{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:42:35Z","timestamp":1790664155812,"version":"4.1.0"},"reference-count":69,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,5,26]],"date-time":"2017-05-26T00:00:00Z","timestamp":1495756800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,5,26]],"date-time":"2017-05-26T00:00:00Z","timestamp":1495756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Noonan syndrome (NS) is caused by mutations in RAS\/ERK pathway genes, and is characterized by craniofacial, growth, cognitive and cardiac defects. NS patients with kinase-activating\n                    <jats:italic>RAF1<\/jats:italic>\n                    alleles typically develop pathological left ventricular hypertrophy (LVH), which is reproduced in\n                    <jats:italic>Raf1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>L613V\/+<\/jats:italic>\n                    <\/jats:sup>\n                    knock-in mice. Here, using inducible\n                    <jats:italic>Raf1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>L613V<\/jats:italic>\n                    <\/jats:sup>\n                    expression, we show that LVH results from the interplay of cardiac cell types. Cardiomyocyte\n                    <jats:italic>Raf1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>L613V<\/jats:italic>\n                    <\/jats:sup>\n                    enhances Ca\n                    <jats:sup>2+<\/jats:sup>\n                    sensitivity and cardiac contractility without causing hypertrophy.\n                    <jats:italic>Raf1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>L613V<\/jats:italic>\n                    <\/jats:sup>\n                    expression in cardiomyocytes or activated fibroblasts exacerbates pressure overload-evoked fibrosis. Endothelial\/endocardial (EC)\n                    <jats:italic>Raf1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>L613V<\/jats:italic>\n                    <\/jats:sup>\n                    causes cardiac hypertrophy without affecting contractility. Co-culture and neutralizing antibody experiments reveal a cytokine (TNF\/IL6) hierarchy in\n                    <jats:italic>Raf1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>L613V<\/jats:italic>\n                    <\/jats:sup>\n                    -expressing ECs that drives cardiomyocyte hypertrophy\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Furthermore, postnatal TNF inhibition normalizes the increased wall thickness and cardiomyocyte hypertrophy\n                    <jats:italic>in vivo<\/jats:italic>\n                    . We conclude that NS-cardiomyopathy involves cardiomyocytes, ECs and fibroblasts, TNF\/IL6 signalling components represent potential therapeutic targets, and abnormal EC signalling might contribute to other forms of LVH.\n                  <\/jats:p>","DOI":"10.1038\/ncomms15518","type":"journal-article","created":{"date-parts":[[2017,5,26]],"date-time":"2017-05-26T06:21:08Z","timestamp":1495779668000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Cellular interplay via cytokine hierarchy causes pathological cardiac hypertrophy in RAF1-mutant Noonan syndrome"],"prefix":"10.1038","volume":"8","author":[{"given":"Jiani C.","family":"Yin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathew J.","family":"Platt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xixi","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter H.","family":"Backx","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy A.","family":"Simpson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiyuki","family":"Araki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin G.","family":"Neel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,5,26]]},"reference":[{"key":"BFncomms15518_CR1","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1016\/S0140-6736(12)60397-3","volume":"381","author":"BJ Maron","year":"2013","unstructured":"Maron, B. J. & Maron, M. S. Hypertrophic cardiomyopathy. Lancet 381, 242\u2013255 (2013).","journal-title":"Lancet"},{"key":"BFncomms15518_CR2","first-page":"1308","volume":"287","author":"BJ Maron","year":"2002","unstructured":"Maron, B. J. Hypertrophic cardiomyopathy: a systemic review. JAMA 287, 1308\u20131320 (2002).","journal-title":"JAMA"},{"key":"BFncomms15518_CR3","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1038\/nrcardio.2011.159","volume":"9","author":"N Frey","year":"2011","unstructured":"Frey, N., Luedde, M. & Katus, H. A. Mechanisms of disease: hypertrophic cardiomyopathy. Nat. Rev. Cardiol. 