Transforming growth factor-β receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor

Abstract

The mechanisms that are responsible for the development of myocardial fibrosis in the inflammatory cardiomyopathy are unknown. Previously we have generated lines of transgenic mice with cardiac restricted overexpression of tumor necrosis factor (MHCsTNF mice), a proinflammatory cytokine. The MHCsTNF mice develop a heart failure phenotype that is characterized by progressive myocardial fibrosis, as well as increase 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 LV systolic and diastolic function were determined using the Langendorff method. Treatment with NP-40208 resulted in a significant decrease in the nuclear translocation of Smad 2/3, a decrease in heart-weight to body-weight ratio, decreased fibrillar collagen content and decreased LV chamber stiffness 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 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.

Distinct mechanisms for diastolic dysfunction in diabetes mellitus and chronic pressure-overload

“…In the present study, MMP-2 activity was, however, similar amongst all groups, which diverges from a previous study where reduced MMP-2 activity was responsible for the ECM changes observed STZ-rats with the same duration of diabetes [45]. It is currently accepted that MMP-2 activity is inhibited by TIMP-2 and its expression increased by TGF-b1 signalling, via Smad 7 [45] and Smad 2/3 activation [36]. In our study we found a tendency for both TIMP-2 and TGF-b 1 to increase.…”

Inhibition of transforming growth factor-β signaling induces left ventricular dilation and dysfunction in the pressure-overloaded heart

“…The effects of the oral TGF␤RI antagonist NP-40208 on transgenic mice with cardiac-restricted overexpression of tumor necrosis factor (MHCsTNF) have also been examined (30). MHCsTNF mice develop a heart failure phenotype characterized by progressive myocardial fibrosis, an increase in TGF-␤ levels, and LV diastolic dysfunction as shown by an increase in the chamber stiffness constant using the Langendorff method.…”

NADPH oxidases and cardiac remodelling

“…These authors reported that TGF-b1 upregulated NOX4 expression and promoted the conversion of fibroblasts to myofibroblasts, which are the main producers of collagen in the extracellular matrix. This study implied that NOX4 may be responsible for driving cardiac fibrosis in response to TGFb1 stimulation, the latter being well established as a driver of cardiac fibrosis [46]. However, TGF-b may also have beneficial actions as evidenced by data that TGF-b inhibition is detrimental in mice after MI [47].…”