{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T02:35:01Z","timestamp":1790130901706,"version":"4.0.1"},"reference-count":57,"publisher":"American Society for Clinical Investigation","issue":"15","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,8,3]]},"abstract":"<jats:p>\n                    Among children with the most severe presentation of Marfan syndrome (MFS), an inherited disorder of connective tissue caused by a deficiency of extracellular fibrillin-1, heart failure is the leading cause of death. Here, we show that, while MFS mice (\n                    <jats:italic>\n                      Fbn1\n                      <jats:sup>C1039G\/+<\/jats:sup>\n                    <\/jats:italic>\n                    mice) typically have normal cardiac function, pressure overload (PO) induces an acute and severe dilated cardiomyopathy in association with fibrosis and myocyte enlargement. Failing MFS hearts show high expression of TGF-\u03b2 ligands, with increased TGF-\u03b2 signaling in both nonmyocytes and myocytes; pathologic ERK activation is restricted to the nonmyocyte compartment. Informatively, TGF-\u03b2, angiotensin II type 1 receptor (AT1R), or ERK antagonism (with neutralizing antibody, losartan, or MEK inhibitor, respectively) prevents load-induced cardiac decompensation in MFS mice, despite persistent PO. In situ analyses revealed an unanticipated axis of activation in nonmyocytes, with AT1R-dependent ERK activation driving TGF-\u03b2 ligand expression that culminates in both autocrine and paracrine overdrive of TGF-\u03b2 signaling. The full compensation seen in wild-type mice exposed to mild PO correlates with enhanced deposition of extracellular fibrillin-1. Taken together, these data suggest that fibrillin-1 contributes to cardiac reserve in the face of hemodynamic stress, critically implicate nonmyocytes in disease pathogenesis, and validate ERK as a therapeutic target in MFS-related cardiac decompensation.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.91588","type":"journal-article","created":{"date-parts":[[2017,8,2]],"date-time":"2017-08-02T11:00:51Z","timestamp":1501671651000},"source":"Crossref","is-referenced-by-count":45,"title":["Nonmyocyte ERK1\/2 signaling contributes to load-induced cardiomyopathy in Marfan mice"],"prefix":"10.1172","volume":"2","author":[{"given":"Rosanne","family":"Rouf","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena Gallo","family":"MacFarlane","sequence":"additional","affiliation":[{"name":"McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of 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