9, 91\u2013100 (2011).","journal-title":"Nat. Rev. Cardiol."},{"key":"BFncomms15518_CR4","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1161\/CIRCULATIONAHA.108.845792","volume":"123","author":"MH Drazner","year":"2011","unstructured":"Drazner, M. H. The progression of hypertensive heart disease. Circulation 123, 327\u2013334 (2011).","journal-title":"Circulation"},{"key":"BFncomms15518_CR5","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1016\/S0092-8674(01)00242-2","volume":"104","author":"JG Seidman","year":"2001","unstructured":"Seidman, J. G. & Seidman, C. The genetic basis for cardiomyopathy. Cell 104, 557\u2013567 (2001).","journal-title":"Cell"},{"key":"BFncomms15518_CR6","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/j.amjmed.2014.10.054","volume":"128","author":"F Rader","year":"2015","unstructured":"Rader, F., Sachdev, E., Arsanjani, R. & Siegel, R. J. Left ventricular hypertrophy in valvular aortic stenosis: mechanisms and clinical implications. Am. J. Med. 128, 344\u2013352 (2015).","journal-title":"Am. J. Med."},{"key":"BFncomms15518_CR7","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1111\/j.1540-8167.2007.00965.x","volume":"19","author":"R Alcalai","year":"2008","unstructured":"Alcalai, R., Seidman, J. G. & Seidman, C. E. Genetic basis of hypertrophic cardiomyopathy: from bench to the clinics. J. Cardiovasc. Electrophysiol. 19, 104\u2013110 (2008).","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"BFncomms15518_CR8","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.phrs.2009.11.012","volume":"61","author":"A Rohini","year":"2010","unstructured":"Rohini, A., Agrawal, N., Koyani, C. N. & Singh, R. Molecular targets and regulators of cardiac hypertrophy. Pharmacol. Res. 61, 269\u2013280 (2010).","journal-title":"Pharmacol. Res."},{"key":"BFncomms15518_CR9","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1038\/nrm1983","volume":"7","author":"J Heineke","year":"2006","unstructured":"Heineke, J. & Molkentin, J. D. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat. Rev. Mol. Cell Biol. 7, 589\u2013600 (2006).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"BFncomms15518_CR10","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1172\/JCI24178","volume":"115","author":"GW Dorn 2nd","year":"2005","unstructured":"Dorn, G. W. 2nd, Force, T. & Ii, G. W. D. Protein kinase cascades in the regulation of cardiac hypertrophy. J. Clin. Invest. 115, 527\u2013537 (2005).","journal-title":"J. Clin. Invest."},{"key":"BFncomms15518_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2119\/molmed.2011.00512","volume":"18","author":"V Sala","year":"2012","unstructured":"Sala, V. & Gallo, S. Signaling to cardiac hypertrophy: insights from human and mouse RASopathies. Mol. Med. 18, 1 (2012).","journal-title":"Mol. Med."},{"key":"BFncomms15518_CR12","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1016\/j.gde.2009.04.001","volume":"19","author":"WE Tidyman","year":"2009","unstructured":"Tidyman, W. E. & Rauen, K. A. The RASopathies: developmental syndromes of Ras\/MAPK pathway dysregulation. Curr. Opin. Genet. Dev. 19, 230\u2013236 (2009).","journal-title":"Curr. Opin. Genet. Dev."},{"key":"BFncomms15518_CR13","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1146\/annurev-genom-091212-153523","volume":"14","author":"KA Rauen","year":"2013","unstructured":"Rauen, K. A. The RASopathies. Annu. Rev. Genomics Hum. Genet. 14, 355\u2013369 (2013).","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"BFncomms15518_CR14","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1172\/JCI46399","volume":"121","author":"BD Gelb","year":"2011","unstructured":"Gelb, B. D. & Tartaglia, M. RAS signaling pathway mutations and hypertrophic cardiomyopathy: getting into and out of the thick of it. J. Clin. Invest. 121, 844\u2013847 (2011).","journal-title":"J. Clin. Invest."