Active Angiotensin-converting Enzyme Research Articles

Integrated analysis of gut microbiome and its metabolites in ACE2-knockout and ACE2-overexpressed mice.

Aberrant activation of the classic renin-angiotensin system (RAS) and intestinal micro dysbiosis adversely affect insulin resistance (IR), dyslipidemia, and other metabolic syndrome markers. However, the action of angiotensin-converting enzyme 2 (ACE2) and gut health in systemic homeostasis vary, and their interaction is not completely understood. We adopted a combinatory approach of metabolomics and fecal 16S rRNA analysis to investigate gut microbiota and metabolite in two different mouse models, ACE2 knockout (ACE2 KO) mice and the ACE2-overexpressing obese mice. 16S rRNA gene sequencing revealed that ACE2 influences microbial community composition and function, and ACE2 KO mice had increased Deferribacteres, Alcaligenaceae, Parasutterella, Catenibacterium, and Anaerotruncus, with decreased short-chain fatty acid (SCFA)-producing bacteria (Marvinbryantia and Alistipes). In contrast, ACE2-overexpressed mice exhibited increased anti-inflammatory probiotic (Oscillospiraceae, Marinifilaceae, and Bifidobacteriaceae) and SCFA-producing microbes (Rikenellaceae, Muribaculaceae, Ruminococcaceae, Odoribacter, and Alistipes) and decreased Firmicutes/Bacteroidetes, Lactobacillaceae, Erysipelotrichaceae, and Lachnospiraceae. Metabolome analysis indicated differential metabolites in ACE2 KO and ACE2-overexpression mice, especially the glucolipid metabolism-related compounds. Furthermore, correlation analysis between gut microbiota and metabolites showed a dynamic mutual influence affecting host health. Our study confirms for the first time a significant association between ACE2 status and gut microbiome and metabolome profiles, providing a novel mechanism for the positive effect of ACE2 on energy homeostasis.

The Potential Mechanisms Behind Adverse Effect of Coronavirus Disease-19 on Heart and Liver Damage: A Review.

Coronaviruses (CoVs) belong to the RNA viruses family. The viruses in this family are known to cause mild respiratory disease in humans. The origin of the novel SARS-COV2 virus that caused the coronavirus-19 disease (COVID-19) is the Wuhan city in China from where it disseminated to cause a global pandemic. Although lungs are the predominant target organ for Coronavirus Disease-19 (COVID-19), since its outbreak, the disease is known to affect heart, blood vessels, kidney, intestine, liver and brain. This review aimed to summarize the catastrophic impacts of Coronavirus disease-19 on heart and liver along with its mechanisms of pathogenesis. The information used in this review was obtained from relevant articles published on PubMed, Google Scholar, Google, WHO website, CDC and other sources. Key searching statements and phrases related to COVID-19 were used to retrieve information. Original research articles, review papers, research letters and case reports were used as a source of information. Besides causing severe lung injury, COVID-19 has also been reported to affect and cause dysfunction of many other organs. COVID-19 infection can affect people by downregulating membrane-bound active angiotensin-converting enzyme (ACE). People who have deficient ACE2 expression are more vulnerable to COVID-19 infection. The patients' pre-existing co-morbidities are major risk factors that predispose individuals to severe COVID-19. The disease severity and its broad spectrum phenotype is a result of combined direct and indirect pathogenic factors. Therefore, protocols that harmonize many therapeutic preferences should be the best alternatives to de-escalate the disease and obviate deaths caused as a result of multiple organ damage and dysfunction induced by the disease.

Adaptive and maladaptive roles of different angiotensin receptors in the development of cardiac hypertrophy and heart failure.

