Souilhol, C., Gauci, I., Feng, S. et al. (7 more authors) (2019) Homeobox B9 integrates bone morphogenic protein 4 with inflammation at atheroprone sites. Cardiovascular Research. ISSN 0008-6363
Abstract
Aims
Atherosclerosis develops near branches and bends of arteries that are exposed to disturbed blood flow which exerts low wall shear stress (WSS). These mechanical conditions alter endothelial cells (EC) by priming them for inflammation and by inducing turnover. Homeobox (Hox) genes are developmental genes involved in the patterning of embryos along their anterior–posterior and proximal–distal axes. Here we identified Hox genes that are regulated by WSS and investigated their functions in adult arteries.
Methods and results
EC were isolated from inner (low WSS) and outer (high WSS) regions of the porcine aorta and the expression of Hox genes was analysed by quantitative real-time PCR. Several Hox genes (HoxA10, HoxB4, HoxB7, HoxB9, HoxD8, HoxD9) were significantly enriched at the low WSS compared to the high WSS region. Similarly, studies of cultured human umbilical vein EC (HUVEC) or porcine aortic EC revealed that the expression of multiple Hox genes (HoxA10, HoxB9, HoxD8, HoxD9) was enhanced under low (4 dyn/cm2) compared to high (13 dyn/cm2) WSS conditions. Gene silencing studies identified Hox genes (HoxB9, HoxD8, HoxD9) that are positive regulators of inflammatory molecule expression in EC exposed to low WSS, and others (HoxB9, HoxB7, HoxB4) that regulated EC turnover. We subsequently focused on HoxB9 because it was strongly up-regulated by low WSS and, uniquely, was a driver of both inflammation and proliferation. At a mechanistic level, we demonstrate using cultured EC and murine models that bone morphogenic protein 4 (BMP4) is an upstream regulator of HoxB9 which elicits inflammation via induction of numerous inflammatory mediators including TNF and downstream NF-κB activation. Moreover, the BMP4-HoxB9-TNF pathway was potentiated by hypercholesterolaemic conditions.
Conclusions
Low WSS induces multiple Hox genes that control the activation state and turnover of EC. Notably, low WSS activates a BMP4-HoxB9-TNF signalling pathway to initiate focal arterial inflammation, thereby demonstrating integration of the BMP and Hox systems in vascular pathophysiology.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Endothelial; Shear stress; Hox; BMP4; NF-κB |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Biomedical Science (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 22 Oct 2019 08:32 |
Last Modified: | 22 Oct 2019 08:32 |
Status: | Published |
Publisher: | Oxford University Press (OUP) |
Refereed: | Yes |
Identification Number: | 10.1093/cvr/cvz235 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:152372 |