{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T03:49:41Z","timestamp":1791344981142,"version":"4.3.1"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Hypertension"],"published-print":{"date-parts":[[2000,1]]},"abstract":"<jats:p><jats:italic>Abstract<\/jats:italic>\u2014Although cAMP is an important second messenger that plays a pivotal role in the regulation of platelet aggregation and dilatation of blood vessels, little is known about the action of cAMP on the growth of vascular smooth muscle cells (VSMCs). Thus, we initially studied the effects of cAMP accumulation by using various cAMP stimulants, including a phosphodiesterase type 3 inhibitor (cilostazol) on human aortic VSMC growth. Accumulation of cAMP inhibited the platelet-derived growth factor (PDGF)-stimulated VSMC growth in a dose-dependent manner (<jats:italic>P<\/jats:italic>&lt;0.01), whereas PDGF significantly stimulated the growth of human VSMCs. Thus, we focused on the role of cell cycle regulatory genes, especially on a negative regulator, an anti-oncogene, p53. The protein of p53 was potentiated by cilostazol as well as forskolin and 8-bromo-cAMP, whereas PDGF decreased p53 expression. Upregulation of p53 protein by cAMP was further confirmed by the observation that the decrease in p21, a p53-inducible protein, by PDGF was significantly attenuated by cilostazol in a dose-dependent manner (<jats:italic>P<\/jats:italic>&lt;0.01). These results revealed that accumulation of cAMP inhibited VSMC proliferation, which was at least in part due to an increase in p53-p21 expression. Because p53 and p21 have been reported to induce apoptosis, we examined apoptotic cells for cAMP accumulation. Incubation of VSMCs with cilostazol resulted in a significant increase in apoptotic cells in a dose-dependent manner compared with vehicle treatment as assessed by nuclear chromatic morphology (<jats:italic>P<\/jats:italic>&lt;0.01); forskolin also stimulated apoptotic cells. Consistent with nuclear staining, DNA fragmentation in VSMCs treated with forskolin as well as 8-bromo-cAMP and cilostazol was significantly increased compared with DNA fragmentation in VSMCs treated with vehicle, whereas PDGF significantly decreased the rate of DNA fragmentation (<jats:italic>P<\/jats:italic>&lt;0.01). Overall, these results demonstrated that cAMP inhibited the proliferation of human aortic VSMCs, accompanied by p53-p21\u2013mediated apoptosis. Analogues of cAMP that have direct inhibitory effects on VSMC proliferation can be considered as potential antiproliferative drugs against VSMC growth.<\/jats:p>","DOI":"10.1161\/01.hyp.35.1.237","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:25:31Z","timestamp":1339460731000},"page":"237-243","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":96,"title":["Cyclic AMP Inhibited Proliferation of Human Aortic Vascular Smooth Muscle Cells, Accompanied by Induction of p53 and p21"],"prefix":"10.1161","volume":"35","author":[{"given":"Shin-ichiro","family":"Hayashi","sequence":"first","affiliation":[{"name":"From the Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuichi","family":"Morishita","sequence":"additional","affiliation":[{"name":"From the Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetsugu","family":"Matsushita","sequence":"additional","affiliation":[{"name":"From the Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironori","family":"Nakagami","sequence":"additional","affiliation":[{"name":"From the Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiaki","family":"Taniyama","sequence":"additional","affiliation":[{"name":"From the Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshinori","family":"Nakamura","sequence":"additional","affiliation":[{"name":"From the Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motokuni","family":"Aoki","sequence":"additional","affiliation":[{"name":"From the Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"From the Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jitsuo","family":"Higaki","sequence":"additional","affiliation":[{"name":"From the Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshio","family":"Ogihara","sequence":"additional","affiliation":[{"name":"From the Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S0026-895X(25)09714-7","volume":"46","year":"1994","unstructured":"Beavo JA, Conti M, Heaslip RJ. Multiple cyclic nucleotide phosphodiesterases. Mol Pharmacol. 