{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T23:09:58Z","timestamp":1767913798288,"version":"3.49.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2014,12,5]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale<\/jats:underline>\n              :\n            <\/jats:title>\n            <jats:p>G protein\u2013coupled receptor kinases (GRKs) acting in the cardiomyocyte regulate important signaling events that control cardiac function. Both GRK2 and GRK5, the predominant GRKs expressed in the heart, have been shown to be upregulated in failing human myocardium. Although the canonical role of GRKs is to desensitize G protein\u2013coupled receptors via phosphorylation, it has been demonstrated that GRK5, unlike GRK2, can reside in the nucleus of myocytes and exert G protein\u2013coupled receptor\u2013independent effects that promote maladaptive cardiac hypertrophy and heart failure.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective<\/jats:underline>\n              :\n            <\/jats:title>\n            <jats:p>To explore novel mechanisms by which GRK5 acting in the nucleus of cardiomyocytes participates in pathological cardiac hypertrophy.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results<\/jats:underline>\n              :\n            <\/jats:title>\n            <jats:p>In this study, we have found that GRK5-mediated pathological cardiac hypertrophy involves the activation of the nuclear factor of activated T cells (NFAT) because GRK5 causes enhancement of NFAT-mediated hypertrophic gene transcription. Transgenic mice with cardiomyocyte-specific GRK5 overexpression activate an NFAT-reporter in mice basally and after hypertrophic stimulation, including transverse aortic constriction and phenylephrine treatment. Complimentary to this, GRK5 null mice exhibit less NFAT transcriptional activity after transverse aortic constriction. Furthermore, the loss of NFATc3 expression in the heart protected GRK5 overexpressing transgenic mice from the exaggerated hypertrophy and early progression to heart failure seen after transverse aortic constriction. Molecular studies suggest that GRK5 acts in concert with NFAT to increase hypertrophic gene transcription in the nucleus via GRK5\u2019s ability to bind DNA directly without a phosphorylation event.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions<\/jats:underline>\n              :\n            <\/jats:title>\n            <jats:p>GRK5, acting in a kinase independent manner, is a facilitator of NFAT activity and part of a DNA-binding complex responsible for pathological hypertrophic gene transcription.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.116.304475","type":"journal-article","created":{"date-parts":[[2014,10,21]],"date-time":"2014-10-21T06:45:51Z","timestamp":1413873951000},"page":"976-985","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":74,"title":["GRK5-Mediated Exacerbation of Pathological Cardiac Hypertrophy Involves Facilitation of Nuclear NFAT Activity"],"prefix":"10.1161","volume":"115","author":[{"given":"Jonathan E.","family":"Hullmann","sequence":"first","affiliation":[{"name":"From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, PA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurel A.","family":"Grisanti","sequence":"additional","affiliation":[{"name":"From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, PA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine A.","family":"Makarewich","sequence":"additional","affiliation":[{"name":"From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, PA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erhe","family":"Gao","sequence":"additional","affiliation":[{"name":"From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, PA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica I.","family":"Gold","sequence":"additional","affiliation":[{"name":"From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, PA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Kurt","family":"Chuprun","sequence":"additional","affiliation":[{"name":"From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, PA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas G.","family":"Tilley","sequence":"additional","affiliation":[{"name":"From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, PA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven R.","family":"Houser","sequence":"additional","affiliation":[{"name":"From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, PA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter J.","family":"Koch","sequence":"additional","affiliation":[{"name":"From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, 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