Angiotensin II (Ang II) is formed by the action of angiotensin-converting enzyme (ACE) in the renin-angiotensin system. This hormone is known to induce cardiac hypertrophy and heart failure and its actions are mediated by the interaction of both pro- and antihypertrophic Ang II receptors (AT1R and AT2R). Ang II is also metabolized by ACE 2 to Ang-(1-7), which elicits the activation of Mas receptors (MasR) for inducing antihypertrophic actions. Since heart failure under different pathophysiological situations is preceded by adaptive and maladaptive cardiac hypertrophy, we have reviewed the existing literature to gain some information regarding the roles of AT1R, AT2R, and MasR in both acute and chronic conditions of cardiac hypertrophy. It appears that the activation of AT1R may be involved in the development of adaptive and maladaptive cardiac hypertrophy as well as subsequent heart failure because both ACE inhibitors and AT1R antagonists exert beneficial effects. On the other hand, the activation of both AT2R and MasR may prevent the occurrence of maladaptive cardiac hypertrophy and delay the progression of heart failure, and thus therapy with different activators of these antihypertrophic receptors under chronic pathological stages may prove beneficial. Accordingly, it is suggested that a great deal of effort should be made to develop appropriate activators of both AT2R and MasR for the treatment of heart failure subjects.

Expression of ACE2 in the Intact and Acutely Injured Kidney.

The actions of angiotensin-converting enzyme 2 (ACE2) oppose those of the renin-angiotensin-aldosterone system. ACE2 may be a cytoprotectant in some tissues. This study examined ACE2 expression in models of AKI. ACE2 mRNA and protein expression and ACE2 activity were assessed in murine ischemic AKI. Renal ACE2 mRNA expression was evaluated in LPS-induced AKI in wild-type (C57BL/6J) mice, in heme oxygenase-1+/+ and heme oxygenase-1-/- mice, and after unilateral ureteral obstruction (UUO) in wild-type mice. The effect of sex and age on renal ACE2 protein expression was also assessed. In ischemic AKI, ACE2 mRNA and protein expression and ACE2 activity were reduced as compared with such indices in the intact kidney. In ischemic AKI, ACE2, which, in health, is prominently expressed in the tubular epithelium, especially proximal tubules, is decreased in expression in these segments. Decreased ACE2 expression in AKI did not reflect reduced GFR, because ACE2 mRNA expression was unaltered after UUO. LPS induced renal ACE2 mRNA expression in wild-type mice, but this effect did not occur in heme oxygenase-1-deficient mice. In ischemic and LPS-induced AKI, renal expression of the Mas receptor was increased. In the intact kidney, renal ACE2 protein expression decreased in female mice as compared with male mice, but was unaltered with age. We conclude that renal ACE2 expression is decreased in ischemic AKI, characterized by decreased GFR and abundant cell death, but is upregulated in LPS-induced AKI, an effect requiring heme oxygenase-1. Determining the significance of ACE2 expression in experimental AKI merits further study. We suggest that understanding the mechanism underlying ACE2 downregulation in AKI may offer insights relevant to COVID-19: ACE2 expression is downregulated after ACE2 mediates SARS-CoV-2 cellular entry; such downregulation is proinflammatory; and AKI commonly occurs and determines outcomes in COVID-19.

Effects of Angiotensin II Type 1A Receptor on ACE2, Neprilysin and KIM-1 in Two Kidney One Clip (2K1C) Model of Renovascular Hypertension.

