The essential autophagy gene ATG7 modulates organ fibrosis via regulation of endothelial-to-mesenchymal transition [Cell Biology]

December 19th, 2014 by Singh, K. K., Lovren, F., Pan, Y., Quan, A., Ramadan, A., Matkar, P. N., Ehsan, M., Sandhu, P., Mantella, L. E., Gupta, N., Teoh, H., Parotto, M., Tabuchi, A., Kuebler, W. M., Al-Omran, M., Finkel, T., Verma, S.

Pulmonary fibrosis is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix components. Although the origin of fibroblasts is multifactorial, recent data implicate endothelial-to-mesenchymal transition (EndMT) as an important source of fibroblasts. We report herein that loss of the essential autophagy gene ATG7 in endothelial cells (ECs) leads to impaired autophagic flux accompanied by marked changes in EC architecture, loss of endothelial and gain of mesenchymal markers consistent with EndMT. Loss of ATG7 also upregulates TGFβ signaling and key pro-fibrotic genes in vitro. In vivo, EC-specific ATG7-knockout mice exhibit a basal reduction in endothelial-specific markers, and demonstrate an increased susceptibility to bleomycin-induced pulmonary fibrosis and collagen accumulation. Our findings help define the role of endothelial autophagy as a potential therapeutic target to limit organ fibrosis, a condition for which presently there are no effective available treatments.