Why the study?
Hepatocyte-derived angiotensinogen is the precursor of angiotensin II, but the effects of hepatocyte-specific antisense oligonucleotides targeting angiotensinogen on blood pressure regulation and atherosclerosis compared with AT1 receptor blockade were unknown.
Does GalNAc AGT ASO reduce blood pressure and atherosclerosis in hypercholesterolemic mice?
Does GalNAc AGT ASO reduce blood pressure and atherosclerosis in hypercholesterolemic mice?
Targeting hepatic angiotensinogen with GalNAc AGT ASO reduces blood pressure, atherosclerosis, and liver steatosis in hypercholesterolemic mice.
I need the full abstract and conclusions to write an accurate implication.Should not yet change practice; leaves open whether hepatic AGT silencing offers benefits beyond ARBs in humans.
Hepatocyte-derived angiotensinogen (AGT) is the precursor of angiotensin II (AngII). We determined the effects of hepatocyte-specific (N-acetylgalactosamine-conjugated) antisense oligonucleotides targeting AGT (GalNAc AGT ASO) on AngII-mediated blood pressure (BP) regulation and atherosclerosis and compared its effects with losartan, an AngII type 1 (AT1) receptor blocker, in hypercholesterolemic mice. Eight-week-old male low-density lipoprotein (LDL) receptor deficient mice were administered vehicle or GalNAc AGT ASO (1, 2.5, or 5 mg/kg) subcutaneously beginning 2 weeks before the initiation of Western diet feeding. All mice were fed Western diet for 12 weeks. Their systolic BP was monitored by the tail-cuff technique, and the atherosclerotic lesion area was measured by an en face method. Although the effects of all 3 doses of GalNAc AGT ASO on plasma AGT concentrations were similar, GalNAc AGT ASO reduced BP and atherosclerotic lesion size in a dose-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 led to more profound increases in plasma renin and reduction in BP but had similar effects on atherosclerosis. Remarkably, GalNAc AGT ASO also reduced liver steatosis, which was not observed in losartan-treated mice. In conclusion, the BP increase and atherosclerosis development in hypercholesterolemic mice are dependent on AngII generated from hepatic AGT. Deleting hepatic AGT improves diet-induced liver steatosis, and this occurs in an AT1 receptor-independent manner.
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Ye et al. (2023) studied this question.
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