Role of endothelial cells in pulmonary fibrosis via SREBP2 activation
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
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
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Research Article Pulmonology Vascular biology

Role of endothelial cells in pulmonary fibrosis via SREBP2 activation

Abstract

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.

Authors

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

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Figure 7

SREBP2 promotes EC-induced vascular damage in the mouse lung.

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SREBP2 promotes EC-induced vascular damage in the mouse lung. (A and B) ...
(A and B) Vascular remodeling resulting from bleomycin (BLM) administration and SREBP2(N) overexpression was revealed by representative images of H&E staining from n = 6 mice per group (cells stained in red, nuclei in black) (A) and representative images of Masson’s trichrome from n = 6 mice per group (cells stained in red, collagen in blue) (B). Scale bars: 100 μm. (C) The level of fibronectin (FN1) and collagen (Col1A1) mRNA from whole lung samples were measured using qPCR. (D) Representative images of an angiogram with the use of Microfil to reveal the lung vascularization (yellow) (n = 4 mice per group). (E) Evans blue was injected via tail vein, and mice were then sacrificed 30 minutes later (n = 4 mice per group). Evans blue effusion in the lung is visualized in the representative images and were quantified by spectrophotometry. Data in C were analyzed by 2-tailed Student’s t test; data are represented as mean ± SEM from n = 4 mice per group. Data in E were analyzed by 2-way ANOVA with Kruskal-Wallis post hoc; data are represented as mean ± SEM from n = 4 mice per group. *P < 0.05 between the indicated groups.