Macrophage-stimulated microRNA expression in mural cells promotes transplantation-induced neointima formation

// Xiaotong Guo 1 , Mengyao Sun 1 , Chaochao Dai 1 , Xun Zhang 1 , Qihui Yin 1 , Jiaqi Ling 1 , Xinyue Li 1 , Xiao Wu 2, 3 , Fan Jiang 1 , Jianli Wang 1 1 Department of Pathology and Pathophysiology, School of Basic Medicine, Shandong University, Jinan, Shandong Province, China 2 Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, Shandong Province, China 3 State-Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong Province, China Correspondence to: Fan Jiang, email: fjiang@sdu.edu.cn Jianli Wang, email: wangmaq@sdu.edu.cn Keywords: transplant vasculopathy, neointima, macrophage, microRNA, mural cells Received: November 02, 2016      Accepted: March 09, 2017      Published: March 16, 2017 ABSTRACT In this study, we tested the possibility that macrophages might contribute to neointima formation by stimulating microRNA expressions in mural cells. Thoracic aortas from F344 rats were transplanted into recipient Lewis rats. Clodronate liposome was used for in vivo macrophage depletion. Using miR-21 as a prototypic example of vascular enriched microRNA, we showed that macrophage depletion reduced the expression level of miR-21, which was upregulated in the allograft. This effect of macrophage depletion was accompanied by attenuations in neointimal hyperplasia and transplantation-induced vascular inflammation. Using in vitro assays, we identified that macrophages might stimulate miR-21 expression in smooth muscle cells and adventitial fibroblasts via the release of tumor necrosis factor-α. We also showed that silencing of miR-21 suppressed tumor necrosis factor-induced proliferation, migration, and inflammatory responses in mural cells. Our results suggest that macrophage may promote transplantation-induced neointima formation by stimulating miR-21 expression in vascular mural cells, which promotes mural cell proliferation, migration and/or inflammation. Moreover, we have established that tumor necrosis factor-α has a major role in mediating this paracrine process.