{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T15:58:33Z","timestamp":1791215913894,"version":"4.1.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2012,8,21]]},"abstract":"<jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>In the normal heart, phosphodiesterase type 5 (PDE5) hydrolyzes cGMP coupled to nitric oxide\u2013 (specifically from nitric oxide synthase 3) but not natriuretic peptide (NP)\u2013stimulated guanylyl cyclase. PDE5 is upregulated in hypertrophied and failing hearts and is thought to contribute to their pathophysiology. Because nitric oxide signaling declines whereas NP-derived cGMP rises in such diseases, we hypothesized that PDE5 substrate selectivity is retargeted to blunt NP-derived signaling.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p>\n              Mice with cardiac myocyte inducible PDE5 overexpression (P5\n              <jats:sup>+<\/jats:sup>\n              ) were crossed to those lacking nitric oxide synthase 3 (N3\n              <jats:sup>\u2212<\/jats:sup>\n              ), and each model, the double cross, and controls were subjected to transaortic constriction. P5\n              <jats:sup>+<\/jats:sup>\n              mice developed worse dysfunction and hypertrophy and enhanced NP stimulation, whereas N3\n              <jats:sup>\u2212<\/jats:sup>\n              mice were protected. However, P5\n              <jats:sup>+<\/jats:sup>\n              \/N3\n              <jats:sup>\u2212<\/jats:sup>\n              mice behaved similarly to P5\n              <jats:sup>+<\/jats:sup>\n              mice despite the lack of nitric oxide synthase 3\u2013coupled cGMP generation, with protein kinase G activity suppressed in both models. PDE5 inhibition did not alter atrial natriuretic peptide\u2013stimulated cGMP in the resting heart but augmented it in the transaortic constriction heart. This functional retargeting was associated with PDE5 translocation from sarcomeres to a dispersed distribution. P5\n              <jats:sup>+<\/jats:sup>\n              hearts exhibited higher oxidative stress, whereas P5\n              <jats:sup>+<\/jats:sup>\n              \/N3\n              <jats:sup>\u2212<\/jats:sup>\n              hearts had low levels (likely owing to the absence of nitric oxide synthase 3 uncoupling). This highlights the importance of myocyte protein kinase G activity as a protection for pathological remodeling.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>These data provide the first evidence for functional retargeting of PDE5 from one compartment to another, revealing a role for natriuretic peptide\u2013derived cGMP hydrolysis by this esterase in diseased heart myocardium. Retargeting likely affects the pathophysiological consequence and the therapeutic impact of PDE5 modulation in heart disease.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.112.090977","type":"journal-article","created":{"date-parts":[[2012,7,26]],"date-time":"2012-07-26T00:19:53Z","timestamp":1343261993000},"page":"942-951","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":44,"title":["Pathological Cardiac Hypertrophy Alters Intracellular Targeting of Phosphodiesterase Type 5 From Nitric Oxide Synthase-3 to Natriuretic Peptide Signaling"],"prefix":"10.1161","volume":"126","author":[{"given":"Manling","family":"Zhang","sequence":"first","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (M.Z., E.T., D.-i.L., T.N., S.H., A.J., T.N., D.B., Y.Y., D.A.K.); Cardiovascular Division, King's College London, British Heart Foundation Centre, London, UK (C.X.C.S., A.M.S.); and The Rayne Institute, Kings College London, St. Thomas Hospital, London, UK (P.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiki","family":"Takimoto","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (M.Z., E.T., D.-i.L., T.N., S.H., A.J., T.N., D.B., Y.Y., D.A.K.); Cardiovascular Division, King's College London, British Heart Foundation Centre, London, UK (C.X.C.S., A.M.S.); and The Rayne Institute, Kings College London, St. Thomas Hospital, London, UK (P.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-ik","family":"Lee","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (M.Z., E.T., D.-i.L., T.N., S.H., A.J., T.N., D.B., Y.Y., D.A.K.); Cardiovascular Division, King's College London, British Heart Foundation Centre, London, UK (C.X.C.S., A.M.S.); and The Rayne Institute, Kings College London, St. Thomas Hospital, London, UK (P.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celio X.C.","family":"Santos","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (M.Z., E.T., D.-i.L., T.N., S.H., A.J., T.N., D.B., Y.Y., D.A.K.); Cardiovascular Division, King's College London, British Heart Foundation Centre, London, UK (C.X.C.S., A.M.S.); and The Rayne Institute, Kings College London, St. Thomas Hospital, London, UK (P.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taishi","family":"Nakamura","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (M.Z., E.T., D.-i.L., T.N., S.H., A.J., T.N., D.B., Y.Y., D.A.K.); Cardiovascular Division, King's College London, British Heart Foundation Centre, London, UK (C.X.C.S., A.M.S.); and The Rayne Institute, Kings College London, St. Thomas Hospital, London, UK (P.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Hsu","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (M.Z., E.T., D.-i.L., T.N., S.H., A.J., T.N., D.B., Y.Y., D.A.K.); Cardiovascular Division, King's College London, British Heart Foundation Centre, London, UK (C.X.C.S., A.M.S.); and The Rayne Institute, Kings College London, St. Thomas Hospital, London, UK (P.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiyang","family":"Jiang","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (M.Z., E.T., D.-i.L., T.N., S.H., A.J., T.N., D.B., Y.Y., D.A.K.); Cardiovascular Division, King's College London, British Heart Foundation Centre, London, UK (C.X.C.S., A.M.S.); and The Rayne Institute, Kings College London, St. Thomas Hospital, London, UK (P.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Nagayama","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (M.Z., E.T., D.-i.L., T.N., S.H., A.J., T.N., D.B., Y.Y., D.A.K.); Cardiovascular Division, King's College London, British Heart Foundation Centre, London, UK (C.X.C.S., A.M.S.); and The Rayne Institute, Kings College London, St. Thomas Hospital, London, UK (P.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Djahida","family":"Bedja","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (M.Z., E.T., D.