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Global Translational Medicine

ORIGINAL RESEARCH ARTICLE
Antisense oligonucleotides targeting hepatic

angiotensinogen reduce atherosclerosis and
liver steatosis in hypercholesterolemic mice

1,2
Dien Ye , Congqing Wu 1,3,4,5 , Lei Cai , Deborah A. Howatt , Ching-Ling Liang ,
1
1
1
6,7
Yuriko Katsumata , Adam E. Mullick , Ryan E. Temel , A.H. Jan Danser ,
8
2
1,9
Alan Daugherty 1,3,9 , and Hong S. Lu 1,3,9 *
1 Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA
2 Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC,
Rotterdam, Netherlands
3 Saha Aortic Center, University of Kentucky, Lexington, KY, USA
4 Department of Surgery, University of Kentucky, Lexington, KY, USA
5 Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky,
Lexington, KY, USA
6 Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA
7 Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA
8 Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA
9 Department of Physiology, University of Kentucky, Lexington, KY, USA

Abstract
Hepatocyte-derived angiotensinogen (AGT) is the precursor of angiotensin II
(AngII). We determined the effects of hepatocyte-specific (N-acetylgalactosamine-
*Corresponding author: conjugated) antisense oligonucleotides targeting AGT (GalNAc AGT ASO) on AngII-
Hong S. Lu mediated blood pressure (BP) regulation and atherosclerosis and compared its
(Hong.Lu@uky.edu) effects with losartan, an AngII type 1 (AT1) receptor blocker, in hypercholesterolemic
Citation: Ye D, Wu C, Cai L, et al., mice. Eight-week-old male low-density lipoprotein (LDL) receptor deficient mice
2023, Antisense oligonucleotides were administered vehicle or GalNAc AGT ASO (1, 2.5, or 5 mg/kg) subcutaneously
targeting hepatic angiotensinogen
reduce atherosclerosis and liver beginning 2 weeks before the initiation of Western diet feeding. All mice were fed
steatosis in hypercholesterolemic Western diet for 12 weeks. Their systolic BP was monitored by the tail-cuff technique,
mice. Global Transl Med, 2(1): 288. and the atherosclerotic lesion area was measured by an en face method. Although
https://doi.org/10.36922/gtm.288
the effects of all 3 doses of GalNAc AGT ASO on plasma AGT concentrations were
Received: December 8, 2022 similar, GalNAc AGT ASO reduced BP and atherosclerotic lesion size in a dose-
Accepted: February 7, 2023
Published Online: February 24, 2023 dependent manner. Subsequently, we compared the effects of GalNAc AGT ASO
(5 mg/kg) with losartan (15 mg/kg/day). Compared to losartan, GalNAc AGT ASO
Copyright: © 2023 Author(s).
This is an Open Access article led to more profound increases in plasma renin and reduction in BP but had similar
distributed under the terms of the effects on atherosclerosis. Remarkably, GalNAc AGT ASO also reduced liver steatosis,
Creative Commons Attribution which was not observed in losartan-treated mice. In conclusion, the BP increase
License, permitting distribution,
and reproduction in any medium, and atherosclerosis development in hypercholesterolemic mice are dependent on
provided the original work is AngII generated from hepatic AGT. Deleting hepatic AGT improves diet-induced liver
properly cited. steatosis, and this occurs in an AT1 receptor-independent manner.
Publisher’s Note: AccScience
Publishing remains neutral with Keywords: Angiotensinogen; Antisense oligonucleotides; Blood pressure; Liver steatosis;
regard to jurisdictional claims in
published maps and institutional Atherosclerosis
affiliations.

Volume 2 Issue 1 (2023) 1 https://doi.org/10.36922/gtm.288