{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:46:02Z","timestamp":1791326762289,"version":"4.3.1"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2012,1,20]]},"abstract":"\n \n Rationale:<\/jats:underline>\n <\/jats:title>\n \n Phosphorylation of \u03b2\n 2<\/jats:sub>\n -adrenergic receptor (\u03b2\n 2<\/jats:sub>\n AR) by a family of serine\/threonine kinases known as G protein\u2013coupled receptor kinase (GRK) and protein kinase A (PKA) is a critical determinant of cardiac function. Upregulation of G protein\u2013coupled receptor kinase 2 (GRK2) is a well-established causal factor of heart failure, but the underlying mechanism is poorly understood.\n <\/jats:p>\n <\/jats:sec>\n \n \n Objective:<\/jats:underline>\n <\/jats:title>\n \n We sought to determine the relative contribution of PKA- and GRK-mediated phosphorylation of \u03b2\n 2<\/jats:sub>\n AR to the receptor coupling to G\n i<\/jats:sub>\n signaling that attenuates cardiac reserve and contributes to the pathogenesis of heart failure in response to pressure overload.\n <\/jats:p>\n <\/jats:sec>\n \n \n Methods and Results:<\/jats:underline>\n <\/jats:title>\n \n Overexpression of GRK2 led to a G\n i<\/jats:sub>\n -dependent decrease of contractile response to \u03b2AR stimulation in cultured mouse cardiomyocytes and in vivo. Importantly, cardiac-specific transgenic overexpression of a mutant \u03b2\n 2<\/jats:sub>\n AR lacking PKA phosphorylation sites (PKA-TG) but not the wild-type \u03b2\n 2<\/jats:sub>\n AR (WT-TG) or a mutant \u03b2\n 2<\/jats:sub>\n AR lacking GRK sites (GRK-TG) led to exaggerated cardiac response to pressure overload, as manifested by markedly exacerbated cardiac maladaptive remodeling and failure and early mortality. Furthermore, inhibition of G\n i<\/jats:sub>\n signaling with pertussis toxin restores cardiac function in heart failure associated with increased \u03b2\n 2<\/jats:sub>\n AR to G\n i<\/jats:sub>\n coupling induced by removing PKA phosphorylation of the receptor and in GRK2 transgenic mice, indicating that enhanced phosphorylation of \u03b2\n 2<\/jats:sub>\n AR by GRK and resultant increase in G\n i<\/jats:sub>\n -biased \u03b2\n 2<\/jats:sub>\n AR signaling play an important role in the development of heart failure.\n <\/jats:p>\n <\/jats:sec>\n \n \n Conclusions:<\/jats:underline>\n <\/jats:title>\n \n Our data show that enhanced \u03b2\n 2<\/jats:sub>\n AR phosphorylation by GRK, in addition to PKA, leads the receptor to G\n i<\/jats:sub>\n -biased signaling, which, in turn, contributes to the pathogenesis of heart failure, marking G\n i<\/jats:sub>\n -biased \u03b2\n 2<\/jats:sub>\n AR signaling as a primary event linking upregulation of GRK to cardiac maladaptive remodeling, failure and cardiodepression.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circresaha.111.253260","type":"journal-article","created":{"date-parts":[[2011,12,16]],"date-time":"2011-12-16T01:53:04Z","timestamp":1324000384000},"page":"265-274","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":71,"title":["G\n i<\/sub>\n -Biased \u03b2\n 2<\/sub>\n AR Signaling Links GRK2 Upregulation to Heart Failure"],"prefix":"10.1161","volume":"110","author":[{"given":"Weizhong","family":"Zhu","sequence":"first","affiliation":[{"name":"From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (W.Z., N.P., A.Z., K.C., M.T., E.G.L., R.-P.X.); Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (W.Z., E.G., J.K.C., W.J.K.); the Department of Anesthesiology, Division of Molecular Medicine, University of California, Los Angeles, CA (S.R., Y.W.); the Department of Internal Medicine, Washington University School of Medicine, St Louis, MO (G.W.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Petrashevskaya","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (W.Z., N.P., A.Z., K.C., M.T., E.G.L., R.-P.X.); Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (W.Z., E.G., J.K.C., W.J.K.); the Department of Anesthesiology, Division of Molecular Medicine, University of California, Los Angeles, CA (S.R., Y.W.); the Department of Internal Medicine, Washington University School of Medicine, St Louis, MO (G.W.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuxun","family":"Ren","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (W.Z., N.P., A.Z., K.C., M.T., E.G.L., R.-P.X.); Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (W.Z., E.G., J.K.C., W.J.K.); the Department of Anesthesiology, Division of Molecular Medicine, University of California, Los Angeles, CA (S.R., Y.W.); the Department of Internal Medicine, Washington University School of Medicine, St Louis, MO (G.W.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aizhi","family":"Zhao","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (W.Z., N.P., A.Z., K.C., M.T., E.G.L., R.-P.X.); Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (W.Z., E.G., J.K.C., W.J.K.); the Department of Anesthesiology, Division of Molecular Medicine, University of California, Los Angeles, CA (S.R., Y.W.); the Department of Internal Medicine, Washington University School of Medicine, St Louis, MO (G.W.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid","family":"Chakir","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (W.Z., N.P., A.Z., K.C., M.T., E.G.L., R.