Angiotensinogen Exerts Effects Independent of Angiotensin II

Lü, Hong; Wu, Congqing; Howatt, Deborah A.; Balakrishnan, Anju; Moorleghen, Jessica J.; Chen, Xiaofeng; Zhao, Mingming; Graham, Mark; Mullick, Adam E.; Crooke, Rosanne M.; Feldman, David L.; Cassis, Lisa A.; Kooi, Craig W. Vander; Daugherty, Alan

doi:10.1161/atvbaha.115.306740

Cited by 75 publications

(144 citation statements)

References 53 publications

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“…12 This injection route was also used in our previous studies for AAV vector expressing mouse angiotensinogen, which led to profound increases of plasma angiotensinogen concentrations in mice lack systemic angiotensinogen. 14,15 Collectively, our study provides evidence that intraperitoneal injection is a feasible method for efficient AAV infection to deliver mouse PCSK9D377Y mutation.…”

Section: Discussionmentioning

confidence: 69%

Hypercholesterolemia Induced by a PCSK9 Gain-of-Function Mutation Augments Angiotensin II–Induced Abdominal Aortic Aneurysms in C57BL/6 Mice—Brief Report

Lü

Howatt

Balakrishnan

et al. 2016

ATVB

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Objective Gain-of-function mutations of proprotein convertase subtilisin/kexin type 9 (PCSK9) lead to hypercholesterolemia. This study was to determine whether infection of normocholesterolemic mice with an adeno-associated viral vector (AAV) expressing a gain-of-function mutation of mouse PCSK9 increased angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs). Approach and Results In an initial study, male C57BL/6 mice were injected intraperitoneally with either an empty vector or PCSK9 gain-of-function mutation (D377Y).AAV at three doses and fed a saturated fat-enriched diet for 6 weeks. Two weeks after AAV injection, mice were infused with AngII for 4 weeks. Plasma PCSK9 concentrations were increased dose-dependently in mice injected with AAV containing PCSK9D377Y mutation, and positively associated with elevations of plasma cholesterol concentrations. Infection with intermediate and high doses of PCSK9D377Y.AAV led to equivalent increases of maximal width of abdominal aortas in C57BL/6 mice infused with AngII. Therefore, the intermediate dose was used in subsequent experiments. We then determined effects of PCSK9D377Y.AAV infection on 5 normolipidemic mouse strains, demonstrating that C57BL/6 mice were the most susceptible to this AAV infection. PCSK9D377Y.AAV infected male C57BL/6 mice were also compared with age-matched male low-density lipoprotein (LDL) receptor −/− mice. Although plasma cholesterol concentrations were lower in mice infected with PCSK9D377Y.AAV, these mice had equivalent AAA formation, compared to LDL receptor −/− mice. In a separate study, reduced plasma PCSK9 concentrations by PCSK9 antisense oligonucleotides in male LDL receptor −/− mice did not influence AngII-induced AAAs. Conclusion AAV-mediated infection with a mouse PCSK9 gain-of-function mutation is a rapid, easy, and efficient approach for inducing hypercholesterolemia and promoting AAAs in C57BL/6 mice infused with AngII.

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Section: Discussionmentioning

confidence: 69%

Hypercholesterolemia Induced by a PCSK9 Gain-of-Function Mutation Augments Angiotensin II–Induced Abdominal Aortic Aneurysms in C57BL/6 Mice—Brief Report

Lü

Howatt

Balakrishnan

et al. 2016

ATVB

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“…Such findings are consistent with previous reports showing that the circulating pool of AGT is primarily liver derived in both lean 9 and obese mice. 7,8 The hypotension, hyperkalemia, and acute renal failure associated with RAAS blockade could be largely attributable to inappropriate inhibition of intrarenal RAAS. Indeed, liver-selective GalNAc AGT ASO treatment provided superior tolerability during a severe RAAS challenge compared with treatments of Gen 2.5 AGT ASO, captopril, or losartan.…”

Section: Discussionmentioning

confidence: 99%

“…6 AGT (angiotensinogen) is the source of all downstream angiotensin metabolites. The liver is the principal source of circulating AGT, [7][8][9] although extrahepatic sites of expression, such as in the kidney, have been implicated in the regulation of blood pressure (BP), sodium, and water homeostasis. 10 More aggressive RAAS inhibition, as attempted by combining different classes of RAAS inhibitors, has demonstrated poor clinical utility due in part to adverse effects, such as hyperkalemia, hypotension, and acute renal failure.…”

mentioning

confidence: 99%

Blood Pressure Lowering and Safety Improvements With Liver Angiotensinogen Inhibition in Models of Hypertension and Kidney Injury

