{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T15:47:18Z","timestamp":1791215238470,"version":"4.1.0"},"reference-count":44,"publisher":"National Academy of Sciences","issue":"18","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,4,30]]},"abstract":"<jats:p>\n                    Extracellular signal-regulated kinases 1 and 2 (ERK1\/2) are central mediators of cardiac hypertrophy and are discussed as potential therapeutic targets. However, direct inhibition of ERK1\/2 leads to exacerbated cardiomyocyte death and impaired heart function. We have previously identified ERK\n                    <jats:sup>Thr188<\/jats:sup>\n                    autophosphorylation as a regulatory phosphorylation of ERK1\/2 that is a key factor in cardiac hypertrophy. Here, we investigated whether interference with ERK\n                    <jats:sup>Thr188<\/jats:sup>\n                    phosphorylation permits the impairment of ERK1\/2-mediated cardiac hypertrophy without increasing cardiomyocyte death. The impact of ERK\n                    <jats:sup>Thr188<\/jats:sup>\n                    phosphorylation on cardiomyocyte hypertrophy and cell survival was analyzed in isolated cells and in mice using the mutant ERK2\n                    <jats:sup>T188A<\/jats:sup>\n                    , which is dominant-negative for ERK\n                    <jats:sup>Thr188<\/jats:sup>\n                    signaling. ERK2\n                    <jats:sup>T188A<\/jats:sup>\n                    efficiently attenuated cardiomyocyte hypertrophic responses to phenylephrine and to chronic pressure overload, but it affected neither antiapoptotic ERK1\/2 signaling nor overall physiological cardiac function. In contrast to its inhibition of pathological hypertrophy, ERK2\n                    <jats:sup>T188A<\/jats:sup>\n                    did not interfere with physiological cardiac growth occurring with age or upon voluntary exercise. A preferential role of ERK\n                    <jats:sup>Thr188<\/jats:sup>\n                    phosphorylation in pathological types of hypertrophy was also seen in patients with aortic valve stenosis: ERK\n                    <jats:sup>Thr188<\/jats:sup>\n                    phosphorylation was increased 8.5 \u00b1 1.3-fold in high-gradient, rapidly progressing cases (\u226540 mmHg gradient), whereas in low-gradient, slowly progressing cases, the increase was not significant. Because interference with ERK\n                    <jats:sup>Thr188<\/jats:sup>\n                    phosphorylation (\n                    <jats:italic>i<\/jats:italic>\n                    ) inhibits pathological hypertrophy and (\n                    <jats:italic>ii<\/jats:italic>\n                    ) does not impair antiapoptotic ERK1\/2 signaling and because ERK\n                    <jats:sup>Thr188<\/jats:sup>\n                    phosphorylation shows strong prevalence for aortic stenosis patients with rapidly progressing course, we conclude that interference with ERK\n                    <jats:sup>Thr188<\/jats:sup>\n                    phosphorylation offers the possibility to selectively address pathological types of cardiac hypertrophy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1221999110","type":"journal-article","created":{"date-parts":[[2013,4,15]],"date-time":"2013-04-15T21:53:08Z","timestamp":1366062788000},"page":"7440-7445","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":84,"title":["Interference with ERK\n                    <sup>Thr188<\/sup>\n                    phosphorylation impairs pathological but not physiological cardiac hypertrophy"],"prefix":"10.1073","volume":"110","author":[{"given":"Catharina","family":"Ruppert","sequence":"first","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of W\u00fcrzburg, 97078 W\u00fcrzburg, Germany;"},{"name":"Comprehensive Heart Failure Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Deiss","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of W\u00fcrzburg, 97078 W\u00fcrzburg, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Comprehensive Heart Failure Center, and"},{"name":"Departments of cInternal Medicine I and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Vidal","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of W\u00fcrzburg, 97078 W\u00fcrzburg, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehmet","family":"Oezkur","sequence":"additional","affiliation":[{"name":"Comprehensive Heart Failure Center, and"},{"name":"Thoracic and Cardiovascular Surgery, University Hospital W\u00fcrzburg, 97080 W\u00fcrzburg, Germany; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armin","family":"Gorski","sequence":"additional","affiliation":[{"name":"Comprehensive Heart Failure Center, and"},{"name":"Thoracic and Cardiovascular Surgery, University Hospital W\u00fcrzburg, 97080 W\u00fcrzburg, Germany; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Weidemann","sequence":"additional","affiliation":[{"name":"Comprehensive Heart Failure Center, and"},{"name":"Departments of cInternal Medicine I and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin J.","family":"Lohse","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of W\u00fcrzburg, 97078 W\u00fcrzburg, Germany;"},{"name":"Comprehensive Heart Failure Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Lorenz","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of W\u00fcrzburg, 97078 W\u00fcrzburg, Germany;"},{"name":"Comprehensive Heart Failure Center, and"},{"name":"Department of Pharmacology and Toxicology, Medical Faculty, Dresden University of Technology, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,4,15]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199005313222203"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1080\/01926230500419421"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00033.2006"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2010.04.005"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2009.11.012"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2009.08.002"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1983"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1104499108"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI34472"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.255695"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0610906104"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000138190.50127.6A"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3500891"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1893"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs249"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.104.073122"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.78.6.954"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00168.2006"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119709"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3373"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.46.27489"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000137836.95625.D4"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2004.11.004"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2009.05088.x"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.02.059"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.613562"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.hco.0000162397.44843.83"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/hc0102.101365"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1272"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2181"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs271"},{"key":"e_1_3_3_32_2","doi-asserted-by":"crossref","unstructured":"CH George D Parthimos NC Silvester A network-oriented perspective on cardiac calcium signaling. 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