},{"key":"BFncomms15518_CR15","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/ng.497","volume":"42","author":"IC Cirstea","year":"2009","unstructured":"Cirstea, I. C. et al. A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat. Genet. 42, 27\u201329 (2009).","journal-title":"Nat. Genet."},{"key":"BFncomms15518_CR16","doi-asserted-by":"publisher","first-page":"4315","DOI":"10.1093\/hmg\/ddu148","volume":"23","author":"E Flex","year":"2014","unstructured":"Flex, E. et al. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis. Hum. Mol. Genet. 23, 4315\u20134327 (2014).","journal-title":"Hum. Mol. Genet."},{"key":"BFncomms15518_CR17","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1038\/ng.425","volume":"41","author":"V Cordeddu","year":"2009","unstructured":"Cordeddu, V. et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat. Genet. 41, 1022\u20131026 (2009).","journal-title":"Nat. Genet."},{"key":"BFncomms15518_CR18","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1136\/jmedgenet-2015-103018","volume":"52","author":"GL Yamamoto","year":"2015","unstructured":"Yamamoto, G. L. et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J. Med. Genet. 52, 413\u2013421 (2015).","journal-title":"J. Med. Genet."},{"key":"BFncomms15518_CR19","doi-asserted-by":"publisher","first-page":"11473","DOI":"10.1073\/pnas.1324128111","volume":"111","author":"P-C Chen","year":"2014","unstructured":"Chen, P.-C. et al. Next-generation sequencing identifies rare variants associated with Noonan syndrome. Proc. Natl Acad. Sci. USA 111, 11473\u201311478 (2014).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms15518_CR20","doi-asserted-by":"publisher","first-page":"2237","DOI":"10.1002\/ajmg.a.37781","volume":"170A","author":"KW Gripp","year":"2016","unstructured":"Gripp, K. W. et al. A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles noonan syndrome with loose anagen hair. Am. J. Med. Genet. 170A, 2237\u20132247 (2016).","journal-title":"Am. J. Med. Genet."},{"key":"BFncomms15518_CR21","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1038\/ng2073","volume":"39","author":"B Pandit","year":"2007","unstructured":"Pandit, B. et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat. Genet. 39, 1007\u20131012 (2007).","journal-title":"Nat. Genet."},{"key":"BFncomms15518_CR22","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1172\/JCI44929","volume":"121","author":"X Wu","year":"2011","unstructured":"Wu, X. et al. MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1L613V mutation. J. Clin. Invest. 121, 1009\u20131025 (2011).","journal-title":"J. Clin. Invest."},{"key":"BFncomms15518_CR23","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1242\/dev.125.10.1943","volume":"125","author":"J Chen","year":"1998","unstructured":"Chen, J., Kubalak, S. W. & Chien, K. R. Ventricular muscle-restricted targeting of the RXRalpha gene reveals a non-cell-autonomous requirement in cardiac chamber morphogenesis. Development 125, 1943\u20131949 (1998).","journal-title":"Development"},{"key":"BFncomms15518_CR24","doi-asserted-by":"publisher","first-page":"2362","DOI":"10.1101\/gad.1124803","volume":"17","author":"K Jiao","year":"2003","unstructured":"Jiao, K. et al. An essential role of Bmp4 in the atrioventricular septation of the mouse heart service an essential role of Bmp4 in the atrioventricular septation of the mouse heart. Genes Dev. 17, 2362\u20132367 (2003).","journal-title":"Genes Dev."},{"key":"BFncomms15518_CR25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1085\/jgp.105.1.1","volume":"105","author":"PH Backx","year":"1995","unstructured":"Backx, P. H., Gao, W. D., Azan-Backx, M. D. & Marban, E. The relationship between contractile force and intracellular [Ca2+] in intact rat cardiac trabeculae. J. Gen. Physiol. 105, 1\u201319 (1995).","journal-title":"J. Gen. Physiol."},{"key":"BFncomms15518_CR26","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1111\/j.1469-7793.1998.431bw.x","volume":"506","author":"JC Kentish","year":"1998","unstructured":"Kentish, J. C. & Wrzosek, A. Changes in force and cytosolic Ca2+ concentration after length changes in isolated rat ventricular trabeculae. J. Physiol. 506, 431\u2013444 (1998).","journal-title":"J. Physiol."