Activation of the renin angiotensin system plays a pivotal role in the regulation of blood pressure, which is mainly attributed to the formation of angiotensin-II (Ang II). The actions of Ang II are mediated through binding to the Ang-II type 1 receptor (AT1R) which leads to increased blood pressure, fluid retention, and aldosterone secretion. In addition, Ang II is also involved in cell injury, vascular remodeling, and inflammation. The actions of Ang II could be antagonized by its conversion to the vasodilator peptide Ang (1–7), partly generated by the action of angiotensin converting enzyme 2 (ACE2) and/or neprilysin (NEP). Previous studies demonstrated increased urinary ACE2 shedding in the db/db mouse model of diabetic kidney disease. The aim of the study was to investigate whether renal and urinary ACE2 and NEP are altered in the 2K1C Goldblatt hypertensive mice. Since AT1R is highly expressed in the kidney, we also researched the effect of global deletion of AT1R on renal and urinary ACE2, NEP, and kidney injury marker (KIM-1). Hypertension and albuminuria were induced in AT1R knock out (AT1RKO) and WT mice by unilateral constriction of the renal artery of one kidney. The 24 h mean arterial blood pressure (MAP) was measured using radio-telemetry. Two weeks after 2K1C surgery, MAP and albuminuria were significantly increased in WT mice compared to AT1RKO mice. Results demonstrated a correlation between MAP and albuminuria. Unlike db/db diabetic mice, ACE2 and NEP expression and activities were significantly decreased in the clipped kidney of WT and AT1RKO compared with the contralateral kidney and sham control (p < 0.05). There was no detectable urinary ACE2 and NEP expression and activity in 2K1C mice. KIM-1 was significantly increased in the clipped kidney of WT and AT1KO (p < 0.05). Deletion of AT1R has no effect on the increased urinary KIM-1 excretion detected in 2K1C mice. In conclusion, renal injury in 2K1C Goldblatt mouse model is associated with loss of renal ACE2 and NEP expression and activity. Urinary KIM-1 could serve as an early indicator of acute kidney injury. Deletion of AT1R attenuates albuminuria and hypertension without affecting renal ACE2, NEP, and KIM-1 expression.

Tri- and dipeptides identification in whey protein and porcine liver protein hydrolysates by fast LC-MS/MS neutral loss screening and de novo sequencing.

We describe a fast (5 min) liquid chromatography tandem mass spectrometry method (LC-MS/MS) based on a 46 Da neutral loss of formic acid (H2 O and CO) to identify tri- and dipeptides (DIPEP) in whey protein and porcine liver protein hydrolysates and confirmed by further de novo sequencing. Sample solutions were acidified to favor [dipep + H]+ ions, and a m/z range of 50-300 was used to improve sensitivity. All dipeptide candidates were selected based on all possibilities of the 20 amino acid combinations, and their collision-induced dissociation fragments were screened via de novo sequencing. To determine their biological activities, sequenced dipeptides were compared with the Biopep database and other data from literature. Altogether, 18 dipeptides and 7 tripeptides were identified from the whey protein hydrolysate; they seemed to be broadly active, and peptides were identified as active dipeptidyl peptidase IV inhibitors and active angiotensin-converting enzyme (ACE), according to available information. Porcine liver hydrolysate showed 14 dipeptides which exhibit similar biological activities to whey protein hydrolysate.

A Machine Learning Approach to Management of Heart Failure Populations

BackgroundHeart failure is a prevalent, costly disease for which new value-based payment models demand optimized population management strategies. ObjectivesThis study sought to generate a strategy for managing populations of patients with heart failure by leveraging large clinical datasets and machine learning. MethodsGeisinger electronic health record data were used to train machine learning models to predict 1-year all-cause mortality in 26,971 patients with heart failure who underwent 276,819 clinical episodes. There were 26 clinical variables (demographics, laboratory test results, medications), 90 diagnostic codes, 41 electrocardiogram measurements and patterns, 44 echocardiographic measurements, and 8 evidence-based “care gaps”: flu vaccine, blood pressure of <130/80 mm Hg, A1c of <8%, cardiac resynchronization therapy, and active medications (active angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker/angiotensin receptor-neprilysin inhibitor, aldosterone receptor antagonist, hydralazine, and evidence-based beta-blocker) were collected. Care gaps represented actionable variables for which associations with all-cause mortality were modeled from retrospective data and then used to predict the benefit of prospective interventions in 13,238 currently living patients. ResultsMachine learning models achieved areas under the receiver-operating characteristic curve (AUCs) of 0.74 to 0.77 in a split-by-year training/test scheme, with the nonlinear XGBoost model (AUC: 0.77) outperforming linear logistic regression (AUC: 0.74). Out of 13,238 currently living patients, 2,844 were predicted to die within a year, and closing all care gaps was predicted to save 231 of these lives. Prioritizing patients for intervention by using the predicted reduction in 1-year mortality risk outperformed all other priority rankings (e.g., random selection or Seattle Heart Failure risk score). ConclusionsMachine learning can be used to priority-rank patients most likely to benefit from interventions to optimize evidence-based therapies. This approach may prove useful for optimizing heart failure population health management teams within value-based payment models.

