Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease

Angiotensin-converting enzyme 2 (ACE2) shares some homology with angiotensin-converting enzyme (ACE) but is not inhibited by ACE inhibitors. The main role of ACE2 is the degradation of Ang II resulting in the formation of angiotensin 1–7 (Ang 1–7) which opposes the actions of Ang II. Increased Ang II levels are thought to upregulate ACE2 activity, and in ACE2 deficient mice Ang II levels are approximately double that of wild-type mice, whilst Ang 1–7 levels are almost undetectable. Thus, ACE2 plays a crucial role in the RAS because it opposes the actions of Ang II. Consequently, it has a beneficial role in many diseases such as hypertension, diabetes, and cardiovascular disease where its expression is decreased. Not surprisingly, current therapeutic strategies for ACE2 involve augmenting its expression using ACE2 adenoviruses, recombinant ACE2 or compounds in these diseases thereby affording some organ protection

Association of dietary sodium intake with atherogenesis in experimental diabetes and with cardiovascular disease in patients with Type 1 diabetes

Abstract It is recommended that individuals with diabetes restrict their dietary sodium intake. However, although salt intake is correlated with BP (blood pressure), it also partly determines the activation state of the RAAS (reninangiotensin-aldosterone system), a key mediator of diabetes-associated atherosclerosis. apoE KO (apolipoprotein E knockout) mice were allocated for the induction of diabetes with streptozotocin or citrate buffer (controls) and further randomized to isocaloric diets containing 0.05 %, 0.3 % or 3.1 % sodium with or without the ACEi [ACE (angiotensin-converting enzyme) inhibitor] perindopril. After 6 weeks of study, plaque accumulation was quantified and markers of atherogenesis were assessed using RT-PCR (reverse transcription-PCR) and ELISA. The association of sodium intake and adverse cardiovascular and mortality outcomes were explored in 2648 adults with Type 1 diabetes without prior CVD (cardiovascular disease) from the FinnDiane study. A 0.05 % sodium diet was associated with increased plaque accumulation in diabetic apoE KO mice, associated with activation of the RAAS. By contrast, a diet containing 3.1 % sodium suppressed atherogenesis associated with suppression of the RAAS, with an efficacy comparable with ACE inhibition. In adults with Type 1 diabetes, low sodium intake was also associated with an increased risk of all-cause mortality and new-onset cardiovascular events. However, high sodium intake was also associated with adverse outcomes, leading to a J-shaped relationship overall. Although BP lowering is an important goal for the management of diabetes, off-target actions to activate the RAAS may contribute to an observed lack of protection from cardiovascular complications in patients with Type 1 diabetes with low sodium intake

Angiotensin-converting enzyme 2 is a key modulator of the renin-angiotensin system in cardiovascular and renal disease

Abstract PURPOSE OF REVIEW: Angiotensin-converting enzyme 2 (ACE2) has recently emerged as a key regulator of the renin-angiotensin system in both health and disease. RECENT FINDINGS: ACE2 deficiency is associated with elevated tissue and circulating levels of angiotensin II and reduced levels of angiotensin 1-7. Phenotypically, this results in a modest elevation in systolic blood pressure and left ventricular hypertrophy. In atherosclerosis-prone apolipoprotein E knockout mice, ACE2 deficiency results in augmented vascular inflammation and an inflammatory response that contributes to increased atherosclerotic plaque formation. In the kidney, ACE2 deficiency is associated with progressive glomerulosclerosis. Interventions such as ACE2 replenishment or augmentation of its actions have proven successful in reducing hypertension, plaque accumulation, and renal and cardiac damage in a range of different models. Although promising, the balance of the renin-angiotensin system remains complicated, with some evidence that overexpression of ACE2 may have adverse cardiac effects, and ACE2 and its metabolic products may promote epithelial-to-mesenchymal transition. SUMMARY: Repletion of ACE2's activities offers a new strategy to complement current clinical interventions in treating hypertension, renal and cardiovascular disease. In particular conditions where ACE inhibition and angiotensin receptor blockade are partially effective, the adjunctive actions of ACE2 may not only reduce clinical escape but also augment the efficacy of interventions

Angiotensin converting enzyme 2 and atherosclerosis

Angiotensin converting enzyme 2 (ACE2) is a homolog of angiotensin converting enzyme (ACE) which generates angiotensin II from angiotensin I. ACE, its product angiotensin II and the downstream angiotensin type I receptor are important components of the renin-angiotensin system (RAS). Angiotensin II, the most important component of the RAS, promotes the development of atherosclerosis. The identification of ACE2 in 2000 opened a new chapter of research on the regulation of the RAS. ACE2 degrades pro-atherosclerotic angiotensin II and generates anti-atherosclerotic angiotensin 1-7. In this review, we explored the importance of ACE2 in protecting experimental animals from developing atherosclerosis and its involvement in human atherosclerosis. We also examined the published evidence assessing the importance of ACE2 in different cell types relevant to atherosclerosis and putative underlying cellular and molecular mechanisms linking ACE2 with protection from atherosclerosis. ACE2 shifts the balance from angiotensin II to angiotensin 1-7 inhibiting the progression of atherosclerosis in animal models

Heparanase is involved in the pathogenesis of proteinuria as a result of glomerulonephritis

The β-D-endoglycosidase heparanase has been proposed to be important in the pathogenesis of proteinuria by selectively degrading the negatively charged side chains of heparan sulfate proteoglycans within the glomerular basement membrane. A loss of negat

