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2017 Cardiovascular Research Day Abstract Book

95 Targeting of HB-EGF

95 Targeting of HB-EGF against hypertension and renal damage Lihua Yang, MS 1 • Seonwook Kim 1 • Debra Rateri 1 • Richard Lee, PhD 2 • Mark Graham, PhD 2 • Sangderk Lee, PhD 1 1Saha Cardiovascular Research Center, University of Kentucky • 2 Cardiovascular Antisense Drug Discovery Group, Ionis Pharmaceuticals Staff Study goal: Previous reports suggested that the heparin binding EGF-like growth factor (HB-EGF), which is an EGFR ligand, is positively involved in the development of renal disease. In this study, we tested the effects of the HB-EGF targeting using antisense oligonucleotide (ASO) administration on the blood pressure and renal damage induced by AngII infusion in mouse model systems. Experimental design and results: To test the effects of the HB-EGF ASO administration on the AngIIinduced hypertension, C57BL/6 mice (male, 10 weeks of age) were pretreated with control and HB- EGF ASO for 2 weeks and cotreated with AngII infusion (1,000ng/min/kg) for additional 4 weeks. We monitored blood pressure changes during 6 weeks using standard tail-cuff procedure. We observed that the HB-EGF ASO administration significantly downregulated basal and AngII-induced blood pressure in the system. The HB-EGF targeting also reduced the kidney size. To test the effects of the HB-EGF targeting on the renal damage, the LDLR KO mice (male, 16 weeks of age) were pretreated with control and HB-EGF ASO and cotreated with high fat diet (HFD; 42% calorie from fat, 0.2% cholesterol) and AngII-infusion (1,000ng/min/kg) for additional 4 weeks. At the termination step, we compared plasma creatinine and BUN levels as markers of the status of the renal damage. The result showed that the HB-EGF ASO administration effectively protected against HFD and AngII-induced renal damage in the mouse model system. Conclusion: These results suggested that the HB-EGF signaling positively involved in regulating blood pressure and renal damage. The targeting of the HB-EGF signaling might be an approach to delay the development of the hypertension associated with renal damage. 111

96 HB-EGF is a Key Positive Regulator of Hepatic VLDL Secretion Seonwook Kim 1 • Lihua Yang, MS 1 • Debra Rateri 1 • Ryan Temel, PhD 1 • Richard Lee, PhD 2 • Mark Graham, PhD 2 • Sangderk Lee, PhD 1 1Saha Cardiovascular Research Center, University of Kentucky • 2 Cardiovascular Antisense Drug Discovery Group, Ionis Pharmaceuticals Staff Study goal: Unbalanced hepatic VLDL production (assembly/secretion) is a risk factor for the development of hypertriglyceridemia or non-alcoholic fatty liver disease (NAFLD) under metabolic stress conditions like metabolic syndrome. Previous reports showed that the circulatory heparinbinding EGF-like growth factor (HB-EGF), which is a ligand of EGFR, is correlated with cholesterol level and risk of coronary artery disease in human. From these previous data, we tested the hypothesis that the HB-EGF signaling is a positive regulator of VLDL production in the liver. Experimental procedure and results: In Hep-G2 cells, the recombinant HB-EGF induced increase of the apoB secretion, which is an essential component of VLDL particle. In C57BL/6 mice, the administration of recombinant HB-EGF increased hepatic VLDL secretion; in contrast, the HB-EGF antisense oligonucleotide (ASO) administration or the tail-vein injection of EGFR blocker BIBX1382 induced significant suppressions of the hepatic VLDL secretion. The HB-EGF ASO administration effectively downregulated circulatory lipid levels (TG and cholesterol) associated with VLDL particles in multiple mouse strains (C57BL/6, LDLR KO, and apoE KO). At the same time, the targeting induced accumulation of neutral lipids in the liver, specifically, TG and cholesterol ester. Conclusion: These results indicate that the HB-EGF signaling positively regulates VLDL secretion in the liver under normal and metabolic stress condition. Future study of the interaction with insulin signaling for the regulation would be interesting in understand the pathology of metabolic symptom. 112

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