Up-regulation of BMP-2 antagonizes TGF-?1/ROCK-enhanced cardiac fibrotic signalling through activation of Smurf1/Smad6 complex.

ABSTRACT: Rho-associated kinase (ROCK) plays a critical role in pressure overload-induced left ventricular remodelling. However, the underlying mechanism remains unclear. Here, we reported that TGF-?1-induced ROCK elevation suppressed BMP-2 level and strengthened fibrotic response. Exogenous BMP-2 supply effectively attenuated TGF-?1 signalling pathway through Smad6-Smurf-1 complex activation. In vitro cultured cardiomyocytes, mechanical stretch up-regulated cardiac TGF-?1, TGF-?1-dependent ROCK and down-regulated BMP-2, but BMP-2 level could be reversed through blocking TGF-?1 receptor by SB-431542 or inhibition of ROCK by Y-27632. TGF-?1 could also activate ROCK and suppress endogenous BMP-2 level in a dose-dependent manner. Knock-down BMP-2 enhanced TGF-?1-mediated PKC-? and Smad3 signalling cascades. In contrast, treatment with Y-27632 or SB-431542, respectively suppressed ROCK-dependent PKC-? and Smad3 activation, but BMP-2 was only up-regulated by Y-27632. In addition, BMP-2 silencing abolished the effect of Y-27632, but not SB-431542 on suppression of TGF-?1 pathway. Further experiments showed that Smad6 Smurf1 interaction were required for BMP-2-evoked antagonizing effects. Smad6 overexpression attenuated TGF-?1-induced activation of PKC-? and Smad3, promoted TGF-? RI degradation in BMP-2 knock-down cardiomyocytes, and could be abolished after knocking-down Smurf-1, in which Smad6/Smurf1 complex formation was critically involved. In vivo data showed that pressure overload-induced collagen deposition was attenuated, cardiac function was improved and TGF-?1-dependent activation of PKC-? and Smad3 was reduced after 2 weeks treatment with rhBMP-2(0.5 mg/kg) or Y-27632 (10 mg/kg) in mice that underwent surgical transverse aortic constriction. In conclusion, we propose that BMP-2, as a novel fibrosis antagonizing cytokine, may have potential beneficial effect in attenuating pressure overload-induced cardiac fibrosis.

SUBMITTER: Wang S 

PROVIDER: S-EPMC3823423 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature