{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T06:24:18Z","timestamp":1790922258656,"version":"4.1.0"},"reference-count":38,"publisher":"American Physiological Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2007,6]]},"abstract":"<jats:p> We endeavored to use a basic and well-controlled experimental system to characterize the extent and time sequence of sarco(endo)plasmic reticulum Ca<jats:sup>2+<\/jats:sup>-ATPase (SERCA) involvement in the development of cardiac hypertrophy, including transcription, protein expression, Ca<jats:sup>2+<\/jats:sup> transport, and cytoplasmic Ca<jats:sup>2+<\/jats:sup> signaling. To this end, hypertrophy of neonatal rat cardiac myocytes in culture was obtained after adrenergic activation with phenylephrine (PE). Micrographic assessment of myocyte size, rise of [<jats:sup>14<\/jats:sup>C]phenylalanine incorporation and total protein expression, and increased transcription of atrial natriuretic factor demonstrated unambiguously the occurrence of hypertrophy. An early and prominent feature of hypertrophy was a reduction of the SERCA2 transcript, as determined by RT-PCR with reference to a stable marker such as glyceraldehyde-3-phosphate dehydrogenase. Reduction of Ca<jats:sup>2+<\/jats:sup>-ATPase protein levels and Ca<jats:sup>2+<\/jats:sup> transport activity to \u223c50% of control values followed with some delay, evidently as a consequence of a primary effect on transcription. Cytosolic Ca<jats:sup>2+<\/jats:sup> signaling kinetics, measured with a Ca<jats:sup>2+<\/jats:sup>-sensitive dye after electrical stimuli, were significantly altered in hypertrophic myocytes. However, the effect of PE hypertrophy on cytosolic Ca<jats:sup>2+<\/jats:sup> signaling kinetics was less prominent than observed in myocytes subjected to drastic SERCA2 downregulation with small interfering RNA or inhibition with thapsigargin (10 nM). We conclude that SERCA2 undergoes significant downregulation after hypertrophic stimuli, possibly due to lack of SERCA gene involvement by the hypertrophy transcriptional program. The consequence of SERCA2 downregulation on Ca<jats:sup>2+<\/jats:sup> signaling is partially compensated by alternate Ca<jats:sup>2+<\/jats:sup> transport mechanisms. These alterations may contribute to a gradual onset of functional failure in long-term hypertrophy. <\/jats:p>","DOI":"10.1152\/ajpcell.00441.2006","type":"journal-article","created":{"date-parts":[[2007,2,8]],"date-time":"2007-02-08T01:29:52Z","timestamp":1170898192000},"page":"C2269-C2275","source":"Crossref","is-referenced-by-count":27,"title":["Phenylephrine hypertrophy, Ca<sup>2+<\/sup>-ATPase (SERCA2), and Ca<sup>2+<\/sup> signaling in neonatal rat cardiac myocytes"],"prefix":"10.1152","volume":"292","author":[{"given":"A. M.","family":"Prasad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Sumbilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. I.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. G.","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Inesi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"crossref","unstructured":"Arai M, Alpert NR, MacLennan DH, Barton P, Periasami M. Alterations in sarcoplasmic reticulum gene expression in human heart failure. A possible mechanism for alterations in systolic and diastolic properties of the failing myocardium. Circ Res 72: 463\u2013469, 1993.","DOI":"10.1161\/01.RES.72.2.463"},{"key":"R2","doi-asserted-by":"crossref","unstructured":"Bers DM, Eisner DA, Valdivia HH. Sarcoplasmic reticulum Ca2+ and heart failure: roles of diastolic leak and Ca2+ transport. Circ Res 93: 487\u2013490, 2003.","DOI":"10.1161\/01.RES.0000091871.54907.6B"},{"key":"R3","doi-asserted-by":"crossref","unstructured":"Cavagna M, O'Donnell JM, Sumbilla C, Inesi G, Klein MG. Exogenous Ca2+-ATPase isoform effects on Ca2+ transients of embryonic