Plasma Angiotensin-converting Enzyme Levels Research Articles

Antihypertensive effects of Pleurospermum lindleyanum aqueous extract in spontaneously hypertensive rats.

Pleurospermum lindleyanum (Lipsky) B. Fedtsch is a perennial herb classified in the Apiaceae family, genus Pleurospermum, chiefly native to the Taxkorgan County, Xinjiang, China. In the Xinjiang Province, it is a well-known ethnic traditional herb, often addressed by its tribal name, Kurumuti. It grows in harsh conditions over 4000m above sea level, such as the Pamirs plateau. It is rich in flavonoids, coumarins, terpenoids, essential oil, substances that have been widely applied in the prevention and treatment of hypertension, diabetes, coronary heart disease, and cerebral thrombosis by local Tajik residents. The present study aimed to evaluate the antihypertensive effects of the Pleurospermum Lindleyanum aqueous extract (PLAE) in spontaneously hypertensive rats (SHRs). The Pleurospermum lindleyanum was collected from the Taxkorgan Tajik Autonomous County, Xinjiang, China. The main chemical composition of PLAE was identified using the ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS). SHRs were treated by gavage with PLAE (equivalent to Pleurospermum lindleyanum 5 or 10g/kg/day) for 6 weeks, using Captopril (10mg/kg/day) as positive control. The systolic blood pressure (SBP), renal and cardiac morphology, plasma levels of angiotensin-converting enzyme (ACE), aldosterone (ALD), angiotensinⅡ (AngⅡ), superoxide dismutase (SOD), endothelin-1 (ET-1) and nitric oxide (NO) were measured. A total of 30 compounds were identified in PLAE. PLAE significantly attenuated the SBP of SHRs. The effects began after 3 weeks of administration and then became steady and long-lasting. Its potential mechanisms may be associated with the protective effects on renal and cardiac injury caused by hypertension, the decrease of plasma vasoconstrictors, such as ACE, ALD, AngⅡ, and ET-1 levels, the maintenance of NO/ET balance, the increase in plasma NO levels and SOD activity, thereby reducing oxidative stress. Pleurospermum lindleyanum can be suggested as a novel antihypertensive ethnic traditional herb, which lays the foundation for researching safe and effective antihypertensive herbal medicines.

EVALUATION OF SERUM ANGIOTENSIN CONVERTING ENZYME, OXIDATIVE STRESS, AND ANTIOXIDANT LEVELS IN CEREBROVASCULAR DISORDERS AND HEALTHY CONTROL – A COMPARATIVE STUDY

Objective: Several studies indicate the existence of an abnormal balance between the oxidative and protective mechanisms in patients can be a causative factor for cerebrovascular disease. High plasma levels of angiotensin-converting enzyme (ACE) contribute to the development of vascular diseases. Serum ACE and antioxidant levels were determined in cerebrovascular disorders (CVD) and compared between CVD and healthy person. Methods: A cross-sectional study was conducted on 50 cases of stroke and 10 cases of transient ischemic attack (TIA) with 60 controls matched for age and sex. Fasting blood samples were estimated for serum angiotensin-converting enzyme, serum lipid profile, MDA, SOD, and serum Vitamin E). ACE was estimated by spectrophotometry. The levels of ACE were correlated with the severity and outcome of the stroke. Results: The level of serum ACE was significantly higher in stroke (27.50±1.14U/L) and TIA (31.60±2.02 U/L) as compared to controls (22.61±0.79 U/L). Fasting blood sugar, total cholesterol, triglycerides, LDL cholesterol, and MDA were significantly increased whereas a significant decrease was observed in serum HDL, erythrocyte SOD, and Vitamin E levels in cerebrovascular disease patients as compared to the control group. Statistical p<0.05 was considered significant. Conclusion: Oxidative stress is a potential contributor to acute ischemic stroke and TIA besides deranged lipid profile. The oxidant-antioxidant imbalance may contribute to the severity of stroke. The levels of serum ACE increase significantly in stroke and TIA patients and are associated with increased severity and worse outcome of cerebrovascular diseases.

