Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with limited treatment options. Despite endothelial cells (ECs) comprising 30% of the lung cellular composition, the role of EC dysfunction in pulmonary fibrosis (PF) remains unclear. We hypothesize that sterol regulatory element-binding protein 2 (SREBP2) plays a critical role in the pathogenesis of PF via EC phenotypic modifications. Transcriptome data demonstrate that SREBP2 overexpression in ECs led to the induction of the TGF, Wnt, and cytoskeleton remodeling gene ontology pathways and the increased expression of mesenchymal genes, such as snail family transcriptional repressor 1 (snai1), α-smooth muscle actin, vimentin, and neural cadherin. Furthermore, SREBP2 directly bound to the promoter regions and transactivated these mesenchymal genes. This transcriptomic change was associated with an epigenetic and phenotypic switch in ECs, leading to increased proliferation, stress fiber formation, and ECM deposition. Mice with endothelial-specific transgenic overexpression of SREBP2 (EC-SREBP2[N]-Tg mice) that were administered bleomycin to induce PF demonstrated exacerbated vascular remodeling and increased mesenchymal transition in the lung. SREBP2 was also found to be markedly increased in lung specimens from patients with IPF. These results suggest that SREBP2, induced by lung injury, can exacerbate PF in rodent models and in human patients with IPF.
Marcy Martin, Jiao Zhang, Yifei Miao, Ming He, Jian Kang, Hsi-Yuan Huang, Chih-Hung Chou, Tse-Shun Huang, Hsiao-Chin Hong, Shu-Han Su, Simon S. Wong, Rebecca L. Harper, Lingli Wang, Rakesh Bhattacharjee, Hsien-Da Huang, Zhen Bouman Chen, Atul Malhotra, Marlene Rabinovitch, James S. Hagood, John Y-J. Shyy
Bleomycin-induced (BLM-induced) SREBP2(N) mediates profibrotic pathways in ECs.