TY - JOUR
T1 - Transforming growth factor-β receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor
AU - Sakata, Yasushi
AU - Chancey, Amanda L.
AU - Divakaran, Vijay G.
AU - Sekiguchi, Kenichi
AU - Sivasubramanian, Natarajan
AU - Mann, Douglas L.
N1 - Funding Information:
The authors would like to acknowledge the technical assistance of Dorellyn Lee and Feng Gao. This research was supported by research funds from Scios, Inc. and the N.I.H. (P50 HL-O6H and RO1 HL58081, and RO1 HL73017).
PY - 2008/1
Y1 - 2008/1
N2 - The mechanisms that are responsible for the development of myocardial fibrosis in inflammatory cardiomyopathy are unknown. We have previously generated lines of transgenic mice with cardiac-restricted overexpression of tumor necrosis factor (MHCsTNF mice), a pro-inflammatory cytokine. The MHCsTNF mice develop a heart failure phenotype that is characterized by progressive myocardial fibrosis, as well as increased levels transforming growth factor-β (TGF-β)(mRNA and protein. In order to determine whether TGF-β-mediated signaling was responsible for the myocardial fibrosis observed in the MHCsTNF mice, we treated MHCsTNF and littermate control mice from 4 to 12 weeks of age with a novel orally available TGF-β receptor antagonist (NP-40208). At the time of terminal study, myocardial collagen content was determined using the picrosirius red technique, and left ventricular (LV) systolic and diastolic function were determined using the Langendorff method. Treatment with NP-40208 resulted in a significant (P < 0.05) 65% decrease in nuclear translocation of Smad 2/3, a significant (P < 0.05), decrease in the heart-weight to body-weight ratio from 6.5 to 5.7, a ∼37% decrease in fibrillar collagen content (P < 0.01) and a significant (P < 0.05) decrease in the LV chamber stiffness by ∼25% in the MHCsTNF mice when compared to diluent-treated controls. Treatment with NP-40208 had no discernable effect on LV systolic function, nor any effect on cardiac myocyte size or fetal gene expression in the MHCsTNF mice. Taken together, these observations suggest that sustained pro-inflammatory signaling in the adult heart is associated with a pro-fibrotic phenotype that arises, at least in part, from TGF-β-mediated signaling, with resultant activation of Smad 2/3, leading to increased myocardial fibrosis and increased LV diastolic chamber stiffness.
AB - The mechanisms that are responsible for the development of myocardial fibrosis in inflammatory cardiomyopathy are unknown. We have previously generated lines of transgenic mice with cardiac-restricted overexpression of tumor necrosis factor (MHCsTNF mice), a pro-inflammatory cytokine. The MHCsTNF mice develop a heart failure phenotype that is characterized by progressive myocardial fibrosis, as well as increased levels transforming growth factor-β (TGF-β)(mRNA and protein. In order to determine whether TGF-β-mediated signaling was responsible for the myocardial fibrosis observed in the MHCsTNF mice, we treated MHCsTNF and littermate control mice from 4 to 12 weeks of age with a novel orally available TGF-β receptor antagonist (NP-40208). At the time of terminal study, myocardial collagen content was determined using the picrosirius red technique, and left ventricular (LV) systolic and diastolic function were determined using the Langendorff method. Treatment with NP-40208 resulted in a significant (P < 0.05) 65% decrease in nuclear translocation of Smad 2/3, a significant (P < 0.05), decrease in the heart-weight to body-weight ratio from 6.5 to 5.7, a ∼37% decrease in fibrillar collagen content (P < 0.01) and a significant (P < 0.05) decrease in the LV chamber stiffness by ∼25% in the MHCsTNF mice when compared to diluent-treated controls. Treatment with NP-40208 had no discernable effect on LV systolic function, nor any effect on cardiac myocyte size or fetal gene expression in the MHCsTNF mice. Taken together, these observations suggest that sustained pro-inflammatory signaling in the adult heart is associated with a pro-fibrotic phenotype that arises, at least in part, from TGF-β-mediated signaling, with resultant activation of Smad 2/3, leading to increased myocardial fibrosis and increased LV diastolic chamber stiffness.
KW - Myocardial fibrosis
KW - Transforming growth factor
KW - Transgenes
KW - Tumor necrosis factor
UR - http://www.scopus.com/inward/record.url?scp=37549050584&partnerID=8YFLogxK
U2 - 10.1007/s00395-007-0689-5
DO - 10.1007/s00395-007-0689-5
M3 - Article
C2 - 18034274
AN - SCOPUS:37549050584
SN - 0300-8428
VL - 103
SP - 60
EP - 68
JO - Basic Research in Cardiology
JF - Basic Research in Cardiology
IS - 1
ER -