovascular Diseases, Second University of Naples, Naples 80134, Italy; Division of Anesthesiology, and Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Department of Pharmacological Sciences, University of Salerno, Salerno 84084, Italy; and Division of Hypertension, Mayo Clinic Foundation,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Di Tuoro","sequence":"additional","affiliation":[{"name":"Departments of General Pathology, Medicine, Clinical Pathology, and Human Pathology, University of Naples, 80131 Naples, Italy; Excellence Research Center on Cardiovascular Diseases, Second University of Naples, Naples 80134, Italy; Division of Anesthesiology, and Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Department of Pharmacological Sciences, University of Salerno, Salerno 84084, Italy; and Division of Hypertension, Mayo Clinic Foundation,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orlando","family":"Pignalosa","sequence":"additional","affiliation":[{"name":"Departments of General Pathology, Medicine, Clinical Pathology, and Human Pathology, University of Naples, 80131 Naples, Italy; Excellence Research Center on Cardiovascular Diseases, Second University of Naples, Naples 80134, Italy; Division of Anesthesiology, and Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Department of Pharmacological Sciences, University of Salerno, Salerno 84084, Italy; and Division of Hypertension, Mayo Clinic Foundation,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"De Rosa","sequence":"additional","affiliation":[{"name":"Departments of General Pathology, Medicine, Clinical Pathology, and Human Pathology, University of Naples, 80131 Naples, Italy; Excellence Research Center on Cardiovascular Diseases, Second University of Naples, Naples 80134, Italy; Division of Anesthesiology, and Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Department of Pharmacological Sciences, University of Salerno, Salerno 84084, Italy; and Division of Hypertension, Mayo Clinic Foundation,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Sica","sequence":"additional","affiliation":[{"name":"Departments of General Pathology, Medicine, Clinical Pathology, and Human Pathology, University of Naples, 80131 Naples, Italy; Excellence Research Center on Cardiovascular Diseases, Second University of Naples, Naples 80134, Italy; Division of Anesthesiology, and Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Department of Pharmacological Sciences, University of Salerno, Salerno 84084, Italy; and Division of Hypertension, Mayo Clinic Foundation,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis J.","family":"Ignarro","sequence":"additional","affiliation":[{"name":"Departments of General Pathology, Medicine, Clinical Pathology, and Human Pathology, University of Naples, 80131 Naples, Italy; Excellence Research Center on Cardiovascular Diseases, Second University of Naples, Naples 80134, Italy; Division of Anesthesiology, and Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Department of Pharmacological Sciences, University of Salerno, Salerno 84084, Italy; and Division of Hypertension, Mayo Clinic Foundation,..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2004,5,28]]},"reference":[{"key":"e_1_3_2_1_2","first-page":"1844","volume":"46","year":"1987","unstructured":"Lakatta, E. G. & Spurgeon, H. A. (1987) Fed. Proc. 46, 1844\u20131849.3556606","journal-title":"Fed. Proc."},{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"M147","DOI":"10.1093\/geronj\/44.5.M147","volume":"44","year":"1989","unstructured":"Blumenthal, J. A., Emery, C. F., Madden, D. J., George, L. K., Coleman, R. E., Riddle, M. W., McKee, D. C., Reasoner, J. & Williams, R. S. (1989) J. Gerontol. 44, M147\u2013M157.2768768","journal-title":"J. Gerontol."},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.30.3.767"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198112173052501"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.2519\/jospt.2002.32.2.36"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.7.963"},{"key":"e_1_3_2_7_2","first-page":"E42","volume":"23","year":"2003","unstructured":"Thompson, P. D., Buchner, D., Pina, I. L., Balady, G. J., Williams, M. A., Marcus, B. H., Berra, K., Blair, S. N., Costa, F., Gordon, N. F., et al. (2003) Arterioscler. Thromb. Vasc. Biol. 23, E42\u2013E49.","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000075572.40158.77"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0831097100"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000080893.55729.28"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00421-002-0640-2"},{"key":"e_1_3_2_12_2","first-page":"18","volume":"29","year":"2003","unstructured":"Keller, C., Fleury, J. & Mujezinovic-Womack, M. (2003) J. Gerontol. Nurs. 29, 18\u201323.","journal-title":"J. Gerontol. Nurs."