Biliverdin reductase deficiency triggers an endothelial-to-mesenchymal transition in human endothelial cells.

Abstract

Endothelial dysfunction accompanied by the loss of endothelial cell phenotype plays an essential role in cardiovascular diseases. Here, we report that knockdown of biliverdin reductase (BVR), the enzyme of the heme degradation pathway converting biliverdin to bilirubin, shifts endothelial phenotype of the primary human aortic endothelial cells (HAECs) to mesenchymal-like one. It is reflected by the loss of endothelial markers and angiogenic response, with concomitant acquiring of mesenchymal markers, increased migratory capacity and metalloproteinase activity. BVR-deficiency induces the activity of Nrf2 transcription factor and increases heme oxygenase-1 (HO-1) level, which is accompanied by the reduction of cellular heme content, increase in a free iron fraction and oxidative stress. Accordingly, the phenotype of BVR-deficient cells can be mimicked by hemin or iron overload. Depletion of HO-1 in BVR-deficient ECs abrogates the increase in intracellular free iron and oxidative stress, preventing the loss of endothelial markers. Treatment of BVR-deficient cells with bilirubin does not rescue the endothelial phenotype of HAECs. Unlike BLVRA mRNA level, the expression of HMOX1, HMOX1:BLVRA ratio and HO-1 protein level positively correlate with abdominal aortic aneurysm size in clinical samples. Collectively, the non-enzymatic activity of BVR contributes to the maintenance of healthy endothelial phenotype through the prevention of HO-1-dependent iron-overload, oxidative stress and subsequent endothelial-to-mesenchymal transition (EndMT).

• Authors: Damian Klóska, Aleksandra Kopacz, Aleksandra Piechota-Polańczyk, Christoph Neumayer, Ihor Huk, Józef Dulak, Alicja Józkowicz, Anna Grochot-Przęczek
• Journal: Archives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 678 Pg. 108182 (12 15 2019) ISSN: 1096-0384 [Electronic] United States
• PMID: 31704097 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Oxidoreductases Acting on CH-CH Group Donors
• BLVRA protein, human

Topics

• Cell Transdifferentiation (genetics)
• Endothelial Cells (cytology)
• Gene Knockdown Techniques
• Humans
• Mesoderm (cytology)
• Oxidoreductases Acting on CH-CH Group Donors (deficiency, genetics)
• Phenotype