| Affiliation: | 1. Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, 40536, USA;2. Cardiovascular Antisense Drug Discovery Group, Ionis Pharmaceuticals, Carlsbad, CA, 92010, USA;3. Department of Physiology, University of Kentucky, Lexington, KY, 40536, USA;4. Department of Medicine-Cardiology, University of California-Los Angeles (UCLA) School of Medicine, Los Angeles, CA, 90095, USA;5. Department of Human Genetics, University of California-Los Angeles (UCLA) School of Medicine, Los Angeles, CA, 90095, USA;6. Department of Microbiology, Immunology & Molecular Genetics, University of California-Los Angeles (UCLA), Los Angeles, CA, 90095, USA;7. Department of Pathology and Laboratory Medicine, University of California-Los Angeles (UCLA), Los Angeles, CA, 90095, USA;8. Department of Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, KY, 40536, USA |
| Abstract: | ![]()
Background and aimsHeparin-binding EGF-like growth factor (HB-EGF) is a representative EGF family member that interacts with EGFR under diverse stress environment. Previously, we reported that the HB-EGF-targeting using antisense oligonucleotide (ASO) effectively suppressed an aortic aneurysm in the vessel wall and circulatory lipid levels. In this study, we further examined the effects of the HB-EGF ASO administration on the development of hyperlipidemia-associated atherosclerosis using an atherogenic mouse model.Methods and resultsThe male and female LDLR deficient mice under Western diet containing 21% fat and 0.2% cholesterol content were cotreated with control and HB-EGF ASOs for 12 weeks. We observed that the HB-EGF ASO administration effectively downregulated circulatory VLDL- and LDL-associated lipid levels in circulation; concordantly, the HB-EGF targeting effectively suppressed the development of atherosclerosis in the aorta. An EGFR blocker BIBX1382 administration suppressed the hepatic TG secretion rate, suggesting a positive role of the HB-EGF signaling for the hepatic VLDL production. We newly observed that there was a significant improvement of the insulin sensitivity by the HB-EGF ASO administration in a mouse model under the Western diet as demonstrated by the improvement of the glucose and insulin tolerances.ConclusionThe HB-EGF ASO administration effectively downregulated circulatory lipid levels by suppressing hepatic VLDL production rate, which leads to effective protection against atherosclerosis in the vascular wall. |