The role of plasma angiotensin-converting enzyme and interleukin-6 levels on the prognosis of non-dialysis chronic kidney disease patients

Context: Inflammatory factors and oxidative stress were discovered to play significant roles in the progression of chronic kidney disease (CKD). There is, however, no research on the direct impact of high plasma angiotensin converting enzyme (ACE) and interleukin (IL)-6 levels on CKD prognosis, particularly in non-hemodialysis patients. Aims: To investigate the potential role of plasma ACE and IL-6 levels in CKD prognosis. Methods: A total of 75 non-dialysis CKD patients participated in this cross-sectional study. The estimated glomerular filtration rate (e-GFR) and albuminuria were used to determine the prognosis of CKD. The plasma ACE and IL-6 levels were measured using an enzyme-linked immunoassay (ELISA). Spearman's rank correlational analysis was used to examine the relationship between ACE and IL-6 plasma levels with the prognosis of CKD. Results: The result showed a statistically significant correlation between age and plasma ACE (p = 0.038, r = 0.241), serum creatinine, and urine albumin-creatinine ratio with CKD prognosis (p<0.0001). A negative significant correlation was found between the e-GFR and CKD prognosis (p<0.0001). Additionally, there were also significant correlations between plasma ACE and IL-6 with CKD prognosis (p = 0.021, r = 0.266 and p = 0.04, r = 0.238, respectively). A significant positive correlation was also found between plasma ACE and IL-6 (p = 0.024, r = 0.260). Conclusions: There was a significant correlation between plasma ACE and IL-6 levels with CKD prognosis. Further investigation revealed a statistically significant positive relationship between plasma ACE and IL-6 levels.

The Effect of Angiotensin Converting Enzyme (ACE) I/D Polymorphism on Atherosclerotic Cardiovascular Disease and Cardiovascular Mortality Risk in Non-Hemodialyzed Chronic Kidney Disease: The Mediating Role of Plasma ACE Level.

The association between angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphisms and plasma ACE levels may allow for the optimization of a preventive intervention to reduce cardiovascular morbidity and mortality in the chronic kidney disease (CKD) population. In this study, we aimed to analyze the association between ACE I/D polymorphism and cardiovascular mortality risk among non-hemodialyzed chronic kidney disease patients. This cross-sectional study examined 70 patients of Javanese ethnic origin with stable CKD who did not receive hemodialysis. ACE I/D polymorphisms, plasma ACE levels, atherosclerotic cardiovascular disease (ASCVD) risk, and cardiovascular mortality risk were investigated. As per our findings, the I allele was found to be more frequent (78.6) than the D allele (21.4), and the DD genotype was less frequent than the II genotype (4.3 vs. 61.4). The ACE I/D polymorphism had a significant direct positive effect on plasma ACE levels (path coefficient = 0.302, p = 0.021). Similarly, plasma ACE levels had a direct and significant positive effect on the risk of atherosclerotic cardiovascular disease (path coefficient = 0.410, p = 0.000). Moreover, atherosclerotic cardiovascular disease risk had a significant positive effect on cardiovascular mortality risk (path coefficient = 0.918, p = 0.000). The ACE I/D polymorphism had no direct effect on ASCVD and cardiovascular mortality risk. However, our findings show that the indirect effects of high plasma ACE levels may be a factor in the increased risk of ASCVD and cardiovascular mortality in Javanese CKD patients.

Basal VEGF-A and ACE Plasma Levels of Metastatic Colorectal Cancer Patients Have Prognostic Value for First-Line Treatment with Chemotherapy Plus Bevacizumab.

