| First Author | Rouf R | Year | 2017 |
| Journal | JCI Insight | Volume | 2 |
| Issue | 15 | PubMed ID | 28768908 |
| Mgi Jnum | J:299043 | Mgi Id | MGI:6490094 |
| Doi | 10.1172/jci.insight.91588 | Citation | Rouf R, et al. (2017) Nonmyocyte ERK1/2 signaling contributes to load-induced cardiomyopathy in Marfan mice. JCI Insight 2(15) |
| abstractText | 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 (Fbn1C1039G/+ 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-beta ligands, with increased TGF-beta signaling in both nonmyocytes and myocytes; pathologic ERK activation is restricted to the nonmyocyte compartment. Informatively, TGF-beta, 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-beta ligand expression that culminates in both autocrine and paracrine overdrive of TGF-beta 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. |