chicken and neonatal rat cardiac myocytes. J Physiol 528: 53\u201363, 2000.","DOI":"10.1111\/j.1469-7793.2000.00053.x"},{"key":"R4","doi-asserted-by":"crossref","unstructured":"Chien KR. Meeting Koch's postulates for calcium signaling in cardiac hypertrophy. J Clin Invest 105: 1339\u20131342, 2000.","DOI":"10.1172\/JCI10079"},{"key":"R5","doi-asserted-by":"crossref","unstructured":"Del Monte F, Hajjar RJ. Targeting calcium cycling proteins in heart failure through gene transfer. J Physiol 546: 49\u201361, 2003.","DOI":"10.1113\/jphysiol.2002.026732"},{"key":"R6","doi-asserted-by":"crossref","unstructured":"Del Monte F, Williams E, Lebeche D, Schmidt U, Rosenzweig A, Gwathmey JK, Lewandowski ED, Hajjar RJ. Improvement in survival and cardiac metabolism after gene transfer of sarcoplasmic reticulum Ca2+-ATPase in a rat model of heart failure. Circulation 104: 1424\u20131429, 2001.","DOI":"10.1161\/hc3601.095574"},{"key":"R7","doi-asserted-by":"crossref","unstructured":"Deng XF, Rokosh DG, Simpson PC. Autonomous and growth factor-induced hypertrophy in cultured neonatal mouse cardiac myocytes. Comparison with rat. Circ Res 87: 781\u2013788, 2000.","DOI":"10.1161\/01.RES.87.9.781"},{"key":"R8","doi-asserted-by":"crossref","unstructured":"Flesch M, Schwinger RH, Schnabel P, Schiffer F, van Gelder I, Bavendiek U, Sudkamp M, Kuhn-Regnier F, Bohm M. Sarcoplasmic reticulum Ca2+ ATPase and phospholamban mRNA and protein levels in end-stage heart failure due to ischemic or dilated cardiomyopathy. J Mol Med 74: 321\u2013332, 1996.","DOI":"10.1007\/BF00207509"},{"key":"R9","doi-asserted-by":"crossref","unstructured":"Frey N, Olson EN. Cardiac hypertrophy: the good, the bad, and the ugly. Annu Rev Physiol 65: 45\u201379, 2003.","DOI":"10.1146\/annurev.physiol.65.092101.142243"},{"key":"R10","doi-asserted-by":"crossref","unstructured":"Giordano FJ, He H, McDonough P, Meyer M, Sayen MR, Dillmann WH. Adenovirus-mediated gene transfer reconstitutes depressed sarcoplasmic reticulum Ca2+-ATPase levels and shortens prolonged cardiac myocyte Ca2+ transients. Circulation 96: 400\u2013403, 1997.","DOI":"10.1161\/01.CIR.96.2.400"},{"key":"R11","doi-asserted-by":"crossref","unstructured":"Hanford DS, Thuerauf DJ, Murray SF, Glembotski CC. Brain natriuretic peptide is induced by alpha 1-adrenergic agonists as a primary response gene in cultured rat cardiac myocytes. J Biol Chem 269: 26227\u201326233, 1994.","DOI":"10.1016\/S0021-9258(18)47183-9"},{"key":"R12","doi-asserted-by":"crossref","unstructured":"Hardy S, Kitamura M, Harris-Stansil T, Dai Y, Phipps ML. Construction of adenovirus vectors through Cre-lox recombination. J Virol 71: 1842\u20131849, 1997.","DOI":"10.1128\/jvi.71.3.1842-1849.1997"},{"key":"R13","doi-asserted-by":"crossref","unstructured":"Hasenfuss G, Meyer M, Schillinger W, Preuss M, Pieske B, Just H. Calcium handling proteins in the failing human heart. Basic Res Cardiol 92: 87\u201393, 1997.","DOI":"10.1007\/BF00794072"},{"key":"R14","doi-asserted-by":"crossref","unstructured":"Hasenfuss G, Reinecke H, Studer R, Meyer M, Pieske B, Holtz J, Holubarsch C, Posival H, Just H, Drexler H. Relation between myocardial function and expression of sarcoplasmic reticulum Ca2+ ATPase in failing and nonfailing human myocardium. Circ Res 75: 434\u2013442, 1994.","DOI":"10.1161\/01.RES.75.3.434"},{"key":"R15","doi-asserted-by":"crossref","unstructured":"He H, Giordano FJ, Hilal-Dandan R, Choi DJ, Rockman HA, McDonough PM, Bluhm WF, Meyer M, Sayen MR, Swanson E, Dillmann WH. Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation. J Clin Invest 100: 380\u2013389, 1997.","DOI":"10.1172\/JCI119544"},{"key":"R16","doi-asserted-by":"crossref","unstructured":"Inesi G, Lewis D, Sumbilla C, Nandi A, Strock C, Huff KW, Rogers TB, Johns DC, Kessler PD, Ordahl CP. Cell-specific promoter in adenovirus vector for transgenic expression of SERCA1 ATPase in cardiac myocytes. Am J Physiol Cell Physiol 274: C645\u2013C653, 1998.","DOI":"10.1152\/ajpcell.1998.274.3.C645"},{"key":"R17","doi-asserted-by":"crossref","unstructured":"Jeong MY, Kinugawa K, Vinson C, Long CS. AFos dissociates cardiac myocyte hypertrophy and expression of the pathological gene program. Circulation 111: 1645\u20131651, 2005.","DOI":"10.1161\/01.CIR.0000160367.99928.87"},{"key":"R18","doi-asserted-by":"crossref","unstructured":"Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680\u2013685, 1970.","DOI":"10.1038\/227680a0"},{"key":"R19","doi-asserted-by":"crossref","unstructured":"Lehnart SE, Schillinger W, Pieske B, Prestle J, Just H, Hasenfuss G. Sarcoplasmic reticulum proteins in heart failure. Ann NY Acad Sci 853: 220\u2013230, 1998.","DOI":"10.1111\/j.1749-6632.1998.tb08270.x"},{"key":"R20","doi-asserted-by":"crossref","unstructured":"Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 322: 1561\u20131566, 1990.","DOI":"10.1056\/NEJM199005313222203"},{"key":"R21","doi-asserted-by":"crossref","unstructured":"Loukianov E, Ji Y, Grupp IL, Kirkpatrick DL, Baker DL, Loukianova T, Grupp G, Lytton J, Walsh RA, Periasamy M. Enhanced myocardial contractility and increased Ca2+ transport function in transgenic hearts expressing the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+-ATPase. Circ Res 83: 889\u2013897, 1998.","DOI":"10.1161\/01.RES.83.9.889"},{"key":"R22","doi-asserted-by":"crossref","unstructured":"Ma H, Sumbilla CM, Farrance IK, Klein MG, Inesi G. Cell-specific expression of SERCA, the exogenous Ca2+ transport ATPase, in cardiac myocytes. Am J Physiol Cell Physiol 286: C556\u2013C564, 2004.","DOI":"10.1152\/ajpcell.00328.2003"},{"key":"R23","doi-asserted-by":"crossref","unstructured":"Mercadier JJ, Lompre AM, Duc P, Boheler KR, Fraysse JB, Wisnewsky C, Allen PD, Komajda M, Schwartz K. Altered sarcoplasmic reticulum Ca2+ ATPase gene expression in the human ventricle during end-stage heart failure. J Clin Invest 85: 305\u2013309, 1990.","DOI":"10.1172\/JCI114429"},{"key":"R24","doi-asserted-by":"crossref","unstructured":"Meyer M, Schillinger W, Pieske B, Holubarsch C, Heilmann C, Posival H, Kuwajima G, Mikoshiba K, Just H, Hesenfuss G. Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. Circulation 92: 778\u2013784, 1995.","DOI":"10.1161\/01.CIR.92.4.778"},{"key":"R25","doi-asserted-by":"crossref","unstructured":"Miyamoto MI, del Monte F, Schmidt U, DiSalvo TS, Kang ZB, Matsui T, Guerrero JL, Gwathmey JK, Rosenzweig A, Hajjar RJ. Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure. Proc Natl Acad Sci USA 97: 793\u2013798, 2000.","DOI":"10.1073\/pnas.97.2.793"},{"key":"R26","doi-asserted-by":"crossref","unstructured":"Movsesian MA, Karimi M, Green K, Jones LR. Ca2+ transporting ATPase, phospholamban and calsequestrin levels in nonfailing and failing human myocardium. Circulation 90: 653\u2013657, 1994.","DOI":"10.1161\/01.CIR.90.2.653"},{"key":"R27","doi-asserted-by":"crossref","unstructured":"O'Donnell JM, Sumbilla CM, Ma H, Farrance IK, Cavagna M, Klein MG, Inesi G. Tight control of exogenous SERCA expression is required to obtain acceleration of calcium transients with minimal cytotoxic effects in cardiac myocytes. Circ Res 88: 415\u2013421, 2001.","DOI":"10.1161\/01.RES.88.4.415"},{"key":"R28","doi-asserted-by":"crossref","unstructured":"Okayama H, Hamada M, Kawakami H, Ikeda S, Hashida H, Shigematsu Y, Hiwada K. Alterations in expression of sarcoplasmic reticulum gene in Dahl rats during the transition from compensatory myocardial hypertrophy to heart failure. J Hypertens 15:1767\u20131774, 1997.","DOI":"10.1097\/00004872-199715120-00087"},{"key":"R29","doi-asserted-by":"crossref","unstructured":"Pieske B, Maier LS, Schmidt-Schweda S. Sarcoplasmic reticulum Ca2+ load in human heart