1994;46:399\u2013405.","journal-title":"Mol Pharmacol"},{"key":"e_1_3_2_2_2","first-page":"215","volume":"25","year":"1992","unstructured":"Tani T, Sakurai K, Kimura Y, Ishikawa T, Hidaka H. Pharmacological manipulation of tissue cyclic AMP by inhibitors: effects of phosphodiesterase inhibitors on the functions of platelets and vascular endothelial cells. Adv Second Messenger Phosphoprotein Res. 1992;25:215\u2013227.","journal-title":"Adv Second Messenger Phosphoprotein Res"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1159\/000138400"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.98.7.678"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/str.20.5.2718208"},{"key":"e_1_3_2_6_2","first-page":"121","volume":"31","year":"1995","unstructured":"Fujitani K, Kambayashi J, Murata K, Yano Y, Shiozaki K, Yukawa M, Sakon M, Murata T, Kawasaki T, Shiba E, Mori T. Clinical evaluation of combined administration of oral prostacyclin analogue beraprost and phosphodiesterase inhibitor cilostazol. Pharmacol Res. 1995;31:121\u2013125.","journal-title":"Pharmacol Res"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(92)90116-Z"},{"key":"e_1_3_2_8_2","first-page":"242","volume":"20","year":"1993","unstructured":"Koh E, Morimoto S, Jiang B, Inoue T, Nabata T, Kitano S, Yasuda O, Fukuo K, Ogihara T. Effects of beraprost sodium, a stable analogue of prostacyclin, on hyperplasia, hypertrophy and glycosaminoglycan synthesis of rat aortic smooth muscle cells. Artery. 1993;20:242\u2013252.","journal-title":"Artery"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0021-9150(84)90107-2"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.130.1.193"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.11.3.1759"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0797-775"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.100.1.21"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9149(97)00052-0"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-199322008-00034"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041150217"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.41.1118"},{"key":"e_1_3_2_18_2","unstructured":"Aoki M Morishita R Matsushita H Nakano N Hayashi S Tomita N Yamamoto K Moriguchi A Higaki J Ogihara T. Serum deprivation induced apoptosis accompanied by up-regulation of p53 and bax in human aortic vascular smooth muscle cells. Heart Vessels. 1997;S12:71\u201375."},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/hyp.34.2.192"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/0008-8749(95)80024-D"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.18.8474"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117123"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.13.5855"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7824950"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90500-P"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90499-G"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90534-7"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.10.4495"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/352345a0"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/28.12.1815"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)50019-3"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.77.4.660"},{"key":"e_1_3_2_33_2","first-page":"521","volume":"63","year":"1990","unstructured":"Lampugnani MG, Giorgi M, Gaboli M, Dejana E, Marchisio PC. Endothelial cell motility, integrin receptor clustering, and microfilament organization are inhibited by agents that increase intracellular cAMP. Lab Invest. 1990;63:521\u2013531.","journal-title":"Lab Invest"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(99)01414-0"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90421-8"},{"key":"e_1_3_2_36_2","first-page":"15","volume":"258","year":"1992","unstructured":"Lane DP. p53: guardian of the genome. Nature. 1992;258:15\u201316.","journal-title":"Nature"},{"key":"e_1_3_2_37_2","first-page":"3131","volume":"54","year":"1994","unstructured":"Miyashita T, Harigai M, Hanada M, Reed JC. Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res. 1994;54:3131\u20133135.","journal-title":"Cancer Res"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90412-3"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3300640"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8023160"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.7.3534"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/0039-128X(96)00031-1"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1161\/hyp.31.1.493"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.91.11.2703"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1006\/excr.1995.1156"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)53100-8"}],"container-title":["Hypertension"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/01.HYP.35.1.237","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T19:44:20Z","timestamp":1743363860000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/01.HYP.35.1.237"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,1]]},"references-count":46,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2000,1]]}},"alternative-id":["10.1161\/01.HYP.35.1.237"],"URL":"https:\/\/doi.org\/10.1161\/01.hyp.35.1.237","relation":{},"ISSN":["0194-911X","1524-4563"],"issn-type":[{"value":"0194-911X","type":"print"},{"value":"1524-4563","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,1]]},"assertion":[{"value":"1999-09-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"1999-10-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2000-01-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}