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Effect of hyperglycemia and rosiglitazone on renal and urinary neprilysin in db/db diabetic mice.

Alteration in renin‐angiotensin system (RAS) has been implicated in the pathophysiology of diabetic kidney disease (DKD). The deleterious actions of angiotensin II (Ang II) could be antagonized by the formation of Ang‐(1–7), generated by the actions of angiotensin‐converting enzyme 2 (ACE2) and neprilysin (NEP). NEP degrades several peptides, including natriuretic peptides, bradykinin, amyloid beta, and Ang I. Although combination of Ang II receptor and NEP inhibitor treatment benefits patients with heart failure, the role of NEP in renal pathophysiology is a matter of active research. NEP pathway is a potent enzyme in Ang I to Ang‐(1–7) conversion in the kidney of ACE2‐deficient mice, suggesting a renoprotective role of NEP. The aim of the study is to test the hypothesis that chronic hyperglycemia downregulates renal NEP protein expression and activity in db/db diabetic mice and treatment with rosiglitazone normalizes hyperglycemia, renal NEP expression, and attenuates albuminuria. Mice received rosiglitazone (20 mg kg−1 day−1) for 10 weeks. Western blot analysis, immunohistochemistry, and enzyme activity revealed a significant decrease in renal and urinary NEP expression and activity in 16‐wk db/db mice compared with lean control (p < .0001). Rosiglitazone also attenuated albuminuria and increased renal and urinary NEP expressions (p < .0001). In conclusion, data support the hypothesis that diabetes decreases intrarenal NEP, which could have a pivotal role in the pathogenesis of DKD. Urinary NEP may be used as an index of intrarenal NEP status. The renoprotective effects of rosiglitazone could be mediated by upregulation of renal NEP expression and activity in db/db diabetic mice.

Phenolic compounds of Heliotropium europaeum and their biological activities

Background: Heliotropium europaeum L. is known to contain pyrrolizidine alkaloids and possesses a wide variety of biological activities. Objective: The objective of the study was to discover antioxidant phytochemical compounds in H. europaeum and assess their in vitro lipoxygenase (LOX)- and angiotensin-converting enzyme (ACE) inhibitory activities. Materials and Methods: H. europaeum herbs were extracted exhaustively by maceration using 90% aqueous ethanol. Solvent fractionation with n-hexane, dichloromethane (CH2Cl2), ethyl acetate (EtOAc), and n-butanol was performed with the dried extract until complete exhaustion. Two antioxidant active fractions (CH2Cl2and EtOAc) were combined and subjected to medium pressure liquid chromatography followed by reversed-phase high-performance liquid chromatography. Quantitative evaluation in terms of the antioxidant activities of the isolated compounds was performed using the 2,2-diphenyl-1-picrylhydrazyl assay. The potential limiting effects on the action of ACE and soybean LOX were assessed quantitatively. Results: Isolates of eight newly identified phenolic compounds from H. europaeum exhibited antioxidant and ACE- and LOX-inhibitory activities. The isolated compounds were identified as kaempferol (1), luteolin (2), quercetin (3), kaempferol-3-O-glucoside (4), and luteolin-7-O-glucoside (5), in addition to caffeic acid (6), rosmarinic acid (7), and methyl rosmarinate (8). Among the isolated compounds, quercetin possessed the most potent antioxidant activity (IC50= 8.1 μM) and ACE-inhibitory activity (IC50= 17.5 μM), whereas rosmarinic acid and its methyl ester showed the strongest LOX-inhibitory activity (IC50s = 4.2 μM and 3.6 μM, respectively). Conclusion: Our study is the first report on the phenolic constituents of the H. europaeum herbal extract and their biological activities. A total of eight phenolics were identified in this extract and isolated for the first time. Our results on H. europaeum extract constituents provide some scientific evidence on the beneficial effects of its traditional uses.