},{"key":"BFncomms15518_CR27","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1172\/JCI0215518","volume":"110","author":"M Iwano","year":"2002","unstructured":"Iwano, M. et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest. 110, 341\u2013350 (2002).","journal-title":"J. Clin. Invest."},{"key":"BFncomms15518_CR28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1172\/JCI74783","volume":"124","author":"T Moore-morris","year":"2014","unstructured":"Moore-morris, T. et al. Resident fibroblast lineages mediate pressure overload\u2014induced cardiac fibrosis. J. Clin. Invest. 124, 1\u201314 (2014).","journal-title":"J. Clin. Invest."},{"key":"BFncomms15518_CR29","doi-asserted-by":"publisher","first-page":"H1363","DOI":"10.1152\/ajpheart.00395.2013","volume":"305","author":"P Kong","year":"2013","unstructured":"Kong, P., Christia, P., Saxena, A., Su, Y. & Frangogiannis, N. G. Lack of specificity of fibroblast-specific protein 1 in cardiac remodeling and fibrosis. Am. J. Physiol. Heart Circ. Physiol. 305, H1363\u2013H1372 (2013).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"BFncomms15518_CR30","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1038\/nm1613","volume":"13","author":"EM Zeisberg","year":"2007","unstructured":"Zeisberg, E. M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat. Med. 13, 952\u2013961 (2007).","journal-title":"Nat. Med."},{"key":"BFncomms15518_CR31","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1152\/physrev.00017.2002","volume":"83","author":"DL Brutsaert","year":"2003","unstructured":"Brutsaert, D. L. Cardiac endothelial-myocardial signaling: its role in cardiac growth, contractile performance, and rhythmicity. Physiol. Rev. 83, 59\u2013115 (2003).","journal-title":"Physiol. Rev."},{"key":"BFncomms15518_CR32","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1002\/jlb.56.1.27","volume":"56","author":"CL Newell","year":"1994","unstructured":"Newell, C. L., Deisseroth, A. B. & Lopezberestein, G. Interaction of nuclear proteins with an Ap-1 Cre-like promoter sequence in the human Tnf-alpha gene. J. Leukoc. Biol. 56, 27\u201335 (1994).","journal-title":"J. Leukoc. Biol."},{"key":"BFncomms15518_CR33","doi-asserted-by":"publisher","first-page":"6577","DOI":"10.1074\/jbc.270.12.6577","volume":"270","author":"B Kramer","year":"1995","unstructured":"Kramer, B., Wiegmann, K. & Kronke, M. Regulation of the human TNF promoter by the transcription factor Ets. J. Biol. Chem. 270, 6577\u20136583 (1995).","journal-title":"J. Biol. Chem."},{"key":"BFncomms15518_CR34","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1146\/annurev.immunol.19.1.163","volume":"19","author":"M Feldmann","year":"2001","unstructured":"Feldmann, M. & Maini, R. N. Anti-TNF (alpha) therapy or rheumatoid arthritis: What have we learned? Annu. Rev. Immunol. 19, 163\u2013196 (2001).","journal-title":"Annu. Rev. Immunol."},{"key":"BFncomms15518_CR35","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/nri3661","volume":"14","author":"MF Neurath","year":"2014","unstructured":"Neurath, M. F. Cytokines in inflammatory bowel disease. Nat. Rev. Immunol. 14, 329\u2013342 (2014).","journal-title":"Nat. Rev. Immunol."},{"key":"BFncomms15518_CR36","doi-asserted-by":"publisher","first-page":"23173","DOI":"10.1074\/jbc.270.39.23173","volume":"270","author":"JJ Hunter","year":"1995","unstructured":"Hunter, J. J. et al. Nucleic acids, protein synthesis, and molecular genetics: ventricular expression of a MLC-2v- ras fusion gene induces cardiac hypertrophy and selective diastolic dysfunction in transgenic mice ventricular expression of a MLC-2v- ras fusion gene induces. J. Biol. Chem. 270, 23173\u201323178 (1995).","journal-title":"J. Biol. Chem."},{"key":"BFncomms15518_CR37","doi-asserted-by":"publisher","first-page":"14074","DOI":"10.1073\/pnas.0610906104","volume":"104","author":"NH Purcell","year":"2007","unstructured":"Purcell, N. H. et al. Genetic inhibition of cardiac ERK1\/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo. Proc. Natl Acad. Sci. 104, 14074\u201314079 (2007).","journal-title":"Proc. Natl Acad. Sci."},{"key":"BFncomms15518_CR38","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1161\/01.CIR.0000138190.50127.6A","volume":"110","author":"IS Harris","year":"2004","unstructured":"Harris, I. S. et al. Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload. Circulation 110, 718\u2013723 (2004).","journal-title":"Circulation"},{"key":"BFncomms15518_CR39","doi-asserted-by":"publisher","first-page":"H424","DOI":"10.1152\/ajpheart.00110.2003","volume":"286","author":"M Zheng","year":"2004","unstructured":"Zheng, M. et al. Sarcoplasmic reticulum calcium defect in Ras-induced hypertrophic cardiomyopathy heart. Am. J. Physiol. Heart Circ. Physiol. 286, H424\u2013H433 (2004).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"BFncomms15518_CR40","doi-asserted-by":"publisher","first-page":"6341","DOI":"10.1093\/emboj\/19.23.6341","volume":"19","author":"OF Bueno","year":"2000","unstructured":"Bueno, O. F. et al. The MEK1-ERK1\/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J. 19, 6341\u20136350 (2000).","journal-title":"EMBO J."},{"key":"BFncomms15518_CR41","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1172\/JCI200420317","volume":"114","author":"O Yamaguchi","year":"2004","unstructured":"Yamaguchi, O. et al. Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis J. Clin. Invest. 114, 937\u2013943 (2004).","journal-title":"J. Clin. Invest."},{"key":"BFncomms15518_CR42","doi-asserted-by":"publisher","first-page":"2160","DOI":"10.1073\/pnas.0510876103","volume":"103","author":"P Uhlen","year":"2006","unstructured":"Uhlen, P. et al. Gain-of-function\/Noonan syndrome SHP-2\/Ptpn11 mutants enhance calcium oscillations and impair NFAT signaling. Proc. Natl Acad. Sci. 103, 2160\u20132165 (2006).","journal-title":"Proc. Natl Acad. Sci."},{"key":"BFncomms15518_CR43","doi-asserted-by":"publisher","first-page":"1086","DOI":"10.1152\/ajpheart.00501.2014","volume":"308","author":"SA Clay","year":"2015","unstructured":"Clay, S. A., Domeier, T. L., Hanft, L. M., Mcdonald, K. S. & Krenz, M. Elevated Ca2+ transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines. Am. J. Physiol. Heart Circ. Physiol. 308, 1086\u20131095 (2015).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"BFncomms15518_CR44","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.stemcr.2016.07.018","volume":"7","author":"R Josowitz","year":"2016","unstructured":"Josowitz, R. et al. Autonomous and non-autonomous defects underlie hypertrophic cardiomyopathy in BRAF-mutant hiPSC-derived cardiomyocytes. Stem Cell Rep. 7, 355\u2013369 (2016).","journal-title":"Stem Cell Rep."},{"key":"BFncomms15518_CR45","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.cardiores.2004.12.022","volume":"66","author":"J Layland","year":"2005","unstructured":"Layland, J., Solaro, R. J. & Shah, A. M. Regulation of cardiac contractile function by troponin I phosphorylation. Cardiovasc. Res. 66, 12\u201321 (2005).","journal-title":"Cardiovasc. Res."},{"key":"BFncomms15518_CR46","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1002\/prca.200780076","volume":"2","author":"C Yuan","year":"2008","unstructured":"Yuan, C. & Solaro, R. J. Myofilament proteins: from cardiac disorders to proteomic changes. Proteomics Clin. Appl. 2, 788\u2013799 (2008).","journal-title":"Proteomics Clin. Appl."},{"key":"BFncomms15518_CR47","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1152\/physrev.00012.2007","volume":"87","author":"FG Spinale","year":"2007","unstructured":"Spinale, F. G. Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol. Rev. 87, 1285\u20131342 (2007).","journal-title":"Physiol. Rev."},{"key":"BFncomms15518_CR48","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1161\/01.RES.67.1.23","volume":"67","author":"G Olivetti","year":"1990","unstructured":"Olivetti, G., Capasso, J. M., Sonnenblick, E. H. & Anversa, P. Side-to-Side slippage of myocytes participates in ventricular wall remodeling acutely after myocardial infarction in rats. Circ. Res. 67, 23\u201334 (1990).","journal-title":"Circ. Res."},{"key":"BFncomms15518_CR49","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.amjcard.2004.03.078","volume":"94","author":"M H\u00f6gye","year":"2004","unstructured":"H\u00f6gye, M., M\u00e1ndi, Y., Csan\u00e1dy, M., Sepp, R. & Buz\u00e1s, K. Comparison of circulating levels of interleukin-6 and tumor necrosis factor-alpha in hypertrophic cardiomyopathy and in idiopathic dilated cardiomyopathy. Am. J. Cardiol. 