et al. 2017

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566T he discovery and development of renin-angiotensin-aldosterone system (RAAS) inhibitors have established a role of angiotensin II (Ang II) in disease, leading to therapies that are the foundation of treatment for cardiovascular and renal diseases.1 Yet, as effective as RAAS inhibitors have been in the clinic, there is a need to improve the efficacy, safety, and tolerability of this drug class.Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARBs) elicit compensatory pathways resulting in angiotensin reactivation and aldosterone breakthrough such that plasma Ang II and aldosterone return to pretreatment levels or higher. 2,3 This phenomenon may contribute to the suboptimal efficacy of RAAS blockade in patients with resistant hypertension and heart failure. 4,5 Noncanonical pathways of Ang II generation and intracellular RAAS signaling are considered important mechanisms that limit the therapeutic potential of this drug class. 6 AGT (angiotensinogen) is the source of all downstream angiotensin metabolites. The liver is the principal source of circulating AGT, 7-9 although extrahepatic sites of expression, such as in the kidney, have been implicated in the regulation of blood pressure (BP), sodium, and water homeostasis. 10 More aggressive RAAS inhibition, as attempted by combining different classes of RAAS inhibitors, has demonstrated poor clinical utility due in part to adverse effects, such as hyperkalemia, hypotension, and acute renal failure.11 A current hypothesis is that such untoward effects are because of excessive renal RAAS inhibition. 12 Thus, a more effective therapeutic strategy would (1) work upstream of the RAAS enzymes and receptors, thereby avoiding compensatory mechanisms and intracrine signaling that limit therapeutic efficacy, and (2) have limited kidney activity, thereby providing the benefits of aggressive RAAS suppression without provoking renal complications.To this end, we developed a liver-selective AGT antisense oligonucleotide (ASO) that produced potent and durable reductions of liver AGT expression after systemic administration. Liver targeting is achieved by covalent linkage of triantennary N-acetylgalactosamine (GalNAc), a high-affinity ligand for the hepatocyte-specific asialoglycoprotein receptor, to an ASO. This GalNAc-conjugate approach results in enhanced ASO delivery to hepatocytes Abstract-Uncontrolled hypertension is an important contributor to cardiovascular disease. Despite the armamentarium of antihypertensive treatments, there remains a need for novel agents effective in individuals who cannot reach acceptable blood pressure levels. Inhibitors targeting the renin-angiotensin-aldosterone system (RAAS) are widely used but may not optimally inhibit RAAS and demonstrate an acceptable safety profile. Experiments were conducted to characterize a series of AGT (angiotensinogen) antisense oligonucleotides (ASOs) and compare their efficacy and tolerability to traditional RAAS blockade. AGT ASOs which target multiple systemic sites of AGT versus an N...

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“…Development of hepatocyte-specific AGT deficient mice has been reported previously. 4,9,10 AGT floxed (termed "Agt f/f") x albumin-Cre -/-(hepAGT +/+) and Agt f/f x albumin-Cre +/-(hepAGT -/-) littermates were used for experiments described in this manuscript. Genotypes were determined prior to weaning and validated after termination by Cre PCR, and confirmed by measuring plasma AGT concentrations during the study and after termination.…”

Section: Animalsmentioning

confidence: 99%

The Two Amino Acids Proximate to the Renin Cleavage Site of Human Angiotensinogen Do Not Affect Angiotensin II-mediated Functions in Mice

Howatt

et al. 2019

Preprint

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Objective: Renin cleavage of angiotensinogen (AGT) has species specificity. Since the residues at positions 11 and 12 of AGT are different between human and mouse AGT, we determined whether these two residues in AGT affect renin cleavage and angiotensin II-mediated functions using an adeno-associated viral (AAV) approach for manipulating AGT in vivo. Approach and Results:Hepatocyte-specific AGT deficient (hepAGT-/-) mice in an LDL receptor -/-background were infected with AAVs containing a null insert, human AGT, or mouse AGT expressing the same residues of the human protein at positions 11 and 12 [mouse AGT (L11V;Y12I)]. Expression of human AGT in hepAGT-/-mice led to high plasma human AGT concentrations without changes in plasma mouse endogenous AGT, plasma renin concentrations, blood pressure, or atherosclerosis. This is consistent with human AGT not being cleaved by mouse renin. To determine whether the residues at positions 11 and 12 in human AGT lead to the inability of mouse renin to cleave human AGT, hepAGT-/-mice were injected with AAV encoding mouse AGT (L11V;Y12I). Expression of mouse AGT (L11V;Y12I) resulted in increased plasma mouse AGT concentrations, reduced renin concentrations, and increased renal AngII concentrations that were comparable to their concentrations in hepAGT+/+ mice. This mouse AGT variant increased blood pressure and atherosclerosis in hepAGT-/-mice to the magnitude of hepAGT+/+ mice. Conclusion:Replacement of L11 and Y12 to V11 and I12, respectively, in mouse AGT does not affect renin cleavage and AngII-mediated functions in mice. HIGHLIGHTS •Human AGT is not cleaved by mouse renin and does not change AngII-mediated functions in hepatocyte-specific AGT -/-mice. • Replacement of the N-terminal amino acids at 11 and 12 positions from mouse to human AGT does not affect renin cleavage and AngII-mediated functions in hepatocyte-specific AGT -/-mice.

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Angiotensinogen Exerts Effects Independent of Angiotensin II

Cited by 75 publications

References 53 publications

Hypercholesterolemia Induced by a PCSK9 Gain-of-Function Mutation Augments Angiotensin II–Induced Abdominal Aortic Aneurysms in C57BL/6 Mice—Brief Report

Hypercholesterolemia Induced by a PCSK9 Gain-of-Function Mutation Augments Angiotensin II–Induced Abdominal Aortic Aneurysms in C57BL/6 Mice—Brief Report

Blood Pressure Lowering and Safety Improvements With Liver Angiotensinogen Inhibition in Models of Hypertension and Kidney Injury

The Two Amino Acids Proximate to the Renin Cleavage Site of Human Angiotensinogen Do Not Affect Angiotensin II-mediated Functions in Mice

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