H19/TET1 axis promotes TGF-β signaling linked to endothelial-to-mesenchymal transition
Open Access
- 1 June 2020
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 34 (6), 8625-8640
- https://doi.org/10.1096/fj.202000073RRRRR
Abstract
While emerging evidence suggests the link between endothelial activation of TGF-beta signaling, induction of endothelial-to-mesenchymal transition (EndMT), and cardiovascular disease (CVD), the molecular underpinning of this connection remains enigmatic. Here, we report aberrant expression of H19 lncRNA and TET1 in endothelial cells (ECs) of human atherosclerotic coronary arteries. Using primary human umbilical vein endothelial cells (HUVECs) and aortic endothelial cells (HAoECs) we show that TNF-alpha, a known risk factor for endothelial dysfunction and CVD, induces H19 expression which in turn activates TGF-beta signaling and EndMT via a TET1-dependent epigenetic mechanism. We also show that H19 regulates TET1 expression at the posttranscriptional level. Further, we provide evidence that this H19/TET1-mediated regulation of TGF-beta signaling and EndMT occurs in mouse pulmonary microvascular ECs in vivo under hyperglycemic conditions. We propose that endothelial activation of the H19/TET1 axis may play an important role in EndMT and perhaps CVD.Funding Information
- National Institute of Diabetes and Digestive and Kidney Diseases
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