Roles of Angiotensin Peptides and Recombinant Human ACE2 in Heart Failure

Basu, Ratnadeep; Poglitsch, Marko; Yogasundaram, Haran; Thomas, Jissy; Rowe, Brian H.; Oudit, Gavin Y.

doi:10.1016/j.jacc.2016.11.064

Cited by 173 publications

(199 citation statements)

References 41 publications

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“…Briefly, serum conditioning for equilibrium analysis was performed at 37°C followed by stabilization through the addition of an enzyme inhibitor cocktail (Waters, Milford, Massachusetts), as described previously . Previous results have shown similar qualitative outcomes when comparing the quantification of circulating (stabilized immediately at blood drawing) and equilibrium angiotensin peptide levels . Stabilized equilibrated serum samples were further spiked with stable isotope labeled internal standards for each angiotensin metabolite as well as with the deuterated internal standard for aldosterone (aldosterone D4) at a concentration of 200 pg/mL.…”

Section: Methodsmentioning

confidence: 99%

“…The major end‐metabolites of the classical RAAS are angiotensin II and aldosterone, both of which directly or indirectly mediate sodium and water retention, vasoconstriction, and pathological remodeling of cardiac, vascular, and renal tissues . Recent reports describe an alternative RAAS pathway mediated by ACE2, prolyl‐carboxy‐peptidase 16, prolyl‐endo‐peptidase, and neprilysin, with production of the metabolites angiotensin 1‐9, angiotensin 1‐7 and angiotensin 1‐5 in people and dogs . Additional metabolites within this cascade have also been discovered including angiotensin 2‐10, angiotensin 2‐7, and angiotensin 3‐7 .…”

Section: Introductionmentioning

confidence: 99%

“…Additional metabolites within this cascade have also been discovered including angiotensin 2‐10, angiotensin 2‐7, and angiotensin 3‐7 . Whereas the functional importance of some metabolites is not yet known, angiotensin 1‐7 has counterbalancing vasodilatory and natriuretic properties …”

Section: Introductionmentioning

confidence: 99%

“…Although the RAAS has historically been challenging to investigate, renin‐angiotensin system equilibrium analysis has emerged as a novel technique that allows for comprehensive evaluation of this complex neurohormonal system. Catalyzing enzymes other than ACE (such as ACE2, neprilysin, chymase, and aminopeptidases) mediate production of RAAS metabolites in this pathway, and recent publications have begun to shed light on blood and tissue activities in dogs . This methodology has shown that ACE‐inhibitors not only suppress angiotensin II formation, but also increase levels of the beneficial peptide hormone angiotensin 1‐7, which is known to be metabolized to angiotensin 1‐5 by the N‐domain of ACE .…”

Section: Introductionmentioning

confidence: 99%

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Renin‐angiotensin aldosterone profile before and after angiotensin‐converting enzyme‐inhibitor administration in dogs with angiotensin‐converting enzyme gene polymorphism

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Domenig³

et al. 2020

Veterinary Internal Medicne

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Background An angiotensin‐converting enzyme (ACE) gene polymorphism occurs in dogs; however, functional importance is not well studied. Hypothesis We hypothesized that dogs with the polymorphism would show alternative renin‐angiotensin aldosterone system (RAAS) pathway activation and classical RAAS pathway suppression before and after ACE‐inhibitor administration, as compared to dogs without the polymorphism that would show this pattern only after ACE‐inhibitor administration. Animals Twenty‐one dogs with mitral valve disease that were genotyped for the ACE gene polymorphism. Methods This retrospective study utilized stored samples from 8 ACE gene polymorphism‐negative (PN) dogs and 13 ACE gene polymorphism‐positive (PP) dogs before and after enalapril administration. Equilibrium analysis was performed to evaluate serum RAAS metabolites and enzyme activities. Results were compared before and after enalapril, and between groups. Results The classical RAAS pathway was suppressed and the alternative RAAS pathway was enhanced for both genotypes after administration of enalapril, with no differences before enalapril administration. Aldosterone breakthrough occurred in both PN (38%) and PP (54%) dogs despite angiotensin II suppression. Aldosterone was significantly higher (P = .02) in ACE gene PP dogs (median, 92.17 pM; IQR, 21.85‐184.70) compared to ACE gene PN dogs (median, 15.91 pM; IQR, <15.00‐33.92) after enalapril. Conclusions and Clinical Importance The ACE gene polymorphism did not alter baseline RAAS activity. Aldosterone breatkthrough in some dogs suggests nonangiotensin mediated aldosterone production that might be negatively influenced by genotype. These results support the use of aldosterone receptor antagonists with ACE‐inhibitors when RAAS inhibition is indicated for dogs, especially those positive for the ACE gene polymorphism.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Renin‐angiotensin aldosterone profile before and after angiotensin‐converting enzyme‐inhibitor administration in dogs with angiotensin‐converting enzyme gene polymorphism