Heparanase inhibition reduces porteinuria in a model of accelerated anti-glomerular basement membrane antibody disease

Background: The β-D-endoglycosidase, heparanase, is emerging as an important contributor to the pathogenesis of proteinuria. The purpose of the present study therefore was to examine the role of heparanase in a model of accelerated anti-glomerular basem

The arterial depressor response to chronic low-dose angiotensin II infusion in female rats is estrogen dependent

Sampson AK, Hilliard LM, Moritz KM, Thomas MC, Tikellis C, Widdop RE, Denton KM. The arterial depressor response to chronic low-dose angiotensin II infusion in female rats is estrogen dependent. Am J Physiol Regul Integr Comp Physiol 302: R159-R165, 2012. First published October 26, 2011; doi:10.1152/ajpregu.00256.2011.-The complex role of the renin-angiotensin-system (RAS) in arterial pressure regulation has been well documented. Recently, we demonstrated that chronic low-dose angiotensin II (ANG II) infusion decreases arterial pressure in female rats via an AT(2)R-mediated mechanism. Estrogen can differentially regulate components of the RAS and is known to influence arterial pressure regulation. We hypothesized that AT2R-mediated depressor effects evident in females were estrogen dependent and thus would be abolished by ovariectomy and restored by estrogen replacement. Female Sprague-Dawley rats underwent ovariectomy or sham surgery and were treated with 17 beta-estradiol or placebo. Mean arterial pressure (MAP) was measured via telemetry in response to a 2-wk infusion of ANG II (50 ng . kg(-1).min(-1) sc) or saline. MAP significantly decreased in females treated with ANG II (-10 +/- 2 mmHg), a response that was abolished by ovariectomy (+4 +/- 2 mmHg) and restored with estrogen replacement (-6 +/- 2 mmHg). Cardiac and renal gene expression of components of the RAS was differentially regulated by estrogen, such that overall, estrogen shifted the balance of the RAS toward the vasodilatory axis. In conclusion, estrogen-dependent mechanisms offset the vasopressor actions of ANG II by enhancing RAS vasodilator pathways in females. This highlights the potential for these vasodilator pathways as therapeutic targets, particularly in women

Circulating Soluble ACE2 Plays an Independent Role to Protect against Vascular Damage in Diabetic Mice

Circulating levels of soluble ACE2 are increased by diabetes. Although this increase is associated with the presence and severity of cardiovascular disease, the specific role of soluble ACE2 in atherogenesis is unclear. Previous studies suggested that, like circulating ACE, soluble ACE2 plays a limited role in vascular homeostasis. To challenge this hypothesis, we aimed to selectively increase circulating ACE2 and measure its effects on angiotensin II dependent atherogenesis. Firstly, in Ace2/ApoE DKO mice, restoration of circulating ACE2 with recombinant murine soluble (rmACE219-613; 1 mg/kg/alternate day IP) reduced plaque accumulation in the aortic arch, suggesting that the phenotype may be driven as much by loss of soluble ACE2 as the reduction in local ACE2. Secondly, in diabetic ApoE KO mice, where activation of the renin angiotensin system drives accelerated atherosclerosis, rmACE219-613 also reduced plaque accumulation in the aorta after 6 weeks. Thirdly, to ensure consistent long-term delivery of soluble ACE2, an intramuscular injection was used to deliver a DNA minicircle encoding ACE219-613. This strategy efficiently increased circulating soluble ACE2 and reduced atherogenesis and albuminuria in diabetic ApoE KO mice followed for 10 weeks. We propose that soluble ACE2 has independent vasculoprotective effects. Future strategies that increase soluble ACE2 may reduce accelerated atherosclerosis in diabetes and other states in which the renin angiotensin system is upregulated

Portal pressure responses and angiotensin peptide production in rat liver are determined by relative activity of ACE and ACE2

Angiotensin converting enzyme (ACE) 2 activity and angiotensin-(1-7) [Ang-(1-7)] levels are increased in experimental cirrhosis; however, the pathways of hepatic Ang-(1-7) production have not been studied. This study investigated the role of ACE2, ACE, and neutral endopeptidase (NEP) in the hepatic formation of Ang-(1-7) from angiotensin I (Ang I) and Ang II and their effects on portal resistance. Ang I or Ang II were administered to rat bile duct ligated (BDL) and control livers alone and in combination with the ACE inhibitor lisinopril, the ACE and NEP inhibitor omapatrilat, or the ACE2 inhibitor MLN4760 (n = 5 per group). BDL markedly upregulated ACE, ACE2, and NEP. Ang-(1-7) was produced from Ang II in healthy and in BDL livers and was increased following ACE inhibition and decreased by ACE2 inhibition. In contrast, Ang-(1-7) production from Ang I was minimal and not affected by ACE or NEP inhibition. Surprisingly, ACE2 inhibition in BDLs dramatically increased Ang-(1-7) production from Ang I, an effect abolished by ACE2/NEP inhibition. Ang II and Ang I induced greater portal pressure increases in BDL livers than controls. The effects of Ang I were closely correlated with Ang II production and were strongly attenuated by both ACE and ACE/NEP inhibition. These findings show that the major substrate for hepatic production of Ang-(1-7) is Ang II and this is catalyzed by ACE2. Ang I is largely converted to Ang II by ACE, and net conversion of Ang I to Ang-(1-7) is small. NEP has the ability to generate large amounts of Ang-(1-7) in the BDL liver from Ang I only when ACE2 activity is greatly decreased or inhibited