B-type natriuretic peptide enhances fibrotic effects via matrix metalloproteinase-2 expression in the mouse atrium in vivo and in human atrial myofibroblasts in vitro.

In this study, we investigated the direct effects of BNP on TNF-α-induced atrial fibrosis mice, as well as its effects on human atrial myofibroblasts. We found that injecting TNF-α-induced mice with recombinant human BNP enhanced atrial fibrosis via matrix metalloproteinase-2 (MMP-2) expression and collagen accumulation. Furthermore, we found that BNP stimulated MMP-2 expression in human atrial myofibroblasts. Treatment of human atrial myofibroblasts with cycloheximide had no effect on this outcome; however, treatment of cells with MG132 enhanced BNP-induced MMP-2 expression, indicating that protein stability and inhibition of proteasome-mediated protein degradation pathways are potentially involved. Inhibition of SIRT1 significantly decreased BNP-induced MMP-2 expression. Additionally, confocal and coimmunoprecipitation data indicated that BNP-regulated MMP-2 expression are likely to be mediated through direct interaction with SIRT1, which is thought to deacetylate MMP-2 and to increase its protein stability in human atrial myofibroblasts. Finally, we confirmed that SIRT1 is expressed and cytoplasmically redistributed as well as colocalized with MMP-2 in mouse fibrotic atrial tissue. We suggest a possible fibrosis-promoting role of BNP in the atrium, although the antifibrotic properties of BNP in the ventricle have been reported in previous studies, and that the coordination between MMP-2 and SIRT1 in BNP-induced atrial myofibroblasts participates in atrial fibrosis. ...
Source: Translational Research : the journal of laboratory and clinical medicine - Category: Laboratory Medicine Authors: Tags: Transl Res Source Type: research