},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000052626.63602.58"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.80.2.234"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000055013.92097.40"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115499"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000014762.06201.06"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119813"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(99)02131-5"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(99)00224-5"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.4065\/76.6.619"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1471-4914(03)00139-4"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9149(02)03145-4"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9629(15)40531-2"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.2174\/0929867013372896"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1995.03530120067043"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0967-2109(97)00142-7"},{"key":"e_1_3_2_28_2","first-page":"246","volume":"11","year":"1999","unstructured":"Reddy Avula, C. P. & Fernandes, G. (1999) Aging 11, 246\u2013252.10605613","journal-title":"Aging"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1020562518071"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.189.11.1699"},{"key":"e_1_3_2_31_2","doi-asserted-by":"crossref","unstructured":"Shern-Brewer R. Santanam N. Wetzstein C. White-Welkley J. Price L. & Parthasarathy S. (2000) in Handbook of Oxidants and Antioxidants in Exercise eds. Sen C. K. Packer L. & Hanninen O. (Elsevier New York) pp. 1053\u20131067.","DOI":"10.1016\/B978-044482650-3\/50036-5"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/hq1001.097106"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2002.tb02085.x"},{"key":"e_1_3_2_34_2","first-page":"E1","volume":"103","year":"2001","unstructured":"Gielen, S., Schuler, G. & Hambrecht, R. (2001) Circulation 103, E1\u2013E6.11136704","journal-title":"Circulation"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.99-0896rev"},{"key":"e_1_3_2_36_2","first-page":"119","volume":"7","year":"2001","unstructured":"Stefano, G. B., Prevot, V., Cadet, P. & Dardik, I. (2001) Int. J. Mol. Med. 7, 119\u2013129.11172614","journal-title":"Int. J. Mol. Med."},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.18.9.1506"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.21.4.585"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/2685"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.2.459"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.240462697"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000012142.69612.25"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.20.3.689"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.41.1.79"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.2001.90.3.933"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0237367100"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2000.278.5.H1679"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.95.2.430"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000013090.96919.FA"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.192244499"},{"key":"e_1_3_2_51_2","unstructured":"Palinski W. Napoli C. & Reaven P. D. (2000) in Vascular Disease and Injury: Preclinical Research. Contemporary Cardiology Series eds. Simons D. I. & Rogers C. (Humana Totowa NJ) pp. 149\u2013174."},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118132"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a021700"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)52451-6"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-8703(97)70155-8"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/71.5.1062"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0336359100"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.15.2003"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.74.2.349"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00360.2001"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02256026"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1006\/niox.2001.0337"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0024-3205(00)00519-1"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9150(01)00685-2"},{"key":"e_1_3_2_65_2","first-page":"R482","volume":"276","year":"1999","unstructured":"Lu, Q., Ceddia, M. A., Price, E. A., Ye, S. M. & Woods, J. A. (1999) Am. J. Physiol. 276, R482\u2013R489.9950928","journal-title":"Am. J. Physiol."},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1071-3581(00)90028-X"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.43.100901.140226"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000046489.24563.79"},{"key":"e_1_3_2_69_2","first-page":"37","volume":"39","year":"2002","unstructured":"Maxwell, A. J., Zapien, M. P., Pearce, G. L., MacCallum, G. & Stone, P. H. (2002) J. Am. Coll. Cardiol. 39, 37\u201345.11755284","journal-title":"J. Am. Coll. Cardiol."},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(99)00602-6"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-0012.2002.1o100.x"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1067\/mhj.2002.123117"}],"updated-by":[{"DOI":"10.1073\/pnas.0409058101","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2004,12,28]],"date-time":"2004-12-28T00:00:00Z","timestamp":1104192000000}}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0402734101","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T09:48:20Z","timestamp":1649756900000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0402734101"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,5,28]]},"references-count":72,"journal-issue":{"issue":"23","published-print":{"date-parts":[[2004,6,8]]}},"alternative-id":["10.1073\/pnas.0402734101"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0402734101","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,5,28]]},"assertion":[{"value":"2004-05-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}