Abstract
Transforming growth factor beta (TGFβ) plays a crucial role in tissue fibrosis. A number of studies have shown that TGFβ3 significantly attenuated tissue fibrosis. However, the mechanism involved in this effect is poorly understood. In this study we found that the expression level of TGFβ3 was higher in human myocardial infarction (MI) tissues than in normal tissues, and interestingly, it increased with the development of fibrosis post‐myocardial infarction (post‐MI). In vitro, human cardiac fibroblasts (CFs) were incubated with angiotensin II (Ang II) to mimic the ischaemic myocardium microenvironment and used to investigate the anti‐fibrotic mechanism of TGFβ3. Then, fibrosis‐related proteins were detected by Western blot. It was revealed that TGFβ3 up‐regulation attenuated the proliferation, migration of human CFs and the expression of collagens, which are the main contributors to fibrosis, promoted the phenotype shift and the cross‐linking of collagens. Importantly, the expression of collagens was higher in the si‐smad7 groups than in the control groups, while silencing smad7 increased the phosphorylation level of the TGFβ/smad signalling pathway. Collectively, these results indicated that TGFβ3 inhibited fibrosis via the TGFβ/smad signalling pathway, possibly attributable to the regulation of smad7, and that TGFβ3 might serve as a potential therapeutic target for myocardial fibrosis post‐MI.
Highlights
Myocardial remodelling after myocardial infarction (MI) is a major factor that accelerates heart failure
These results indicated that TGFβ3 inhibited fibrosis via the TGFβ/smad signalling pathway, possibly attributable to the regulation of smad[7], and that TGFβ3 might serve as a potential therapeutic target for myocardial fibrosis post‐myocardial infarction (post‐MI)
When the antibodies were diluted at 1:2000, the expression of collagen I, collagen III, smad[2], smad[3] and smad[4] and the phosphorylation levels of smad[2] and smad[3] were higher in the si‐smad7‐angiotensin II (Ang II)‐treated group, the si‐smad7‐rTGFβ3 group and the si‐smad7‐Ang II + rTGFβ3 group than the Ang II‐treated group, rTGFβ3 group, Ang II + rTGFβ3 group respectively (P < 0.05 Figure 6A‐C). These results indicated that TGFβ3 affected Ang II‐in‐ duced myocardial fibrosis via TGFβ/smad signalling, in which smad[7] might be involved
Summary
Myocardial remodelling after myocardial infarction (MI) is a major factor that accelerates heart failure. The pathological roles of TGFβ3 in post‐MI fibrosis and the molecular mechanisms un‐ derlying myocardial fibroblasts proliferation, migration, phenotype shift and function remain poorly understood.[7] Many clinical data in‐. We applied exogenous and endogenous TGFβ3 to human CFs to analyse the effects of TGFβ3 on cell proliferation, migration, phenotype shift, collagen synthesis and cross‐linking. To explore the possible molecular mechanism by which TGFβ3 regulates fibrotic potential, we applied Ang II‐induced medium to human CFs and analysed the relative levels of collagen synthesis, cross‐linking, TGFβ/. We examined the role of smad[7] in the TGFβ/smad signalling pathway
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