94, 249\u2013251 (2004).","journal-title":"Am. J. Cardiol."},{"key":"BFncomms15518_CR50","doi-asserted-by":"publisher","first-page":"2369","DOI":"10.1006\/jmcc.2000.1267","volume":"32","author":"R Patel","year":"2000","unstructured":"Patel, R. et al. Variants of trophic factors and expression of cardiac hypertrophy in patients with hypertrophic cardiomyopathy. J. Mol. Cell Cardiol. 32, 2369\u20132377 (2000).","journal-title":"J. Mol. Cell Cardiol."},{"key":"BFncomms15518_CR51","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1093\/cvr\/cvs280","volume":"96","author":"M Velten","year":"2012","unstructured":"Velten, M. et al. Priming with synthetic oligonucleotides attenuates pressure overload-induced inflammation and cardiac hypertrophy in mice. Cardiovasc. Res. 96, 422\u2013432 (2012).","journal-title":"Cardiovasc. Res."},{"key":"BFncomms15518_CR52","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1038\/sj.jhh.1001785","volume":"19","author":"LE Bautista","year":"2005","unstructured":"Bautista, L. E., Vera, L. M., Arenas, I. A. & Gamarra, G. Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-alpha) and essential hypertension. J. Hum. Hypertens. 19, 149\u2013154 (2005).","journal-title":"J. Hum. Hypertens."},{"key":"BFncomms15518_CR53","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/sj.jhh.1001845","volume":"19","author":"G V\u00e1zquez-Oliva","year":"2005","unstructured":"V\u00e1zquez-Oliva, G., Fern\u00e1ndez-Real, J. M., Zamora, A., Vilaseca, M. & Badim\u00f3n, L. Lowering of blood pressure leads to decreased circulating interleukin-6 in hypertensive subjects. J. Hum. Hypertens. 19, 457\u2013462 (2005).","journal-title":"J. Hum. Hypertens."},{"key":"BFncomms15518_CR54","doi-asserted-by":"publisher","first-page":"H935","DOI":"10.1152\/ajpheart.00708.2005","volume":"290","author":"DL Lee","year":"2006","unstructured":"Lee, D. L. et al. Angiotensin II hypertension is attenuated in interleukin-6 knockout mice. Am. J. Physiol. Heart Circ. Physiol. 290, H935\u2013H940 (2006).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"BFncomms15518_CR55","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1056\/NEJM199007263230405","volume":"323","author":"B Levine","year":"1990","unstructured":"Levine, B., Kalman, J., Mayer, L., Fillit, H. M. & Packer, M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N. Engl. J. Med. 323, 236\u2013241 (1990).","journal-title":"N. Engl. J. Med."},{"key":"BFncomms15518_CR56","doi-asserted-by":"publisher","first-page":"1594","DOI":"10.1161\/01.CIR.0000124490.27666.B2","volume":"109","author":"DL Mann","year":"2004","unstructured":"Mann, D. L. et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the randomized ethanercept worldwide evaluation (RENEWAL). Circulation 109, 1594\u20131603 (2004).","journal-title":"Circulation"},{"key":"BFncomms15518_CR57","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1097\/RHU.0b013e3181d06f5b","volume":"16","author":"FAC Rocha","year":"2010","unstructured":"Rocha, F. A. C. & Silva, F. S. Reversible heart failure in a patient receiving etanercept for aankylosing spondylitis. J. Clin. Rheumatol. 16, 81\u201382 (2010).","journal-title":"J. Clin. Rheumatol."},{"key":"BFncomms15518_CR58","doi-asserted-by":"publisher","first-page":"3","DOI":"10.4172\/2155-9880.1000236","volume":"4","author":"K Ma","year":"2013","unstructured":"Ma, K., Dormand, H., Neyses, L. & Ma, M. Heart failure with etanercept therapy: a case report. J. Clin. Exp. Cardiol. 4, 3\u20135 (2013).","journal-title":"J. Clin. Exp. Cardiol."},{"key":"BFncomms15518_CR59","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1093\/eurjhf\/hfp132","volume":"11","author":"MY Emmert","year":"2009","unstructured":"Emmert, M. Y. et al. Severe cardiomyopathy following treatment with the tumour necrosis factor- a inhibitor adalimumab for Crohn\u2019 s disease. Eur. J. Heart Fail. 11, 1106\u20131109 (2009).","journal-title":"Eur. J. Heart Fail."},{"key":"BFncomms15518_CR60","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1161\/CIRCRESAHA.111.243899","volume":"110","author":"Y Tian","year":"2012","unstructured":"Tian, Y. & Morrisey, E. E. Importance of myocyte-nonmyocyte interactions in cardiac development and disease. Circ. Res. 110, 1023\u20131034 (2012).","journal-title":"Circ. Res."