-i.L., T.N., S.H., A.J., T.N., D.B., Y.Y., D.A.K.); Cardiovascular Division, King's College London, British Heart Foundation Centre, London, UK (C.X.C.S., A.M.S.); and The Rayne Institute, Kings College London, St. Thomas Hospital, London, UK (P.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Yuan","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (M.Z., E.T., D.-i.L., T.N., S.H., A.J., T.N., D.B., Y.Y., D.A.K.); Cardiovascular Division, King's College London, British Heart Foundation Centre, London, UK (C.X.C.S., A.M.S.); and The Rayne Institute, Kings College London, St. Thomas Hospital, London, UK (P.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Eaton","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (M.Z., E.T., D.-i.L., T.N., S.H., A.J., T.N., D.B., Y.Y., D.A.K.); Cardiovascular Division, King's College London, British Heart Foundation Centre, London, UK (C.X.C.S., A.M.S.); and The Rayne Institute, Kings College London, St. Thomas Hospital, London, UK (P.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay M.","family":"Shah","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (M.Z., E.T., D.-i.L., T.N., S.H., A.J., T.N., D.B., Y.Y., D.A.K.); Cardiovascular Division, King's College London, British Heart Foundation Centre, London, UK (C.X.C.S., A.M.S.); and The Rayne Institute, Kings College London, St. Thomas Hospital, London, UK (P.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Kass","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (M.Z., E.T., D.-i.L., T.N., S.H., A.J., T.N., D.B., Y.Y., D.A.K.); Cardiovascular Division, King's College London, British Heart Foundation Centre, London, UK (C.X.C.S., A.M.S.); and The Rayne Institute, Kings College London, St. Thomas Hospital, London, UK (P.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.110.002907"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000152262.22968.72"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M404706200"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.906818"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.108.822072"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1175"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2010.08.612"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/circheartfailure.110.944694"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.655266"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/circheartfailure.111.961706"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2007.07.078"},{"key":"e_1_3_3_13_2","unstructured":"Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People With Diastolic Heart Failure (the RELAX study). http:\/\/www.clinicaltrials.gov. Identifier: NCT00763867. Accessed March 28 2012."},{"key":"e_1_3_3_14_2","unstructured":"Revatio for Heart Disease in Duchenne Muscular Dystrophy and Becker Muscular Dystrophy (REVERSE-DBMD). http:\/\/www.clinicaltrials.gov. Identifier: NCT01168908. Accessed March 28 2012."},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2004.09.041"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.626226"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-050410-100030"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2011.09.001"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.106.643536"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.599241"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.108.137422"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.110.230698"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI21968"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.111.259242"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.602532"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(08)01213-5"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2000.278.3.H971"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.00-0538com"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0804738105"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2006.05.008"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2011.08.016"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2009.09.007"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000250046.69918.d5"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.262787199"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.07.030"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-010-0084-5"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2008.08.069"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI17061"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.109.208314"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116887"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00418.2006"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/1071-9164(94)90010-8"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2006.08.066"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.110.226712"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1185988"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0898-6568(03)00092-5"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm958"},{"key":"e_1_3_3_48_2","first-page":"408","article-title":"Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice","volume":"119","author":"Takimoto E","year":"2009","unstructured":"Takimoto E, Koitabashi N, Hsu S, Ketner EA, Zhang M, Nagayama T, Bedja D, Gabrielson KL, Blanton R, Siderovski DP, Mendelsohn ME, Kass DA. Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice. J Clin Invest. 2009;119:408\u2013420.","journal-title":"J Clin Invest"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2011.09.006"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2009.2453"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.2005.033068"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCULATIONAHA.112.090977","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T06:36:21Z","timestamp":1715582181000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.112.090977"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,8,21]]},"references-count":50,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2012,8,21]]}},"alternative-id":["10.1161\/CIRCULATIONAHA.112.090977"],"URL":"https:\/\/doi.org\/10.1161\/circulationaha.112.090977","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,8,21]]},"assertion":[{"value":"2012-01-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2012-06-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2012-07-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}