Adin

Atkins

Domenig³

et al. 2020

Veterinary Internal Medicne

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“…In addition, RAS peptides can also be modulated by pharmacological treatment. In this regard, patients with chronic HF treated with ACE inhibitors have elevated plasma levels of angio tensin 1-7 and reduced plasma levels of angio tensin II, whereas patients with acute HF treated with angio tensin II receptor antagonists have decreased plasma levels of angio tensin 1-7 and increased plasma levels of angiotensin II 134 . Furthermore, the addition of rhACE2 to plasma samples from patients with HF induced the conversion of angiotensin I and angiotensin II into angiotensin 1-9 and angiotensin 1-7, respectively 134 .…”

Section: Challenges In Interpretationmentioning

confidence: 99%

Counter-regulatory renin–angiotensin system in cardiovascular disease

et al. 2019

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| The renin-angiotensin system is an important component of the cardiovascular system. Mounting evidence suggests that the metabolic products of angiotensin I and IIinitially thought to be biologically inactive -have key roles in cardiovascular physiology and pathophysiology. This non-canonical axis of the renin-angiotensin system consists of angiotensin 1-7 , angiotensin 1-9, angiotensin-converting enzyme 2, the type 2 angiotensin II receptor (AT 2 R), the proto-oncogene Mas receptor and the Mas-related G protein-coupled receptor member D. Each of these components has been shown to counteract the effects of the classical reninangiotensin system. This counter-regulatory renin-angiotensin system has a central role in the pathogenesis and development of various cardiovascular diseases and, therefore, represents a potential therapeutic target. In this Review , we provide the latest insights into the complexity and interplay of the components of the non-canonical renin-angiotensin system, and discuss the function and therapeutic potential of targeting this system to treat cardiovascular disease.

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Skeletal muscle atrophy in heart failure with diabetes: from molecular mechanisms to clinical evidence

et al. 2020

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Two highly prevalent and growing global diseases impacted by skeletal muscle atrophy are chronic heart failure (HF) and type 2 diabetes mellitus (DM). The presence of either condition increases the likelihood of developing the other, with recent studies revealing a large and relatively poorly characterized clinical population of patients with coexistent HF and DM (HFDM). HFDM results in worse symptoms and poorer clinical outcomes compared with DM or HF alone, and cardiovascular‐focused disease‐modifying agents have proven less effective in HFDM indicating a key role of the periphery. This review combines current clinical knowledge and basic biological mechanisms to address the critical emergence of skeletal muscle atrophy in patients with HFDM as a key driver of symptoms. We discuss how the degree of skeletal muscle wasting in patients with HFDM is likely underpinned by a variety of mechanisms that include mitochondrial dysfunction, insulin resistance, inflammation, and lipotoxicity. Given many atrophic triggers (e.g. ubiquitin proteasome/autophagy/calpain activity and supressed IGF1‐Akt‐mTORC1 signalling) are linked to increased production of reactive oxygen species, we speculate that a higher pro‐oxidative state in HFDM could be a unifying mechanism that promotes accelerated fibre atrophy. Overall, our proposal is that patients with HFDM represent a unique clinical population, prompting a review of treatment strategies including further focus on elucidating potential mechanisms and therapeutic targets of muscle atrophy in these distinct patients.

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Roles of Angiotensin Peptides and Recombinant Human ACE2 in Heart Failure

Cited by 173 publications

References 41 publications

Renin‐angiotensin aldosterone profile before and after angiotensin‐converting enzyme‐inhibitor administration in dogs with angiotensin‐converting enzyme gene polymorphism

Renin‐angiotensin aldosterone profile before and after angiotensin‐converting enzyme‐inhibitor administration in dogs with angiotensin‐converting enzyme gene polymorphism

Counter-regulatory renin–angiotensin system in cardiovascular disease

Skeletal muscle atrophy in heart failure with diabetes: from molecular mechanisms to clinical evidence

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