-P.X.); Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (W.Z., E.G., J.K.C., W.J.K.); the Department of Anesthesiology, Division of Molecular Medicine, University of California, Los Angeles, CA (S.R., Y.W.); the Department of Internal Medicine, Washington University School of Medicine, St Louis, MO (G.W.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erhe","family":"Gao","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (W.Z., N.P., A.Z., K.C., M.T., E.G.L., R.-P.X.); Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (W.Z., E.G., J.K.C., W.J.K.); the Department of Anesthesiology, Division of Molecular Medicine, University of California, Los Angeles, CA (S.R., Y.W.); the Department of Internal Medicine, Washington University School of Medicine, St Louis, MO (G.W.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Kurt","family":"Chuprun","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (W.Z., N.P., A.Z., K.C., M.T., E.G.L., R.-P.X.); Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (W.Z., E.G., J.K.C., W.J.K.); the Department of Anesthesiology, Division of Molecular Medicine, University of California, Los Angeles, CA (S.R., Y.W.); the Department of Internal Medicine, Washington University School of Medicine, St Louis, MO (G.W.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibin","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (W.Z., N.P., A.Z., K.C., M.T., E.G.L., R.-P.X.); Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (W.Z., E.G., J.K.C., W.J.K.); the Department of Anesthesiology, Division of Molecular Medicine, University of California, Los Angeles, CA (S.R., Y.W.); the Department of Internal Medicine, Washington University School of Medicine, St Louis, MO (G.W.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Talan","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (W.Z., N.P., A.Z., K.C., M.T., E.G.L., R.-P.X.); Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (W.Z., E.G., J.K.C., W.J.K.); the Department of Anesthesiology, Division of Molecular Medicine, University of California, Los Angeles, CA (S.R., Y.W.); the Department of Internal Medicine, Washington University School of Medicine, St Louis, MO (G.W.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"II","given":"Gerald W.","family":"Dorn","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (W.Z., N.P., A.Z., K.C., M.T., E.G.L., R.-P.X.); Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (W.Z., E.G., J.K.C., W.J.K.); the Department of Anesthesiology, Division of Molecular Medicine, University of California, Los Angeles, CA (S.R., Y.W.); the Department of Internal Medicine, Washington University School of Medicine, St Louis, MO (G.W.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward G.","family":"Lakatta","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (W.Z., N.P., A.Z., K.C., M.T., E.G.L., R.-P.X.); Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (W.Z., E.G., J.K.C., W.J.K.); the Department of Anesthesiology, Division of Molecular Medicine, University of California, Los Angeles, CA (S.R., Y.W.); the Department of Internal Medicine, Washington University School of Medicine, St Louis, MO (G.W.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter J","family":"Koch","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (W.Z., N.P., A.Z., K.C., M.T., E.G.L., R.-P.X.); Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (W.Z., E.G., J.K.C., W.J.K.); the Department of Anesthesiology, Division of Molecular Medicine, University of California, Los Angeles, CA (S.R., Y.W.); the Department of Internal Medicine, Washington University School of Medicine, St Louis, MO (G.W.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur M.","family":"Feldman","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (W.Z., N.P., A.Z., K.C., M.T., E.G.L., R.-P.X.); Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (W.Z., E.G., J.K.C., W.J.K.); the Department of Anesthesiology, Division of Molecular Medicine, University of California, Los Angeles, CA (S.R., Y.W.); the Department of Internal Medicine, Washington University School of Medicine, St Louis, MO (G.W.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui-Ping","family":"Xiao","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (W.Z., N.P., A.Z., K.C., M.T., E.G.L., R.-P.X.); Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (W.Z., E.G., J.K.C., W.J.K.); the Department of Anesthesiology, Division of Molecular Medicine, University of California, Los Angeles, CA (S.R., Y.W.); the Department of Internal Medicine, Washington University School of Medicine, St Louis, MO (G.W.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.192666"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.107.728840"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.12.7059"},{"key":"e_1_3_5_5_2","first-page":"H585","article-title":"Cardiomyopathy induced by cardiac Gs alpha overexpression","volume":"272","author":"Iwase M","year":"1997","unstructured":"Iwase M, Uechi M, Vatner DE, Asai K, Shannon RP, Kudej RK, Wagner TE, Wight DC, Patrick TA, Ishikawa Y, Homcy CJ, Vatner SF . 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