},{"key":"BFncomms15518_CR61","doi-asserted-by":"publisher","first-page":"535241","DOI":"10.4061\/2011\/535241","volume":"2011","author":"N Takeda","year":"2011","unstructured":"Takeda, N. & Manabe, I. Cellular interplay between cardiomyocytes and nonmyocytes in cardiac remodeling. Int. J. Inflam. 2011, 535241 (2011).","journal-title":"Int. J. Inflam."},{"key":"BFncomms15518_CR62","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1038\/ng1059","volume":"33","author":"AD Gitler","year":"2003","unstructured":"Gitler, A. D. et al. Nf1 has an essential role in endothelial cells. Nat. Genet. 33, 75\u201379 (2003).","journal-title":"Nat. Genet."},{"key":"BFncomms15518_CR63","doi-asserted-by":"publisher","first-page":"4736","DOI":"10.1073\/pnas.0810053106","volume":"106","author":"T Araki","year":"2009","unstructured":"Araki, T. et al. Noonan syndrome cardiac defects are caused by PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformation. Proc. Natl Acad. Sci. USA 106, 4736\u20134741 (2009).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms15518_CR64","doi-asserted-by":"publisher","first-page":"2989","DOI":"10.1172\/JCI80396","volume":"8126","author":"J Lauriol","year":"2016","unstructured":"Lauriol, J. et al. Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines. J. Clin. Invest. 8126, 2989\u20133005 (2016).","journal-title":"J. Clin. Invest."},{"key":"BFncomms15518_CR65","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1172\/JCI44972","volume":"121","author":"TM Marin","year":"2011","unstructured":"Marin, T. M. et al. Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome \u2013 associated PTPN11 mutation. J. Clin. Invest. 121, 1026\u20131043 (2011).","journal-title":"J. Clin. Invest."},{"key":"BFncomms15518_CR66","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1084\/jem.193.6.741","volume":"193","author":"PA Koni","year":"2001","unstructured":"Koni, P. A. et al. Conditional vascular cell adhesion molecule 1 deletion in mice: impaired lymphocyte migration to bone marrow. J. Exp. Med. 193, 741\u2013754 (2001).","journal-title":"J. Exp. Med."},{"key":"BFncomms15518_CR67","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1016\/j.cell.2012.10.023","volume":"151","author":"B Wu","year":"2012","unstructured":"Wu, B. et al. Endocardial cells form the coronary arteries by angiogenesis through myocardial-endocardial VEGF signaling. Cell 151, 1083\u20131096 (2012).","journal-title":"Cell"},{"key":"BFncomms15518_CR68","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1126\/science.1090922","volume":"303","author":"NA Bhowmick","year":"2004","unstructured":"Bhowmick, N. A. et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303, 848\u2013851 (2004).","journal-title":"Science"},{"key":"BFncomms15518_CR69","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1085\/jgp.201010499","volume":"137","author":"NMP King","year":"2010","unstructured":"King, N. M. P. et al. Mouse intact cardiac myocyte mechanics: cross-bridge and titin-based stress in unactivated cells. J. Gen. Physiol. 137, 81\u201391 (2010).","journal-title":"J. Gen. Physiol."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/ncomms15518.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms15518","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/doifinder\/10.1038\/ncomms15518","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms15518.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T06:49:21Z","timestamp":1719211761000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ncomms15518"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,26]]},"references-count":69,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,8,11]]}},"alternative-id":["BFncomms15518"],"URL":"https:\/\/doi.org\/10.1038\/ncomms15518","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/122150","asserted-by":"object"}]},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,5,26]]},"assertion":[{"value":"1 November 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 April 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 May 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"15518"}}