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Global Translational Medicine GalNAc AGT ASO reduce atherosclerosis

A B C

D E

Figure 4. Effects of hepatocyte-specific antisense oligonucleotides of angiotensinogen versus losartan on renin, systolic blood pressure, and atherosclerotic
lesion size. (A) Plasma renin concentration (PRC); N = 10 per group. (B) Renal renin mRNA abundance by quantitative polymerase chain reaction;
N = 6 per group. (C) Systolic blood pressure (BP) at week 7. (D) En face aortic images; scale bar = 1 mm. (E) Atherosclerotic lesion area in the thoracic
aorta; N = 10 per group.
AngI: Angiotensin I; GalNAc AGT ASO: N-acetylgalactosamine-conjugated antisense oligonucleotides targeting angiotensinogen; PBS: Phosphate-
buffered saline.

risk factor for atherosclerosis, there is a growing body of It is important to note that mice, unlike humans,
evidence suggesting that BP per se does not contribute to display a very high turnover of AGT, reflected by lower
atherosclerosis . The different magnitudes of suppressing plasma AGT concentrations than in humans. Hence, the
[23]
AGT versus blocking AT1 receptor on BP and atherosclerosis des(AngI)AGT/intact AGT ratio is higher in mice than
in this study support this notion. Overall, this study in humans [26] . Although administration of losartan did
unequivocally shows that BP regulation and atherosclerosis not affect AGT and liver steatosis in the present study,
in hypercholesterolemic LDL receptor mice are dependent earlier studies have reported suppression of liver steatosis
-/-
on AngII generated from AGT of hepatic origin, thereby in mice administered with RAS inhibitors [27-29] . This may
agreeing with the observations made in mice displaying reflect a different and larger degree of renin-angiotensin
genetic hepatocyte-specific AGT deficiency [8,24,25] .
blockade, potentially lowering AGT [30] and/or affecting
Remarkably, GalNAc AGT ASO, but not losartan, the des(AngI)AGT/intact AGT ratio. The molecular
reduced Western diet-induced liver steatosis, which mechanism underlying the direct effect of des(AngI)
was manifested as increased cholesterol and triglyceride AGT is unknown. It may involve interference with the
content in the liver. This finding is consistent with our protein kinase B (Akt)/mammalian target of rapamycin
previous studies in hepAGT mice [8,19] . These effects (mTOR)/sterol responsive element-binding protein
-/-
occurred in a dose-independent manner and likely [19]
represent the direct consequence of lowering AGT, which 1c (SREBP-1c) pathway , which is associated with
occurred following GalNAc AGT ASO administration. liver steatosis and suppressed in mice with hepatocyte-
Indeed, the expression of des(AngI)AGT induced liver specific deletion of AGT. It is also unknown whether
steatosis in hepatocyte-specific AGT deficient mice fed a intact AGT exerts similar effects. Studying this would
Western diet . Given the liver-specific activity of GalNAc require the AAV-induced expression of intact AGT
[8]
AGT ASO , we would expect non-hepatic AGT to have in hepAGT mice under complete renin-angiotensin
-/-
[14]
no effect on liver steatosis. blockade.

Volume 2 Issue 1 (2023) 7 https://doi.org/10.36922/gtm.288