Simple SummaryMolecular biology knowledge has enabled the incorporation of targeted therapies, such as the anti-angiogenic drug bevacizumab, into combined chemotherapy regimens for the treatment of metastatic colorectal cancer. However, to date, there are no reliable useful biomarkers to predict the efficacy of this anti-angiogenic therapy. The objective of this prospective study was to evaluate potential circulating plasma biomarkers in mCRC patients prior to the start of first-line treatment with chemotherapy plus bevacizumab. We found that high VEGF-A and low ACE plasma levels were associated with poor OS after treatment. Moreover, a simple scoring system combining both biomarkers efficiently stratified patients into high- or low-risk groups, which allows the selection of patients for anti-angiogenic therapy.The identification of factors that respond to anti-angiogenic therapy would represent a significant advance in the therapeutic management of metastatic-colorectal-cancer (mCRC) patients. We previously reported the relevance of VEGF-A and some components of the renin–angiotensin-aldosterone system (RAAS) in the response to anti-angiogenic therapy in cancer patients. Therefore, this prospective study aims to evaluate the prognostic value of basal plasma levels of VEGF-A and angiotensin-converting enzyme (ACE) in 73 mCRC patients who were to receive bevacizumab-based therapies as a first-line treatment. We found that high basal VEGF-A plasma levels were significantly associated with worse overall survival (OS) and progression-free survival (FPS). On the other hand, low ACE levels were significantly associated with poor OS. Importantly, a simple scoring system combining the basal plasma levels of VEGF-A and ACE efficiently stratified mCRC patients, according to OS, into high-risk or low-risk groups, prior to their treatment with bevacizumab. In conclusion, our study supports that VEGF-A and ACE may be potential biomarkers for selecting those mCRC patients who will most benefit from receiving chemotherapy plus bevacizumab treatment in first-line therapy. Additionally, our data reinforce the notion of a close association between the RAAS and the anti-angiogenic response in cancer.

Elevated mid-pregnancy plasma levels of angiotensin-converting enzyme 2 in women prior to the development of preeclampsia

Preeclampsia and cardiovascular disease (CVD) share multiple features and risk factors. Circulating angiotensin-converting enzyme 2 (ACE2) is increased in CVD and mediates SARS-CoV-2 entry into host cells, causing COVID-19 infection. The role of ACE2 in preeclampsia pathophysiology is unknown. We hypothesized that circulating ACE2 is increased in mid-pregnancy in women later developing preeclampsia. We included 296 women later developing preeclampsia (cases) and 333 women with a continuous healthy pregnancy (controls). Circulating ACE2 was measured with an immunoassay based on proximity extension assay technology, with levels being expressed as relative quantification on a log2 scale. Median (interquartile range) ACE2 levels were higher in cases than in controls; 3.84 (3.50–4.24) vs. 3.72 (3.45–4.04), p = 0.002. Adjusted logistic regression models showed a 60% increased risk for later development of preeclampsia with one unit elevation of ACE2 (adjusted odds ratio (aOR) 1.60, 95% confidence intervals (CI) 1.17–2.18). Preterm preeclampsia (diagnosis before 37 gestational weeks, n = 97) seemed to have a stronger ACE2 association than term preeclampsia, n = 199 (aORs, 95% Cis 2.14, 1.15–3.96 and 1.52, 1.04–2.23, respectively). Circulating ACE2 is increased at mid-pregnancy in women later developing preeclampsia, particularly preterm preeclampsia. Thus, our finding indicates a partly shared pathophysiological pathway between preeclampsia and CVD.

Influence of renin-angiotensin-aldosterone system inhibitors on plasma levels of angiotensin-converting enzyme 2.

