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

// Xu Mingyuan 1 , Pang Qianqian 1 , Xu Shengquan 2 , Ye Chenyi 3 , Lei Rui 1 , Shen Yichen 1 and Xu Jinghong 1 1 Department of Plastic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China 2 Department of Hand Surgery and Microsurgery Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China 3 Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China Correspondence to: Xu Jinghong, email: 1304017@zju.edu.cn Keywords: keloid; hypoxia; hypoxia-Inducible factor-1α; transforming growth factor-β1/Smad; collagen Received: August 08, 2017      Accepted: November 16, 2017      Published: December 14, 2017 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.