Intracrine angiotensin II functions originate from noncanonical pathways in the human heart

Ferrario, Carlos M.; Ahmad, Sarfaraz; Varagić, Jasmina; Cheng, Che Ping; Groban, Leanne; Wang, Hao; Collawn, James F.; Dell’Italia, Louis J.

doi:10.1152/ajpheart.00219.2016

Cited by 59 publications

(63 citation statements)

References 156 publications

(359 reference statements)

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“…6 In support of this hypothesis is work that demonstrate superiority of AGT ASO over lisinopril treatment in reducing kidney cystogenesis in a model of polycystic kidney disease. 23 Future studies are required to determine the mechanism(s) of angiotensin or aldosterone breakthrough in 8% salt-fed SHRs and whether such mechanisms are a common phenomenon in other low renin models of hypertension.…”

Section: Discussionmentioning

confidence: 92%

“…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][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.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 92%

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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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“…Selective chymase inhibitors will be helpful to understand the mechanisms of retinopathy progression and also to develop the early treatment. We have evidence that the intracellular formation of Ang II via chymase pathway is independent and not affected by inhibition of Ang II production by ACE or ARBs [12, 100]. However, further research is needed in this regard to investigate the beneficial effects of chymase inhibition over ACE in the treatment/prevention of retinopathy and other eye diseases.…”

Section: New Therapeutic Approach To Block Cellular Ang II Formationmentioning

confidence: 99%

Role of Tissue Renin-angiotensin System and the Chymase/angiotensin-( 1-12) Axis in the Pathogenesis of Diabetic Retinopathy

Ola

Alhomida

Ferrario

et al. 2017

CMC

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Diabetic retinopathy (DR) is a major diabetes complication and the leading cause for vision loss and blindness in the adult human population. Diabetes, being an endocrinological disorder dysregulates a number of hormonal systems including the renin angiotensin system (RAS), which thereby may damage both vascular and neuronal cells in the retina. Angiotensin II (Ang II), an active component of the RAS is increased in diabetic retina, and may play a significant role in neurovascular damage leading to the progression of DR. In this review article, we highlight the role of Ang II in the pathogenesis of retinal damage in diabetes and discuss a newly identified mechanism involving tissue chymase and angiotensin-(1-12) [Ang-(1-12)] pathways. We also discuss the therapeutic effects of potential RAS inhibitors targeting blockade of cellular Ang II formation to prevent/protect the retinal damage. Thus, a better understanding of Ang II formation pathways in the diabetic retina will elucidate early molecular mechanism of vision loss. These concepts may provide a novel strategy for preventing and/or treating diabetic retinopathy, a leading cause of blindness worldwide.

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“…While an ACE escape mechanism has been suggested to account for the recovery of Ang II [148], no sufficient attention has been paid to the multiple studies showing that chymase, rather than ACE, is the main Ang II-forming enzyme from either Ang I or Ang-(1-12) in humans in tissues like the heart and vascular wall [20, 35–39, 52]. Studies by Wei et al [149] in ACE knockout mice and those of Ahmad et al [40, 50, 51, 150] and Ferrario et al [42] in rats expressing the human AGT gene demonstrate a critical role of chymase as a tissue Ang II forming enzyme.…”

Section: 0 Angiotensin Converting Enzyme Inhibitorsmentioning

confidence: 99%

“…In our minds, such lackluster and/or nonexistent efficacy improvements beyond ACE inhibitors underscores the role of the RAAS in the etiopathogenesis of cardiovascular disease. The small effect of ARBs is suggestive of intracellular sites of Ang II activity that would be largely unopposed [19, 20, 173–175]. That ARBs induce compensatory pathways that increase circulating Ang II as well as increased expression of downstream metabolites like Ang-(1-7) [13, 59] underscore the complexity of understanding the mechanisms that limit their efficacy.…”

Section: 0 Angiotensin Receptor Blockersmentioning

confidence: 99%

Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease

Ferrario

Mullick

2017

Pharmacological Research

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A collective century of discoveries establishes the importance of the renin angiotensin aldosterone system in maintaining blood pressure, fluid volume and electrolyte homeostasis via autocrine, paracrine and endocrine signaling. While research continues to yield new functions of angiotensin II and angiotensin-(1-7), the gap between basic research and clinical application of these new findings is widening. As data accumulates on the efficacy of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers as drugs of fundamental importance in the treatment of cardiovascular and renal disorders, it is becoming apparent that the achieved clinical benefits is suboptimal and surprisingly no different than what can be achieved with other therapeutic interventions. We discuss this issue and summarize new pathways and mechanisms effecting the synthesis and actions of angiotensin II. The presence of renin-independent non-canonical pathways for angiotensin II production are largely unaffected by agents inhibiting renin angiotensin system activity. Hence, new efforts should be directed to develop drugs that can effectively block the synthesis and/or action of intracellular angiotensin II. Improved drug penetration into cardiac or renal sites of disease, inhibiting chymase –the primary angiotensin II forming enzyme in the human heart–, and/or inhibiting angiotensinogen synthesis would all be more effective strategies to inhibit the system. Additionally, given the role of angiotensin II in the maintenance of renal homeostatic mechanisms, any new inhibitor should possess greater selectivity of targeting pathogenic angiotensin II signaling processes and thereby limit inappropriate inhibition.

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Intracrine angiotensin II functions originate from noncanonical pathways in the human heart

Cited by 59 publications

References 156 publications

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

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

Role of Tissue Renin-angiotensin System and the Chymase/angiotensin-( 1-12) Axis in the Pathogenesis of Diabetic Retinopathy

Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease

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