AimsConcern has been raised that treatment with angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers may increase the expression of angiotensin‐converting enzyme 2 (ACE2), which acts as the entry receptor for SARS‐CoV‐2, and lead to an increased risk of death from SARS‐CoV‐2. We aimed to address this concern by evaluating the in vivo relationship of treatment with ACE inhibitors and angiotensin receptor blockers (ARB) with circulating plasma concentrations of ACE2 in a large cohort of patients with established cardiovascular disease (n = 1864) or cardiovascular risk factors (n = 2144) but without a history of heart failure.Methods and resultsAngiotensin‐converting enzyme 2 was measured in 4008 patients (median age 68, 33% women, 31% on ACE‐inhibitors, 31% on ARB) using the SOMAscan proteomic platform (SomaLogic Inc, Colorado, USA). Plasma concentration of ACE2 was comparable in 1250 patients on ACE inhibitors (mean 5.99) versus patients without ACE inhibitors (mean 5.98, P = 0.54). Similarly, plasma concentration of ACE2 was comparable in 1260 patients on ARB (mean 5.99) versus patients without ARB (mean 5.98, P = 0.50). Plasma concentration of ACE2 was comparable in 2474 patients on either ACE inhibitors or ARB (mean 5.99) versus patients without ACE inhibitors or ARB (mean 5.98, P = 0.31). Multivariable quantile regression model analysis confirmed the lack of association between treatment with ACE inhibitors or ARB and ACE2 concentrations. Body mass index showed the only positive association with ACE2 plasma concentration (effect 0.015, 95% confidence interval 0.002 to 0.028, P = 0.024).ConclusionsIn a large cohort of patients with established cardiovascular disease or cardiovascular risk factors but without heart failure, ACE inhibitors and ARB were not associated with higher plasma concentrations of ACE2.

Decreased Plasma Levels of Angiotensin-Converting Enzyme Among Patients With Bipolar Disorder.

BackgroundDysfunctions in the renin-angiotensin system (RAS) seem to be involved in the pathophysiology of several mental illness, including schizophrenia and mood disorders. We carried out a cross-sectional study assessing the levels of RAS-related molecules among bipolar disorder (BD) patients compared to healthy controls.Methodsour sample consisted of 30 outpatients with BD type 1 (10 males, 20 females, age = 35.53 ± 10.59 years, 14 euthymic, 16 experiencing mood episodes) and 30 healthy controls (10 males, 20 females, age = 34.83 ± 11.49 years). Plasma levels of angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), angiotensin-II (Ang II), and angiotensin (1–7) [Ang-(1–7)] were determined by ELISA.ResultsBD patients experiencing ongoing mood episodes had significantly lower ACE levels compared to controls (median: 459.00 vs. 514.10, p < 0.05). There was no association between the levels of these biomarkers and clinical parameters.ConclusionOur findings support the involvement of RAS dysfunction in the pathophysiology of BD. Considering the potential therapeutic implications linked to a better understanding of the role of RAS dysfunction in BD, studies allowing a better characterization of RAS-related molecules level and activity across different mood states are of high interest.

Insertion-deletion polymorphism of angiotensin converting enzyme and susceptibility to rheumatoid arthritis in South Gujarat population

Rheumatoid Arthritis (RA) is a chronic inflammatory disease of synovial joints. High levels of angiotensin-converting enzyme (ACE) have been documented in RA synovial fluid (SF) and pleural effusions. The ACE gene insertion-deletion (INDEL or I/D; Intron 16; AF118569) polymorphism has been associated with the variability of serum ACE activity in which DD and II genotypes possess the highest and lowest ACE activity, respectively.The study investigated the association of ACE gene I/D polymorphism with RA in South Gujarat Population. Total 174 RA patients and 261 healthy controls were genotyped for ACE I/D polymorphism by polymerase chain reaction (PCR) method. The plasma ACE levels in 34 RA patients and 42 healthy controls were estimated by ELISA. The genotype and allele frequencies of the polymorphism were significantly differed between patients and control population (p = 0.0013; p < 0.0001 respectively), suggesting that ACE I/D polymorphism is associated with RA susceptibility in South Gujarat population. The susceptible ‘D’ allele was prevalent in RA group as compared to the control group (67.00% vs 54.00%). Though, there was no significant difference in the levels of ACE between patient and control groups (p = 0.827), the genotype-phenotype analysis revealed that individuals with DD and ID genotypes exhibit increased ACE levels as compared to the II genotypes (p = 0.0174; p = 0.0062 respectively). In addition, ‘DD’ genotype being prevalent in early age of onset group and severe RA group of patients proposes a crucial role of ACE I/D polymorphism in RA development and disease activity.Overall, our study suggests that ACE I/D polymorphism may be associated with RA susceptibility in South Gujarat Population.

