Targeting hepatic heparin-binding EGF-like growth factor (HB-EGF) induces anti-hyperlipidemia leading to reduction of angiotensin II-induced aneurysm development.

Seonwook Kim,Lei Cai,Sangderk Lee,Debra L Rateri,Ryan E Temel,Mark J Graham,Lihua Yang,Aldons J Lusis,Richard G Lee,Judith A Berliner,Seongu Kim,Christian Schulz

doi:10.1371/journal.pone.0182566

Abstract

ObjectiveThe 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 resultsLow-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.ConclusionThis 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.

Highlights

The HBEGF targeting suppressed hepatic very low density lipoprotein (VLDL) secretion rate without changing heparin-releasable plasma triglyceride (TG) hydrolytic activity or fecal neutral cholesterol excretion rate. This result suggested that the HB-epidermal growth factor (EGF) targeting induced protection against aneurysm development through anti-hyperlipidemic effects
Targeting of Heparin binding EGF-like growth factor (HB-EGF) against aneurysm not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript
Heparin binding EGF-like growth factor (HB-EGF), which is a member of epidermal growth factor (EGF) family member and a ligand for EGF-receptor (EGFR) [1], is involved in various pathophysiological processes including atherosclerosis and cancer development [2,3,4,5,6]

Summary

Introduction

Heparin binding EGF-like growth factor (HB-EGF), which is a member of epidermal growth factor (EGF) family member and a ligand for EGF-receptor (EGFR) [1], is involved in various pathophysiological processes including atherosclerosis and cancer development [2,3,4,5,6]. HB-EGF regulates proliferation of vascular smooth muscle cell (VSMC) [9, 10] and inflammatory gene expression in the aortic endothelium under hyperlipidemic environment [11]. Hyperlipidemia is a key risk factor for the development of vascular diseases including aneurysm and atherosclerosis [14, 15]. For lipid or lipoprotein homeostasis, the balance of production and clearance of VLDL in the liver and capillary endothelium of peripheral tissues is critical [16]. For the production of VLDL in the liver cells, the expression and stability of apolipoprotein B (apoB) and lipid transferring protein microsomal triglyceride transfer protein (MTP) are key determinants [17]. The clearance of VLDL in circulation is mainly regulated by vascular endothelial lipoprotein lipase (LPL) [18]

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