S Kim1, M J Graham2, R G Lee2, L Yang1, S Kim1, V Subramanian3, J D Layne1, L Cai1, R E Temel3, D Shih4, A J Lusis5, J A Berliner6, S Lee7. 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. Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, 40536, USA; 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 Medicine-Cardiology, University of California-Los Angeles (UCLA) School of Medicine, Los Angeles, CA, 90095, USA; Department of Human Genetics, University of California-Los Angeles (UCLA) School of Medicine, Los Angeles, CA, 90095, USA; Department of Microbiology, Immunology & Molecular Genetics, University of California-Los Angeles (UCLA), Los Angeles, CA, 90095, USA. 6. Department of Pathology and Laboratory Medicine, University of California-Los Angeles (UCLA), Los Angeles, CA, 90095, USA. 7. Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, 40536, USA; Department of Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, KY, 40536, USA. Electronic address: sangderk.lee@uky.edu.
Abstract
BACKGROUND AND AIMS: Heparin-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 RESULTS: The 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. CONCLUSION: The 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.
BACKGROUND AND AIMS: Heparin-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-EGFASO administration on the development of hyperlipidemia-associated atherosclerosis using an atherogenic mouse model. METHODS AND RESULTS: The 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-EGFASO 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-EGFASO administration in a mouse model under the Western diet as demonstrated by the improvement of the glucose and insulin tolerances. CONCLUSION: The HB-EGFASO administration effectively downregulated circulatory lipid levels by suppressing hepatic VLDL production rate, which leads to effective protection against atherosclerosis in the vascular wall.
Authors: Ryan E Temel; Richard G Lee; Kathryn L Kelley; Matthew A Davis; Ramesh Shah; Janet K Sawyer; Martha D Wilson; Lawrence L Rudel Journal: J Lipid Res Date: 2005-09-08 Impact factor: 5.922
Authors: K Boström; J Borén; M Wettesten; A Sjöberg; G Bondjers; O Wiklund; P Carlsson; S O Olofsson Journal: J Biol Chem Date: 1988-03-25 Impact factor: 5.157
Authors: A Nakata; J Miyagawa; S Yamashita; M Nishida; R Tamura; K Yamamori; T Nakamura; S Nozaki; K Kameda-Takemura; S Kawata; N Taniguchi; S Higashiyama; Y Matsuzawa Journal: Circulation Date: 1996-12-01 Impact factor: 29.690
Authors: J A Abraham; D Damm; A Bajardi; J Miller; M Klagsbrun; R A Ezekowitz Journal: Biochem Biophys Res Commun Date: 1993-01-15 Impact factor: 3.575