Hypoxia-inducible factor-1α activates transforming growth factor-β1/Smad signaling and increases collagen deposition in dermal fibroblasts

Abstract

Hypoxia of local tissue occurs during the scar formation; however, the degree of ischemia and hypoxia in the central areas of keloids is more serious than those in normal scars. Hypoxia-induced factor (HIF), is one of the main cellular responses to hypoxia, allowing cells to adapt to low-oxygen conditions. We investigated the correlation among hypoxia, transforming growth factor-β1/Smad signaling and collagen deposition. Hypoxia up-regulated TGF-β1, Smad2/3, p-Smad2/3, Smad4, and total collagen in both normal and keloid fibroblasts via HIF-1α, which was attenuated by HIF-1α inhibition, but TβRII levels were not significantly altered. Silencing Smad4 under hypoxia decreased the mRNA and protein levels of HIF-1α, suggesting up-regulated Smad4 may also plays a role in promoting HIF-1α. Finally, we examined the role of the TGF-β1/Smad pathway in collagen deposition. When TβRII was inhibited by ITD-1 under hypoxic conditions, p-Smad2/3 levels and collagen deposition decreased. When inhibited TβRII by siRNA under normoxia, the levels of p-Smad2/3, Smad4 and collagen deposition also decreased. This result demonstrated that hypoxia promoted TGF-β1/Smad signaling via HIF-1α and that both HIF-1α and the TGF-β1/Smad signaling promotes collagen deposition in hypoxia, which is an important mechanism of keloid formation.

Cyclosporine a directly affects human and mouse b cell migration in vitro by disrupting a hIF-1 αdependent, o2 sensing, molecular switch

“…PFN2 is an epigenetic regulator of SMAD2/3 (Mothers against decapentaplegic homolog 2/3) [53], which in turn has been shown to promote metastasis in cancer cells [54]. SMAD2 and SMAD3 are also regulated by HIF-1α [55]. In the knowledge-based STRING network, SMAD3 is directly linked to HIF-1α.…”

A high content, phenotypic ‘scar-in-a-jar’ assay for rapid quantification of collagen fibrillogenesis using disease-derived pulmonary fibroblasts

“…Unlike previous techniques, the 'scar-in-a-jar' assay enables the visualisation and quantification of rapid deposition and cross-linking of mature collagen fibrils, more closely resembling the disorganized fibres characteristic of IPF lesions [11,13,30]. In contrast, previous assays have focused on quantifying soluble collagens using the Sircol assay [31] or measuring soluble P1NP (procollagen type I N-terminal propeptide [32]), both of which reflect surrogate markers of ECM turnover [33]. Other methods of quantifying ECM deposition include the histological Picro-Sirius red staining, however this lacks resolution and collagen specificity [34].…”

Endogenous Adaptation to Chronic Mild Hypoxia Shifts the Balance towards Anti-Inflammatory Milieu in Progressive Myelin Oligodendrocyte Glycoprotein Induced EAE

“…HIF-1 has been shown to play a role in T cell differentiation [39], and especially in regulation of Tregs [39]. It was clearly shown that hypoxic conditions via HIF-1a induces transforming growth factor-beta (TGF-β) [40][41][42] which is the main transcription factor involved in the regulation of Th17 and Treg balance. In the absence of proinflammatory cytokines, TGF-β drives differentiation into Treg cells [43][44][45].…”