A new angiotensin-converting enzyme inhibitor from Peperomia pellucida (L.) Kunth

Objective: To isolate, identify, and evaluate a new angiotensin-converting enzyme inhibitor from Peperomia pellucida (L.) Kunth herbs. Methods: A dried sample of Peperomia pellucida herb was successively macerated with n-hexane and ethyl acetate. The ethyl acetate extract solution was evaporated to obtain the crude extract. Vacuum liquid column chromatography and thin layer chromatography were performed to obtain two pure compounds. Then, both compounds were elucidated and identified using the spectroscopic method. Angiotensin-converting enzyme inhibitory activity studies of both compounds were determined using angiotensin-converting enzyme kit WST-1 with spectrophotometer microplate reader 96-well at 450 nm wavelength. Results: Two bioactive compounds were successfully isolated from Peperomia pellucida herb, including a new compound of 2,3,5-trimethoxy-9-(12,14,15-trimethoxybenzyl)-1H-indene and pellucidin A. Both compounds demonstrated angiotensin-converting enzyme inhibitory activity, with IC50 values of 72 μM (27.95 μg/mL) and 11 μM (4.4 μg/mL), respectively. Conclusions: In the present study, two active angiotensin-converting enzyme inhibitors were successfully isolated and purified from Peperomia pellucida which is used as an antihypertensive in traditional medicine, and support its use as an angiotensin-converting enzyme-inhibiting drug.

Effect of centrally acting angiotensin converting enzyme inhibitor on the exercise-induced increases in muscle sympathetic nerve activity.

The arterial baroreflex's operating point pressure is reset upwards and rightwards from rest in direct relation to the increases in dynamic exercise intensity. The intraneural pathways and signalling mechanisms that lead to upwards and rightwards resetting of the operating point pressure, and hence the increases in central sympathetic outflow during exercise, remain to be identified. We tested the hypothesis that the central production of angiotensin II during dynamic exercise mediates the increases in sympathetic outflow and, therefore, the arterial baroreflex operating point pressure resetting during acute and prolonged dynamic exercise. The results identify that perindopril, a centrally acting angiotensin converting enzyme inhibitor, markedly attenuates the central sympathetic outflow during acute and prolonged dynamic exercise. We tested the hypothesis that the signalling mechanisms associated with the dynamic exercise intensity related increases in muscle sympathetic nerve activity (MSNA) and arterial baroreflex resetting during exercise are located within the central nervous system. Participants performed three randomly ordered trials of 70° upright back-supported dynamic leg cycling after ingestion of placebo and two different lipid soluble angiotensin converting enzyme inhibitors (ACEi): perindopril (high lipid solubility), captopril (low lipid solubility). Repeated measurements of whole venous blood (n=8), MSNA (n=7) and arterial blood pressures (n=14) were obtained at rest and during an acute (SS1) and prolonged (SS2) bout of steady state dynamic exercise. Arterial baroreflex function curves were modelled at rest and during exercise. Peripheral venous superoxide concentrations measured by electron spin resonance spectroscopy were elevated during exercise and were not altered by ACEi at rest (P≥0.4) or during exercise (P≥0.3). Baseline MSNA and mean arterial pressure were unchanged at rest (P≥0.1; P≥0.8, respectively). However, during both SS1 and SS2, the centrally acting ACEi perindopril attenuated MSNA compared to captopril and the placebo (P<0.05). Arterial pressures at the operating point and threshold pressures were decreased with perindopril from baseline to SS1 with no further changes in the operating point pressure during SS2 under all three conditions. These data suggest that centrally acting ACEi is significantly more effective at attenuating the increase in the acute and prolonged exercise-induced increases in MSNA.

