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.
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.
Digital Object Identifier (DOI)
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.
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.
S1 Fig. HB-EGF ASO administration downregulated hepatic HB-EGF mRNA levels.
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S2 Fig. HB-EGF ASO administration effectively suppressed thoracic aortic aneurysm (TAA) formation.
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S3 Fig. HB-EGF ASO administration suppressed abdominal aortic aneurysm (AAA) and atherosclerotic lesion formation.
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S4 Fig. The effects of HB-EGF ASO administration in LDLR deficient mice under normal diet condition.
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S5 Fig. The effects of HB-EGF ASO administration on the heart structure and blood pressure in LDLR deficient mice under normal diet.
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S6 Fig. The effects of HB-EGF ASO administration on the in C57BL/6 mice under normal diet.
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S7 Fig. HB-EGF is not involved in heparin-releasable TG hydrolytic activities or regulating fecal neutral sterol excretion rate.
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S1 Table. Primer sequence information used for PCR reactions in the study.
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S1 File. Materials and Procedure-Extended.
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S2 File. ARRIVE guideline.