{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T11:29:54Z","timestamp":1769858994759,"version":"3.49.0"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,6,8]],"date-time":"2017-06-08T00:00:00Z","timestamp":1496880000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,6,8]],"date-time":"2017-06-08T00:00:00Z","timestamp":1496880000000},"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":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Inhibitor of DNA binding (Id) proteins play important roles in regulating cardiac development via paracrine signaling. Id1\/Id3 knockout mice die at mid-gestation with multiple cardiac defects. Single Id knockout studies have not reported cardiomyopathies. To bypass embryonic lethality we used Tie2CRE-mediated recombination to conditionally delete Id1 against global Id3 ablation (Id cDKOs), which develops adult-onset dilated cardiomyopathy. We confirm upregulation of thrombospondin-1 (TSP1) in Id cDKO hearts. Colocalization studies reveal increased TSP1 expression in the vicinity of endothelial cells and near regions of endocardial fibrosis\/disruption. Downstream fibrotic molecules were upregulated. Endocardial capillary density was reduced with evidence of vascular distention. Treatment of Id cDKO cardiac explants with LSKL, a peptide antagonist of TSP1 activation of TGF\u03b2, reversed the increased expression of fibrotic molecules. We conducted bone marrow transplant experiments in which we transferred bone marrow cells from Id cDKO mice into lethally irradiated WT mice. The majority of WT recipients of Id cDKO bone marrow cells phenocopied Id cDKO cardiac fibrosis 4 months post-transplantation. Injection of LSKL into adult Id cDKO mice led to downregulation of fibrotic molecules. The results prompt caution when bone marrow transfers from individuals potentially carrying mutations in the Id axis are applied in clinical settings.<\/jats:p>","DOI":"10.1038\/s41598-017-03160-7","type":"journal-article","created":{"date-parts":[[2017,6,2]],"date-time":"2017-06-02T11:20:07Z","timestamp":1496402407000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Hematopoietic Id Deletion Triggers Endomyocardial Fibrotic and Vascular Defects in the Adult Heart"],"prefix":"10.1038","volume":"7","author":[{"given":"Corey","family":"Chang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingshi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Patrick","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jung H.","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamal","family":"Alzahrani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominic","family":"Del Re","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diego","family":"Fraidenraich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,6,8]]},"reference":[{"key":"3160_CR1","first-page":"239","volume":"306","author":"KR Chien","year":"2004","unstructured":"Chien, K. R., Moretti, A. & Laugwitz, K. L. Development. ES cells to the rescue. Science \n                           306, 239\u2013240 (2004).","journal-title":"ES cells to the rescue. Science"},{"key":"3160_CR2","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/S0962-8924(03)00147-8","volume":"13","author":"MB Ruzinova","year":"2003","unstructured":"Ruzinova, M. B. & Benezra, R. Id proteins in development, cell cycle and cancer. Trends Cell Biol \n                           13, 410\u2013418 (2003).","journal-title":"Trends Cell Biol"},{"key":"3160_CR3","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1126\/science.1102612","volume":"306","author":"D Fraidenraich","year":"2004","unstructured":"Fraidenraich, D. et al. Rescue of cardiac defects in id knockout embryos by injection of embryonic stem cells. Science \n                           306, 247\u2013252 (2004).","journal-title":"Science"},{"key":"3160_CR4","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.ydbio.2010.10.004","volume":"349","author":"Q Zhao","year":"2011","unstructured":"Zhao, Q. et al. Developmental ablation of Id1 and Id3 genes in the vasculature leads to postnatal cardiac phenotypes. Developmental biology \n                           349, 53\u201364, doi:10.1016\/j.ydbio.2010.10.004 (2011).","journal-title":"Developmental biology"},{"key":"3160_CR5","doi-asserted-by":"publisher","first-page":"e0154480","DOI":"10.1371\/journal.pone.0154480","volume":"11","author":"Q Zhao","year":"2016","unstructured":"Zhao, Q. et al. Combined Id1 and Id3 Deletion Leads to Severe Erythropoietic Disturbances. PloS one \n                           11, e0154480, doi:10.1371\/journal.pone.0154480 (2016).","journal-title":"PloS one"},{"key":"3160_CR6","doi-asserted-by":"publisher","first-page":"2049","DOI":"10.1016\/j.ijcard.2013.01.165","volume":"168","author":"J