Angiotensin-converting enzyme 2-Angiotensin 1-7/1-9 system: novel promising targets for heart failure treatment.

Cardiac remodeling (cardiac hypertrophy and fibrosis) is a hallmark of heart failure (HF). It can be induced by the abnormal elevation of several endogenous factors including angiotensin II (Ang II), which is generated from its precursor angiotensin I (Ang I) by the action of angiotensin-converting enzyme. The inhibition of this enzyme or the blockade of the Ang II receptors demonstrated a high clinical value against the progression of HF. Ang I and Ang II may also be converted into angiotensin 1-7 (Ang 1-7) and angiotensin 1-9 (Ang 1-9), respectively, by the action of angiotensin-converting enzyme 2. Both derivatives demonstrated a promising anticardiac remodeling activity especially against the detrimental effects of Ang II. This manuscript thoroughly reviews the available invitro and invivo data on Ang 1-7 and Ang 1-9 in the context of the treatment of HF and discusses the associated molecular mechanisms and the trials to clinically utilize Ang 1-7 mimetics for the treatment of that disease.

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Enalapril

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the marketing authorization of immediate-release, solid oral dosage forms containing enalapril maleate are reviewed. Enalapril, a prodrug, is hydrolyzed by carboxylesterases to the active angiotensin-converting enzyme inhibitor enalaprilat. Enalapril as the maleate salt is shown to be highly soluble, but only 60%-70% of an orally administered dose of enalapril is absorbed from the gastrointestinal tract into the enterocytes. Consequently, enalapril maleate is a Biopharmaceutics Classification System class III substance. Because in situ conversion of the maleate salt to the sodium salt is sometimes used in production of the finished drug product, not every enalapril maleate–labeled finished product actually contains the maleate salt. Enalapril is not considered to have a narrow therapeutic index. With this background, a biowaiver-based approval procedure for new generic products or after major revisions to existing products is deemed acceptable, provided the in vitro dissolution of both test and reference preparation is very rapid (at least 85% within 15 min at pH 1.2, 4.5, and 6.8). Additionally, the test and reference product must contain the identical active drug ingredient.

Angiotensin II regulation of angiotensin-converting enzymes in spontaneously hypertensive rat primary astrocyte cultures.

Angiotensin (Ang) II plays a critical role in cardiovascular and blood pressure regulation. Ang II is produced by angiotensin-converting enzyme (ACE) and it interacts with the Ang AT1 receptor to cause much of its well-known cardiovascular effects. Ang-(1-7) is another active peptide produced by the rennin-angiotensin system. This peptide is produced from Ang I or Ang II by the catalytic activity of ACE2. Ang-(1-7) interacts with the Mas receptor to counteract many of the effects of Ang II. Thus, the ACE2/Ang-(1-7)/Mas axis acts opposite of the ACE/Ang II/AT1 axis. In this study we investigated how Ang II regulates the key enzymes of these axes, ACE and its homolog ACE2, and determined whether they are dysregulated in the hypertensive condition. Brainstem and cerebellum astrocytes isolated from the spontaneously hypertensive rat (SHR) were used in these studies. Ang II effect on the enzymes' mRNA and protein levels was measured using quantitative PCR and western blotting techniques, respectively. Results from this study showed that Ang II up-regulated ACE protein levels, but down-regulated ACE mRNA levels in brainstem and cerebellum astrocytes in both models. Ang II also reduced ACE2 mRNA expression in SHR and Wistar astrocytes isolated from both brain regions. Ang II effects on ACE2 protein were biphasic. In SHR astrocytes, Ang II-mediated ACE2 protein initially increased then decreased at later time points. In contrast, in Wistar astrocytes, Ang II initially decreased ACE2 protein expression, but up-regulated the protein at later time points. The findings of these studies suggest that Ang II has a differential effect on ACE and ACE2 expression. Furthermore, in the SHR model there may be alteration in the ACE/ACE2 balance in a manner that favors increased Ang II generation and decreased Ang-(1-7) production contributing to the hypertensive phenotype observed in this model. The levels of angiotensin (Ang) II depend on the actions of angiotensin-converting enzyme (ACE) and ACE2. We showed in astrocytes isolated from the SHRs that Ang II differentially affects ACE and ACE2 expression. There may be an alteration in the ACE/ACE2 balance favoring Ang II generation. This imbalance may contribute to the hypertensive phenotype observed inthis SHR model.

