2017 Cardiovascular Research Day Abstract Book

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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.
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