Gravning","year":"2013","unstructured":"Gravning, J., Ahmed, M. S., von Lueder, T. G., Edvardsen, T. & Attramadal, H. CCN2\/CTGF attenuates myocardial hypertrophy and cardiac dysfunction upon chronic pressure-overload. International journal of cardiology \n                           168, 2049\u20132056, doi:10.1016\/j.ijcard.2013.01.165 (2013).","journal-title":"International journal of cardiology"},{"key":"3160_CR7","doi-asserted-by":"publisher","first-page":"e6743","DOI":"10.1371\/journal.pone.0006743","volume":"4","author":"AN Panek","year":"2009","unstructured":"Panek, A. N. et al. Connective tissue growth factor overexpression in cardiomyocytes promotes cardiac hypertrophy and protection against pressure overload. PloS one \n                           4, e6743, doi:10.1371\/journal.pone.0006743 (2009).","journal-title":"PloS one"},{"key":"3160_CR8","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/S1535-6108(02)00209-X","volume":"2","author":"OV Volpert","year":"2002","unstructured":"Volpert, O. V. et al. Id1 regulates angiogenesis through transcriptional repression of thrombospondin-1. Cancer cell \n                           2, 473\u2013483 (2002).","journal-title":"Cancer cell"},{"key":"3160_CR9","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1007\/BF03401559","volume":"1","author":"J Folkman","year":"1995","unstructured":"Folkman, J. Angiogenesis inhibitors generated by tumors. Mol Med \n                           1, 120\u2013122 (1995).","journal-title":"Mol Med"},{"key":"3160_CR10","doi-asserted-by":"crossref","unstructured":"Nor, J. E. et al. Thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway. Journal of vascular research \n                           37, 209\u2013218, doi:25733 (2000).","DOI":"10.1159\/000025733"},{"key":"3160_CR11","doi-asserted-by":"publisher","first-page":"851","DOI":"10.2174\/138945008785909347","volume":"9","author":"Y Mirochnik","year":"2008","unstructured":"Mirochnik, Y., Kwiatek, A. & Volpert, O. V. Thrombospondin and apoptosis: molecular mechanisms and use for design of complementation treatments. Curr Drug Targets \n                           9, 851\u2013862 (2008).","journal-title":"Curr Drug Targets"},{"key":"3160_CR12","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1007\/s12272-010-0213-6","volume":"33","author":"XS Xie","year":"2010","unstructured":"Xie, X. S. et al. LSKL, a peptide antagonist of thrombospondin-1, attenuates renal interstitial fibrosis in rats with unilateral ureteral obstruction. Archives of pharmacal research \n                           33, 275\u2013284, doi:10.1007\/s12272-010-0213-6 (2010).","journal-title":"Archives of pharmacal research"},{"key":"3160_CR13","doi-asserted-by":"publisher","first-page":"C1188","DOI":"10.1152\/ajpcell.00330.2009","volume":"298","author":"S Wang","year":"2010","unstructured":"Wang, S., Lincoln, T. M. & Murphy-Ullrich, J. E. Glucose downregulation of PKG-I protein mediates increased thrombospondin1-dependent TGF-{beta} activity in vascular smooth muscle cells. American journal of physiology. Cell physiology \n                           298, C1188\u20131197, doi:10.1152\/ajpcell.00330.2009 (2010).","journal-title":"American journal of physiology. Cell physiology"},{"key":"3160_CR14","doi-asserted-by":"publisher","first-page":"777","DOI":"10.2353\/ajpath.2007.070056","volume":"171","author":"S Belmadani","year":"2007","unstructured":"Belmadani, S. et al. A thrombospondin-1 antagonist of transforming growth factor-beta activation blocks cardiomyopathy in rats with diabetes and elevated angiotensin II. The American journal of pathology \n                           171, 777\u2013789, doi:10.2353\/ajpath.2007.070056 (2007).","journal-title":"The American journal of pathology"},{"key":"3160_CR15","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1159\/000265565","volume":"47","author":"MA Pallero","year":"2010","unstructured":"Pallero, M. A. et al. Stainless steel ions stimulate increased thrombospondin-1-dependent TGF-beta activation by vascular smooth muscle cells: implications for in-stent restenosis. Journal of vascular research \n                           47, 309\u2013322, doi:10.1159\/000265565 (2010).","journal-title":"Journal of vascular research"},{"key":"3160_CR16","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1002\/(SICI)1097-0177(199611)207:3<235::AID-AJA1>3.0.CO;2-I","volume":"207","author":"Y Jen","year":"1996","unstructured":"Jen, Y., Manova, K. & Benezra, R. Expression patterns of Id1, Id2, and Id3 are highly related but distinct from that of Id4 during mouse embryogenesis. Dev Dyn \n                           207, 235\u2013252 (1996).","journal-title":"Dev Dyn"},{"key":"3160_CR17","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/71517","volume":"6","author":"B Jimenez","year":"2000","unstructured":"Jimenez, B. et al. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nature medicine \n                           6, 41\u201348, doi:10.1038\/71517 (2000).","journal-title":"Nature medicine"},{"key":"3160_CR18","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1161\/01.RES.87.6.434","volume":"87","author":"S Dimmeler","year":"2000","unstructured":"Dimmeler, S. & Zeiher, A. M. Endothelial cell apoptosis in angiogenesis and vessel regression. Circulation research \n                           87, 434\u2013439 (2000).","journal-title":"Circulation research"},{"key":"3160_CR19","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1161\/CIRCRESAHA.113.302593","volume":"113","author":"C Gonzalez-Quesada","year":"2013","unstructured":"Gonzalez-Quesada, C. et al. Thrombospondin-1 induction in the diabetic myocardium stabilizes the cardiac matrix in addition to promoting vascular rarefaction through angiopoietin-2 upregulation. Circulation research \n                           113, 1331\u20131344, doi:10.1161\/CIRCRESAHA.113.302593 (2013).","journal-title":"Circulation research"},{"key":"3160_CR20","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.bbrc.2005.11.060","volume":"339","author":"Y Zhou","year":"2006","unstructured":"Zhou, Y., Poczatek, M. H., Berecek, K. H. & Murphy-Ullrich, J. E. Thrombospondin 1 mediates angiotensin II induction of TGF-beta activation by cardiac and renal cells under both high and low glucose conditions. Biochemical and biophysical research communications \n                           339, 633\u2013641, doi:10.1016\/j.bbrc.2005.11.060 (2006).","journal-title":"Biochemical and biophysical research communications"},{"key":"3160_CR21","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1161\/HYPERTENSIONAHA.111.175323","volume":"58","author":"Y Xia","year":"2011","unstructured":"Xia, Y. et al. Endogenous thrombospondin 1 protects the pressure-overloaded myocardium by modulating fibroblast phenotype and matrix metabolism. Hypertension \n                           58, 902\u2013911, doi:10.1161\/HYPERTENSIONAHA.111.175323 (2011).","journal-title":"Hypertension"},{"key":"3160_CR22","doi-asserted-by":"publisher","first-page":"1272","DOI":"10.1161\/CIRCRESAHA.113.302749","volume":"113","author":"Y Ma","year":"2013","unstructured":"Ma, Y., Yabluchanskiy, A. & Lindsey, M. L. Thrombospondin-1: the good, the bad, and the complicated. Circulation research \n                           113, 1272\u20131274, doi:10.1161\/CIRCRESAHA.113.302749 (2013).","journal-title":"Circulation research"},{"key":"3160_CR23","doi-asserted-by":"publisher","first-page":"2935","DOI":"10.1161\/CIRCULATIONAHA.104.510354","volume":"111","author":"NG Frangogiannis","year":"2005","unstructured":"Frangogiannis, N. G. et al. Critical role of endogenous thrombospondin-1 in preventing expansion of healing myocardial infarcts. Circulation \n                           111, 2935\u20132942, doi:10.1161\/CIRCULATIONAHA.104.510354 (2005).","journal-title":"Circulation"},{"issue":"Suppl 1","key":"3160_CR24","doi-asserted-by":"publisher","first-page":"S14","DOI":"10.1038\/ncpcardio0402","volume":"3","author":"D Fraidenraich","year":"2006","unstructured":"Fraidenraich, D. & Benezra, R. Embryonic stem cells prevent developmental cardiac defects in mice. Nature clinical practice. Cardiovascular medicine \n                           3(Suppl 1), S14\u201317 (2006).","journal-title":"Nature clinical practice. Cardiovascular medicine"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03160-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03160-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03160-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T05:04:28Z","timestamp":1671771868000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03160-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,8]]},"references-count":24,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["3160"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-03160-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6,8]]},"assertion":[{"value":"3 November 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 April 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 June 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"D.F. is a member of the Editorial Board of Scientific Reports. Q.Z. and D.F. have the following patent: United States Patent no. 8,802,629, issued on Aug. 12, 2014, was assigned to Rutgers, The State University of New Jersey (New Brunswick, New Jersey). \u201cCorrective roles of insulin-like growth factor-binding protein-3 in cardiomyopathy\u201d was invented by D.F. and Q.Z.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"3079"}}