Historical overview, development and new approaches in design of angiotensin converting enzyme inhibitors and angiotensin receptor antagonists. Part I

The renin-angiotensin system (RAS) plays an important role in pathogenesis of hypertension, congestive heart failure, and chronic renal failure. In addition to a discussion of the current understanding of the chemical structures and the modes of action of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor (ATR) antagonists, review includes their SAR analysis and chemical modification for improving their activity. Nowadays different modeling strategies are underway to develop tailor made molecules with the best of properties among nonpeptide renin inhibitors, dual action receptor antagonists (e.g. angiotensin and endothelin antagonists, ACE/NEP inhibitors, AT 1 /TxA 2 antagonists, balanced AT 1 /AT 2 antagonists), triple inhibitors. In the first part is given an overview of various ACE inhibitors. The second part is devoted to overview of angiotensin receptor antagonists. The advances that have been made, new opportunities, and future directions of design and development of these classes have been discussed.

Can angiotensin-converting enzyme inhibitors impact cognitive decline in early stages of Alzheimer's disease? An overview of research evidence in the elderly patient population.

Alzheimer's disease (AD) is a neurodegenerative disease, in which an accumulation of toxic amyloid beta in the brain precedes the emergence of clinical symptoms. AD spectrum consists of presymptomatic, early symptomatic, and symptomatic phase of dementia. At present, no pharmacotherapy exists to modify or reverse a course of AD, and only symptomatic treatments are available. Many elderly patients, diagnosed with multiple medical conditions (such as cardiovascular diseases, Type 2 diabetes mellitus, and cerebrovascular diseases) are at increased risk of the development of mild cognitive impairment (MCI), AD, and vascular dementia. Studies have revealed reduced rates of cognitive decline, in elderly patients, who were treated with centrally active angiotensin-converting enzyme inhibitors (ACE-Is) (that have an ability to cross the blood–brain barrier). This article reviews recently published literature, focused on possible protective influence of the centrally active ACE-Is, in the elderly population, at risk for cognitive decline.

Abstract P208: Effect of Rosiglitazone on Renal Neprilysin Activity and Protein Expression in Db/db Diabetic Mice

Alteration in renin-angiotensin system has been implicated in the pathophysiology of diabetic kidney disease. The deleterious actions of angiotensin II (Ang II) could be antagonized by the formation of Ang (1-7) partly generated by the actions of angiotensin converting enzyme 2 (ACE2) and neprilysin (NEP). NEP is a member of the zinc-containing metallopeptidase family, and has a main role in the degradation of several peptides, including natriuretic peptides, bradykinin, amyloid beta, and Ang I. Our previous studies demonstrated increased shedding of renal ACE2 in db/db mouse model of type 2 diabetes. We also showed that treatment with the PPAR_ agonist, rosiglitazone normalized hyperglycemia, decreased urinary ACE2 and attenuated albuminuria in db/db mice. The aim of the study was to test the hypothesis that hyperglycemia down-regulates renal NEP in db/db diabetic mice and that treatment with rosiglitazone will normalize renal NEP expression and activity. Seven-week-old db/db male mice were subjected to rosiglitazone treatment (20 mg/kg/day) for 10 weeks. Treatment with rosiglitazone significantly lowered blood glucose levels in db/db mice (p&lt;0.001). Western blot analysis and immunohistochemistry demonstrated a significant decrease in renal and urinary NEP protein expression in 17wk db/db mice compared to lean control mice (p&lt;0.0001). Treatment of db/db mice with rosiglitazone attenuated albuminuria, increased renal NEP protein expression and activity. In conclusion, the renoprotective effects of rosiglitazone could be mediated by up-regulation of renal NEP expression and activity in db/db mice. Alteration in the balance between Ang II and Ang (1-7) forming enzymes could contribute to the development of albuminuria in db/db diabetic mice.

