Targeting Hepatic Heparin-Binding EGF-Like Growth Factor (HB-EGF) Induces Anti-Hyperlipidemia Leading to Reduction of Angiotensin II-Induced Aneurysm Development

Authors

Seonwook Kim, University of KentuckyFollow
Lihua Yang, University of KentuckyFollow
Seongu Kim, University of Kentucky
Richard G. Lee, Ionis Pharmaceuticals, Inc.
Mark J. Graham, Ionis Pharmaceuticals, Inc.
Judith A. Berliner, University of California - Los Angeles
Aldons J. Lusis, University of California - Los Angeles
Lei Cai, University of KentuckyFollow
Ryan E. Temel, University of KentuckyFollow
Debra L. Rateri, University of KentuckyFollow
Sangderk Lee, University of KentuckyFollow

Abstract

Objective

The upregulated expression of heparin binding EGF-like growth factor (HB-EGF) in the vessel and circulation is associated with risk of cardiovascular disease. In this study, we tested the effects of HB-EGF targeting using HB-EGF-specific antisense oligonucleotide (ASO) on the development of aortic aneurysm in a mouse aneurysm model.

Approach and results

Low-density lipoprotein receptor (LDLR) deficient mice (male, 16 weeks of age) were injected with control and HB-EGF ASOs for 10 weeks. To induce aneurysm, the mice were fed a high fat diet (22% fat, 0.2% cholesterol; w/w) at 5 week point of ASO administration and infused with angiotensin II (AngII, 1,000ng/kg/min) for the last 4 weeks of ASO administration. We confirmed that the HB-EGF ASO administration significantly downregulated HB-EGF expression in multiple tissues including the liver. Importantly, the HB-EGF ASO administration significantly suppressed development of aortic aneurysms including thoracic and abdominal types. Interestingly, the HB-EGF ASO administration induced a remarkable anti-hyperlipidemic effect by suppressing very low density lipoprotein (VLDL) level in the blood. Mechanistically, the HB-EGF targeting suppressed hepatic VLDL secretion rate without changing heparin-releasable plasma triglyceride (TG) hydrolytic activity or fecal neutral cholesterol excretion rate.

Conclusion

This result suggested that the HB-EGF targeting induced protection against aneurysm development through anti-hyperlipidemic effects. Suppression of hepatic VLDL production process appears to be a key mechanism for the anti-hyperlipidemic effects by the HB-EGF targeting.

Document Type

Article

Publication Date

8-9-2017

Notes/Citation Information

Published in PLOS ONE, v. 12, 8, e0182566, p. 1-18.

© 2017 Kim et al.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Digital Object Identifier (DOI)

https://doi.org/10.1371/journal.pone.0182566

Funding Information

Funding sources were research grants of National Heart, Lung, and Blood Institute (NHLBI, US) R00HL105577, R01HL030568, R01HL064731, and National Institute of General Medical Sciences (NIGMS, US) P20GM103527.

Repository Citation

Kim, Seonwook; Yang, Lihua; Kim, Seongu; Lee, Richard G.; Graham, Mark J.; Berliner, Judith A.; Lusis, Aldons J.; Cai, Lei; Temel, Ryan E.; Rateri, Debra L.; and Lee, Sangderk, "Targeting Hepatic Heparin-Binding EGF-Like Growth Factor (HB-EGF) Induces Anti-Hyperlipidemia Leading to Reduction of Angiotensin II-Induced Aneurysm Development" (2017). Saha Cardiovascular Research Center Faculty Publications. 32.
https://uknowledge.uky.edu/cvrc_facpub/32