Lower circulating levels of angiotensin-converting enzyme (ACE) in patients with schizophrenia

This study aimed at evaluating changes in the renin-angiotensin system (RAS) in patients with schizophrenia in comparison with controls. Plasma levels of angiotensin-converting enzyme (ACE), ACE2, angiotensin (Ang)-(1–7) and Ang II were assessed in 25 patients with schizophrenia and 20 controls. Patients with schizophrenia presented decreased levels of ACE compared to controls [median (25th–75th percentiles) = 434.79 (341.15–524.02) vs. 508.49 (396.34–608.72); p < 0.05]. No significant differences were found regarding ACE2, Ang-(1–7) and Ang II levels. There were no associations between the measured molecules and clinical parameters. Our results corroborate the hypothesis that the RAS is involved in the pathophysiology of schizophrenia.

Adverse cardiac effects of exogenous angiotensin 1-7 in rats with subtotal nephrectomy are prevented by ACE inhibition.

We previously reported that exogenous angiotensin (Ang) 1–7 has adverse cardiac effects in experimental kidney failure due to its action to increase cardiac angiotensin converting enzyme (ACE) activity. This study investigated if the addition of an ACE inhibitor (ACEi) to Ang 1–7 infusion would unmask any beneficial effects of Ang 1–7 on the heart in experimental kidney failure. Male Sprague–Dawley rats underwent subtotal nephrectomy (STNx) and were treated with vehicle, the ACEi ramipril (oral 1mg/kg/day), Ang 1–7 (subcutaneous 24 μg/kg/h) or dual therapy (all groups, n = 12). A control group (n = 10) of sham-operated rats were also studied. STNx led to hypertension, renal impairment, cardiac hypertrophy and fibrosis, and increased both left ventricular ACE2 activity and ACE binding. STNx was not associated with changes in plasma levels of ACE, ACE2 or angiotensin peptides. Ramipril reduced blood pressure, improved cardiac hypertrophy and fibrosis and inhibited cardiac ACE. Ang 1–7 infusion increased blood pressure, cardiac interstitial fibrosis and cardiac ACE binding compared to untreated STNx rats. Although in STNx rats, the addition of ACEi to Ang 1–7 prevented any deleterious cardiac effects of Ang 1–7, a limitation of the study is that the large increase in plasma Ang 1–7 with ramipril may have masked any effect of infused Ang 1–7.

Imbalanced plasma ACE and ACE2 level in the uremic patients with cardiovascular diseases and its change during a single hemodialysis session

Background: The renin-angiotensin system (RAS) has significant influences on heart and renal disease progression. Angiotensin converting enzyme (ACE) and angiotensin converting enzyme II (ACE2) are major peptidases of RAS components and play counteracting functions through angiotensin II (Ang II)/ATIR and angiotensin-(1–7) (Ang-(1–7))/Mas axis, respectively.Methods: There were 360 uremic patients on regular hemodialysis (HD) treatment (inclusive of 119 HD patients with cardiovascular diseases (CVD) and 241 HD patients without CVD and 50 healthy subjects were enrolled in this study. Plasma ACE, ACE2, Ang II and Ang-(1–7) levels of the HD patients were determined.Results: We compared pre-HD levels of plasma ACE, ACE2, Ang II and Ang-(1–7) in the HD patients with and without CVD to those of the controls. The HD patients, particularly those with CVD, showed a significant increase in the levels of ACE and Ang II, whereas ACE2 and Ang-(1–7) levels were lower than those in the healthy controls. Therefore, imbalanced ACE/ACE2 was observed in the HD patients with CVD. In the course of a single HD session, the plasma ACE, ACE/ACE2 and Ang II levels in the HD patients with CVD were increased from pre-HD to post-HD. On the contrary, ACE2 levels were decreased after the HD session. These changes were not detected in the HD patients without CVD.Conclusions: Pathogenically imbalanced circulating ACE/ACE2 was detected in the HD patients, particularly those with CVD. HD session could increase ACE/Ang II/AT1R axis and decrease ACE2/Ang-(1–7)/Mas axis activity in the circulation of HD patients with CVD.