Abstract 1868: Expression of MAS1 in triple-negative breast cancer

Abstract MAS1 is a receptor for angiotensin 1-7 (A1-7), which is derived from angiotensin II (A-II) by the action of angiotensin converting enzyme (ACE) 2. We examined the role of MAS1 in 132 cases of invasive ductal carcinoma (IDC) of the breast by using immunohistochemistry. While normal mammary tissues expressed MAS1 at high levels, MAS1 expression was attenuated in all IDCs, especially in scirrhous IDCs. The decrease in MAS1 expression was associated with tumor growth, lymph node metastasis, and grade. MAS1 expression was inversely associated with the proliferation index and epidermal growth factor receptor and human epidermal growth factor receptor-2 expression. Of the 132 cases, 12 (9.1%) were triple-negative breast cancer (TNBC) cases. Using the mouse TNBC cell line 4T1, which expresses MAS1, we found that cell growth, anti-apoptotic survival, and invasion were suppressed by A1-7 treatment and enhanced by MAS1 knockdown. Combination treatment with cisplatin, an ACE2 activator, and an A-II type 1 receptor blocker showed synergic effects on tumor growth inhibition. These findings suggest that MAS1 might be a pivotal molecular target for TNBC. Note: This abstract was not presented at the meeting. Citation Format: Yi Luo, Yasuhiko Kitadai, Yukiko Nishiguchi, Rina Fujiwara, Takamitsu Sasaki, Hitoshi Ohmori, Hiroki Kuniyasu. Expression of MAS1 in triple-negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1868. doi:10.1158/1538-7445.AM2015-1868

Expression of MAS1 in breast cancer.

MAS1 is a receptor for angiotensin 1-7 (A1-7), which is derived from angiotensin II (A-II) by the action of angiotensin converting enzyme (ACE) 2. MAS1 induces anti-A-II phenotypes, such as vessel dilation and depression of blood pressure. Using immunohistochemistry, we examined the role of MAS1 in 132 cases of invasive ductal carcinoma (IDC) of the breast. While benign mammary tissues expressed MAS1 at high levels, MAS1 expression was attenuated in all IDC, especially in scirrhous IDC. The decrease in MAS1 expression was associated with tumor growth, lymph node metastasis, and grade. MAS1 expression was inversely associated with the proliferation index and epidermal growth factor receptor and human epidermal growth factor receptor-2 expression. Of the 132 cases, 12 (9.1%) were triple-negative breast cancer (TNBC) cases. All TNBC cases (the 12 cases and the additional 36 cases using a tissue array) expressed MAS1. Using the TNBC cell lines 4T1 and MDA-MB-468, which expresses MAS1, we found that cell growth, anti-apoptotic survival and invasion were suppressed by MAS1 activation with A1-7 treatment and enhanced by MAS1 knockdown. In contrast, synergic effect was found between tamoxifen and A1-7 in a luminal A breast cancer cell line, MCF-7. Combination treatment with cisplatin, an ACE2 activator, and an A-II type 1 receptor blocker showed synergic effects on tumor growth inhibition of 4T1 tumors in a syngeneic mouse model. These findings suggest that MAS1 might act as an inhibitory regulator of breast cancer and may be a possible molecular target for this malignancy.