failure. Basic Res Cardiol 97, Suppl 1: I63\u2013I71, 2002.","DOI":"10.1007\/s003950200032"},{"key":"R30","doi-asserted-by":"crossref","unstructured":"Sadoshima J, Izumo S. The cellular and molecular response of cardiac myocytes to mechanical stress. Annu Rev Physiol 59: 551\u2013571, 1997.","DOI":"10.1146\/annurev.physiol.59.1.551"},{"key":"R31","doi-asserted-by":"crossref","unstructured":"Schultz JJ, Glascock BJ, Witt SA, Nieman ML, Nattamai KJ, Liu LH, Lorenz JN, Shull GE, Kimball TR, Periasamy M. Accelerated onset of heart failure in mice during pressure overload with chronically decreased SERCA2 calcium pump activity. Am J Physiol Heart Circ Physiol 286: H1146\u2013H1153, 2004.","DOI":"10.1152\/ajpheart.00720.2003"},{"key":"R32","doi-asserted-by":"crossref","unstructured":"Schwinger RHG, Bohm M, Schmidt U, Karczewski P, Bavendiek U, Flesch M, Krause EG, Ermann E. Unchanged protein levels of SERCA II and phospholamban but reduced Ca2+ uptake and Ca2+ ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts. Circulation: 92: 3220\u20133228, 1995.","DOI":"10.1161\/01.CIR.92.11.3220"},{"key":"R33","doi-asserted-by":"crossref","unstructured":"Simpson PC. Stimulation of hypertrophy of cultured neonatal rat heart cells through an alpha 1-adrenergic receptor and induction of beating through an alpha 1- and beta 1-adrenergic receptor interaction. Evidence for independent regulation of growth and beating. Circ Res 56: 884\u2013894, 1985.","DOI":"10.1161\/01.RES.56.6.884"},{"key":"R34","doi-asserted-by":"crossref","unstructured":"Simpson P, McGrath A, Savion S. Myocyte hypertrophy in neonatal rat heart cultures and its regulation by serum and by catecholamines. Circ Res 51: 787\u2013801, 1982.","DOI":"10.1161\/01.RES.51.6.787"},{"key":"R35","doi-asserted-by":"crossref","unstructured":"Sumbilla C, Cavagna M, Zhong L, Ma H, Lewis D, Farrance I, Inesi G. Comparison of SERCA1 and SERCA2a expressed in COS-1 cells and cardiac myocytes. Am J Physiol Heart Circ Physiol 277: H2381\u2013H2391, 1999.","DOI":"10.1152\/ajpheart.1999.277.6.H2381"},{"key":"R36","doi-asserted-by":"crossref","unstructured":"Wright G, Singh IS, Hasday JD, Farrance IK, Hall G, Cross AS, Rogers TB. Endotoxin stress-response in cardiomyocytes: NF-\u03baB activation and tumor necrosis factor-\u03b1 expression. Am J Physiol Heart Circ Physiol 282: H872\u2013H879, 2002.","DOI":"10.1152\/ajpheart.00256.2001"},{"key":"R37","doi-asserted-by":"crossref","unstructured":"Yue P, Long CS, Austin R, Chang KC, Simpson PC, Massie BM. Post-infarction heart failure in the rat is associated with distinct alterations in cardiac myocyte molecular phenotype. J Mol Cell Cardiol 30: 1615\u20131630, 1998.","DOI":"10.1006\/jmcc.1998.0727"},{"key":"R38","doi-asserted-by":"crossref","unstructured":"Zheng M, Dilly K, Dos Santos CJ, Li M, Gu Y, Ursitti JA, Chen J, Ross J Jr, Chien KR, Lederer JW, Wang Y. Sarcoplasmic reticulum calcium defect in Ras-induced hypertrophic cardiomyopathy heart. Am J Physiol Heart Circ Physiol 286: H424\u2013H433, 2004.","DOI":"10.1152\/ajpheart.00110.2003"}],"container-title":["American Journal of Physiology-Cell Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.physiology.org\/doi\/pdf\/10.1152\/ajpcell.00441.2006","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T18:02:38Z","timestamp":1718647358000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.physiology.org\/doi\/10.1152\/ajpcell.00441.2006"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,6]]},"references-count":38,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2007,6]]}},"alternative-id":["10.1152\/ajpcell.00441.2006"],"URL":"https:\/\/doi.org\/10.1152\/ajpcell.00441.2006","relation":{},"ISSN":["0363-6143","1522-1563"],"issn-type":[{"value":"0363-6143","type":"print"},{"value":"1522-1563","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,6]]}}}