{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T07:34:35Z","timestamp":1785483275952,"version":"3.56.0"},"reference-count":65,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"22","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Concentric and eccentric cardiac hypertrophy are associated with pressure and volume overload, respectively, in cardiovascular disease both conferring an increased risk of heart failure. These contrasting forms of hypertrophy are characterized by asymmetrical growth of the cardiac myocyte in mainly width or length, respectively. The molecular mechanisms determining myocyte preferential growth in width versus length remain poorly understood. Identification of the mechanisms governing asymmetrical myocyte growth could provide new therapeutic targets for the prevention or treatment of heart failure.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Primary adult rat ventricular myocytes, adeno-associated virus (AAV)\u2013mediated gene delivery in mice, and human tissue samples were used to define a regulatory pathway controlling pathological myocyte hypertrophy. Chromatin immunoprecipitation assays with sequencing and precision nuclear run-on sequencing were used to define a transcriptional mechanism.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              We report that asymmetrical cardiac myocyte hypertrophy is modulated by SRF (serum response factor) phosphorylation, constituting an epigenomic switch balancing the growth in width versus length of adult ventricular myocytes in vitro and in vivo. SRF Ser\n              <jats:sup>103<\/jats:sup>\n              phosphorylation is bidirectionally regulated by RSK3 (p90 ribosomal S6 kinase type 3) and PP2A (protein phosphatase 2A) at signalosomes organized by the scaffold protein mAKAP\u03b2 (muscle A-kinase anchoring protein \u03b2), such that increased SRF phosphorylation activates AP-1 (activator protein-1)-dependent enhancers that direct myocyte growth in width. AAV are used to express in vivo mAKAP\u03b2-derived RSK3 and PP2A anchoring disruptor peptides that block the association of the enzymes with the mAKAP\u03b2 scaffold. Inhibition of RSK3 signaling prevents concentric cardiac remodeling induced by pressure overload, while inhibition of PP2A signaling prevents eccentric cardiac remodeling induced by myocardial infarction, in each case improving cardiac function. SRF Ser\n              <jats:sup>103<\/jats:sup>\n              phosphorylation is significantly decreased in dilated human hearts, supporting the notion that modulation of the mAKAP\u03b2-SRF signalosome could be a new therapeutic approach for human heart failure.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>We have identified a new molecular switch, namely mAKAP\u03b2 signalosome\u2013regulated SRF phosphorylation, that controls a transcriptional program responsible for modulating changes in cardiac myocyte morphology that occur secondary to pathological stressors. Complementary AAV-based gene therapies constitute rationally-designed strategies for a new translational modality for heart failure.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.119.044805","type":"journal-article","created":{"date-parts":[[2020,9,16]],"date-time":"2020-09-16T09:00:17Z","timestamp":1600246817000},"page":"2138-2154","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":42,"title":["Signalosome-Regulated Serum Response Factor Phosphorylation Determining Myocyte Growth in Width Versus Length as a Therapeutic Target for Heart Failure"],"prefix":"10.1161","volume":"142","author":[{"given":"Jinliang","family":"Li","sequence":"first","affiliation":[{"name":"Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA (J.L., Xueyi Li, Y. L., Q.Y., H.T., M.S.K.)."},{"name":"Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (J.L., C.L.P., E.C.M., M.D.K., Xiaofeng Li, H.T., M.S.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuliang","family":"Tan","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, CA (Y.T., K.O., M.G.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine L.","family":"Passariello","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (J.L., C.L.P., E.C.M., M.D.K., Xiaofeng Li, H.T., M.S.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliana C.","family":"Martinez","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (J.L., C.L.P., E.C.M., M.D.K., Xiaofeng Li, H.T., M.S.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Kritzer","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (J.L., C.L.P., E.C.M., M.D.K., Xiaofeng Li, H.T., M.S.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueyi","family":"Li","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA (J.L., Xueyi Li, Y. L., Q.Y., H.T., M.S.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Li","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (J.L., C.L.P., E.C.M., M.D.K., Xiaofeng Li, H.T., M.S.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA (J.L., Xueyi Li, Y. L., Q.Y., H.T., M.S.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Yu","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA (J.L., Xueyi Li, Y. L., Q.Y., H.T., M.S.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Ohgi","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, CA (Y.T., K.O., M.G.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hrishikesh","family":"Thakur","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA (J.L., Xueyi Li, Y. L., Q.Y., H.T., M.S.K.)."},{"name":"Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. 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