Abstract 685: Sterol Regulatory Element-Binding Protein 2-Mediated Endothelial-to-Mesenchymal Transition Contributes to Pulmonary Fibrosis

Objective: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with a median survival rate of 3-5 years. The clinical presentation of IPF relies on the formation of fibroblastic foci, areas of active myofibroblasts depositing extracellular matrix resulting in stiff and dilated alveoli. Whereas therapeutics targeting fibroblast proliferation have made little clinical progress, the role of endothelial cell (EC) dysfunction in pulmonary fibrosis has been overlooked. Having previously identified that sterol regulatory element-binding protein 2 (SREBP2) is a key mediator of innate immune and redox responses in ECs, we postulate that SREBP2 plays a role in promoting EC dysfunction contributing to pulmonary fibrosis. Approach and Results: RNA-sequencing demonstrated that SREBP2 overexpression in ECs led to the induction of TGF, Wnt, and cytoskeleton remodeling gene ontology pathways. SREBP2 regulation of these pathways indicated mesenchymal cell differentiation, which alluded to the promotion of endothelial-to-mesenchymal transition (EndoMT). SREBP2 overexpression in cultured ECs led to increased expression of mesenchymal genes such as snai1 family transcriptional repressor 1 (snai1), α-smooth muscle actin (αSMA), vimentin, and neural cadherin (N-cad). Furthermore, SREBP2 was found to directly bind to the promoter regions and transactivate these mesenchymal genes in ECs. Furthermore, a myofibroblast-like phenotypic switch in ECs was evident, including increased proliferation, stress fiber formation, and ECM deposition. Pulmonary fibrosis mouse models using bleomycin demonstrated exacerbated lung vascular remodeling and increased EndoMT in endothelial-specific SREBP2 overexpression transgenic (EC-SREBP2-Tg) mice when compared to wildtype littermates. Additionally, SREBP2 was found to be markedly increased in lung specimens from IPF patients. Conclusions: SREBP2 promotes EndoMT through direct transactivation of mesenchymal genes (i.e., snai1, αSMA, vimentin, and N-Cad). Pathogenic factors activating SREBP2 specifically in ECs increased EndoMT and exacerbated pulmonary fibrosis in vivo . This suggests that targeting SREBP2 may be a potential therapeutic in pulmonary fibrosis.