{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T07:41:48Z","timestamp":1773301308566,"version":"3.50.1"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2009,3,13]]},"abstract":"<jats:p>\n            p66Shc is an adapter protein that is induced by hypertrophic stimuli and has been implicated as a major regulator of reactive oxygen species (ROS) production and cardiovascular oxidative stress responses. This study implicates p66Shc in an \u03b1\n            <jats:sub>1<\/jats:sub>\n            -adrenergtic receptor (\u03b1\n            <jats:sub>1<\/jats:sub>\n            -AR) pathway that requires the cooperative effects of protein kinase (PK)C\u03b5 and PKC\u03b4 and leads to AKT-FOXO3a phosphorylation in cardiomyocytes. \u03b1\n            <jats:sub>1<\/jats:sub>\n            -ARs promote p66Shc-YY\n            <jats:sup>239\/240<\/jats:sup>\n            phosphorylation via a ROS-dependent mechanism that is localized to caveolae and requires epidermal growth factor receptor (EGFR) and PKC\u03b5 activity. \u03b1\n            <jats:sub>1<\/jats:sub>\n            -ARs also increase p66Shc-S\n            <jats:sup>36<\/jats:sup>\n            phosphorylation via an EGFR transactivation pathway involving PKC\u03b4. p66Shc links \u03b1\n            <jats:sub>1<\/jats:sub>\n            -ARs to an AKT signaling pathway that selectively phosphorylates\/inactivates FOXO transcription factors and downregulates the ROS-scavenging protein manganese superoxide dismutase (MnSOD); the \u03b1\n            <jats:sub>1<\/jats:sub>\n            -AR-p66Shc-dependent pathway involving AKT does not regulate GSK3. Additional studies show that RNA interference-mediated downregulation of endogenous p66Shc leads to the derepression of FOXO3a-regulated genes such as MnSOD, p27Kip1, and BIM-1. p66Shc downregulation also increases proliferating cell nuclear antigen expression and induces cardiomyocyte hypertrophy, suggesting that p66Shc exerts an antihypertrophic action in neonatal cardiomyocytes. The novel \u03b1\n            <jats:sub>1<\/jats:sub>\n            -AR- and ROS-dependent pathway involving p66Shc identified in this study is likely to contribute to cardiomyocyte remodeling and the evolution of heart failure.\n          <\/jats:p>","DOI":"10.1161\/circresaha.108.186288","type":"journal-article","created":{"date-parts":[[2009,1,23]],"date-time":"2009-01-23T03:04:40Z","timestamp":1232679880000},"page":"660-669","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":73,"title":["p66Shc Links \u03b1\n            <sub>1<\/sub>\n            -Adrenergic Receptors to a Reactive Oxygen Species-Dependent AKT-FOXO3A Phosphorylation Pathway in Cardiomyocytes"],"prefix":"10.1161","volume":"104","author":[{"given":"Jianfen","family":"Guo","sequence":"first","affiliation":[{"name":"From the Department of Pharmacology, Columbia University, New York."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zoya","family":"Gertsberg","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Columbia University, New York."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nazira","family":"Ozgen","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Columbia University, New York."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan F.","family":"Steinberg","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Columbia University, New York."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.2001.6.1.19"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.86.10.1054"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1492806"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1069004"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M006951200"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.84.9.980"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M212644200"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2005.09.003"},{"key":"e_1_3_3_9_2","first-page":"20194","volume":"281","year":"2006","unstructured":"Obreztchikova M, Elouardighi H, Ho M, Wilson BA, Gertsberg Z, Steinberg SF. 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