Abstract

An inhibitory Smad7 emerges as a potential therapeutic candidate to intervene the hepatic fibrosis. Given that Smad7 functions through antagonizing the transforming growth factor (TGF)‐beta1 signaling, Smad7 over‐expression might enhance the proliferation of Hepatic Stellate Cells (HSCs). However, our recent monitor show that Smad7 surprisingly promoted apoptosis in these cells. Here we report that such inhibitory machinery of Smad7 during the TGFbeta1‐derived process is coupled to the activity of cyclin‐dependent kinase inhibitors p21 and p27. Initially, Primary isolated HSCs were transiently transfected with an adenoviruses encoding Smad7 gene. Real‐time PCR and western blot analysis was confirmed that the overexpression of Smad7 substantially attenuated TGFbeta1 induced collagen I mRNA and protein levels in HSCs. In parallel, flow cytometric monitoring was recorded that Smad7 gene transfer dramatically enhanced but not abolished the apoptosis in these cells subjected to TGFbeta1. Interestingly, Smad7 induced apoptosis in HSCs was found to be both p21 and p27 linkage by using a specific small interfering RNA technique. In the present of TGFbeta1 was found to stimulate an obvious elevation in p21 protein and mildly increase in p27. However, it was found that Smad7 significantly induced p27 whereas caused a substantial decrease in p21 levels in these cells. Furthermore, silencing of p27 by specific siRNA was found to synergy with the inhibitory effect of Smad7 on the inducible collagen production in these cells. Collectively, our finds indicate the important roles of p21 and p27 in the inhibitory Smad7 working pattern in HSCs in response to TGFbeta1 and thereby provide a novel intracellular basis for associated drug development in the future. (Supported by Guangxi NSF Grants 0135035)

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