The Angiotensin Converting Enzyme Insertion/Deletion Polymorphism Associates with Habitual Physical Activity among European-American Adults

PURPOSE: The angiotensin converting enzyme (ACE) insertion (I) deletion (D) polymorphism (ACE DIP) (rs4340) is a 287 base pair sequence within intron 16 of chromosome 17q23 that accounts for half of the variation in plasma ACE levels. Due to its influence on cardiovascular and renal function, the ACE DIP has been examined for its association with sport performance. The literature regarding associations with habitual physical activity is limited and inconsistent. We examined associations of the ACE DIP and physical activity among 461 European-American adults. METHODS: 203 men and 258 women with a body mass index (BMI) of 24.3±4.8 kg·m2 completed the Paffenbarger Physical Activity Questionnaire to determine weekly walking distance. ACE II (n=119), ID (n=213), and DD (n=129) genotypes were determined using TaqMan allele discrimination assays. Multivariate analysis of covariance (MANCOVA) determined logtransformed differences among ACE DIP genotypes and weekly walking distance with gender as a fixed factor and age and BMI as covariates. Because a significant ACE DIPxBMI interaction was found (p=0.03), we categorized the sample into normal weight (NW:BMI≤24.9 kg·m2) and overweight (OW:BMI>24.9 kg·m2). We repeated the MANCOVA with gender and BMI groups as fixed factors and age as a covariate. Bonferroni corrections were used to control for multiple comparison testing with alpha levels at p<.05. RESULTS: For NW (BMI=21.7±1.8 kg·m2), participants with the ACE II reported walking 1.4±1.0 mi/wk, ID 1.2±0.9 mi/wk, and DD 1.6±1.2 mi/wk, with ID walking less than II and DD (p<0.05). For OW (BMI=29.6±4.4 kg·m2), participants with the ACE II reported walking 1.5±1.1 mi/wk, ID 1.2±1.0 mi/wk, and DD 0.6±0.8 mi/wk, with DD walking less than II (p=0.02). For NW vs OW, weekly walking distance was 1.0±2.2 mi/wk less among OW with the ACE DD genotype than NW with this genotype (p=0.02); there were no other genotype-physical activity differences within or between NW and OW (p>0.05). CONCLUSIONS: BMI interacted with ACE DD to modulate habitual physical activity levels such that weekly walking distance was ~1.0 mi/wk greater among NW than OW with ACE DD. Our findings may provide insight into the discrepancies of this literature, and have public health significance equating to a body weight differential of ~1.4 lb/yr.

A metabolomics approach for investigating urinary and plasma changes in spontaneously hypertensive rats (SHR) fed with chicken skin protein hydrolysates diets

Plasma and urine metabolomics profiles of spontaneously hypertensive rats (SHRs) fed with chicken skin protein hydrolysates (CSPHs) were investigated to establish possible biomarkers of blood pressure regulation. SHR and wistar Kyoto (WKY) rats were randomised into groups that received casein-only (control), CSPHs (0.5 or 1%) or chicken skin meal (CSM 1%) diets for six weeks. Results showed that the diets significantly (P < 0.05) lowered systolic blood pressure (SBP) of SHRs (−36, −31 and −26 mmHg for CSPH 1%, CSPH 0.5% and CSM 1%, respectively) but not WKY. This correlated with decreased plasma angiotensin converting enzyme levels but not with superoxide dismutase activity. Partial least square discrimination analysis of detected metabolites in urine and plasma of rats showed significant changes in levels of symmetric dimethylarginine, N2-acetyl-L-ornithine, buthionine sulfoximine, uric acid, α-tocopherol succinate, L-isoleucine, creatinine, and phospholipids. CSPHs could therefore be used as ingredients in developing nutraceuticals and functional foods for hypertension management.

Blood type gene locus has no influence on ACE association with Alzheimer's disease

The ABO blood group locus was recently found to contribute independently and via interactions with angiotensin-converting enzyme (ACE) gene variation to plasma levels of ACE. Variation in ACE has previously been not only implicated as individually conferring susceptibility for Alzheimer's disease (AD) but also proposed to confer risk via interactions with other as yet unknown genes. More recently, larger studies have not supported ACE as a risk factor for AD, whereas the role of ACE pathway in AD has come under increased levels of scrutiny with respect to various aspects of AD pathology and possible therapies. We explored the potential combined involvement of ABO and ACE variations in the genetic susceptibility of 2067 AD cases compared with 1376 nondemented elderly. Including the effects of ABO haplotype did not provide any evidence for the genetic association of ACE with AD.

Curcumin improves endothelial dysfunction and vascular remodeling in 2K-1C hypertensive rats by raising nitric oxide availability and reducing oxidative stress

Oxidative stress plays a role in maintaining high arterial blood pressure and contributes to the vascular changes that lead to hypertension. Consumption of polyphenol-rich foods has demonstrated their beneficial role in the prevention and treatment of hypertension. Curcumin (CUR), a phenolic compound present in the rhizomes of turmeric, possesses cardiovascular protective, anti-inflammatory and antioxidant properties. The present study was designed to investigate the protective effect of CUR on 2kidney-1clip (2K-1C)-induced hypertension, endothelial dysfunction, vascular remodeling and oxidative stress in male Sprague-Dawley rats. Sham operated or 2K-1C rats were treated with CUR at a dose of 50 or 100 mg/kg/day (or vehicle). After 6 weeks of treatment, CUR ameliorated hemodynamic performance in 2K-1C hypertensive rats (P < 0.05), by reducing blood pressure, increasing hindlimb blood flow and decreasing hindlimb vascular resistance. Hemodynamic restoration was associated with a reduction in plasma angiotensin converting enzyme level. Endothelium-dependent vasorelaxation, in response to acetylcholine, of aortic rings isolated from 2K-1C hypertensive rats-treated with CUR was significantly increased (P < 0.05). CUR also attenuated hypertension-induced oxidative stress and vascular structural modifications. These effects were associated with elevated plasma nitrate/nitrite, upregulated eNOS expression, downregulated p47phox NADPH oxidase and decreased superoxide production in the vascular tissues. The overall findings of this study suggest the mechanisms responsible for the antihypertensive action of CUR in 2K-1C hypertension-induced endothelial dysfunction and vascular remodeling involve the improvement NO bioavailability and a reduction in oxidative stress.

Factors Predicting Long‐Term Mortality in Patients with Hypertrophic Cardiomyopathy

In this study, we aimed to elucidate the factors affecting long-term all-cause mortality in patients with hypertrophic cardiomyopathy (HCM). We retrospectively examined 31 patients (22 males and 9 females) diagnosed with HCM from 1999 to 2013. All subjects had sinus rhythm at the time of evaluation. Four patients had history of paroxysmal atrial fibrillation (PAF). In addition to echocardiographic examination plasma angiotensin-converting enzyme (ACE) activity and gene polymorphism were determined. The variables that were found to be significant in mortality were then included in multivariate analysis. At the final follow-up examination, 12 patients had died, including 2 due to congestive heart failure and 10 due to sudden cardiac death. Patients with PAF had significantly higher mortality (P=0.008). Moreover, left ventricular (LV) end-diastolic diameter (P=0.04), LV systolic diameter (P=0.001), LV mass index (P=0.01), and left atrium diameter (P=0.003) were found to be significantly correlated with mortality. However, no significant correlation was noted between mortality and age, type of HCM (familial/nonfamilial and obstructive/nonobstructive), ACE gene polymorphism, and plasma ACE level. In the multivariate analysis, left atrial (LA) diameter was still significantly associated with mortality. The LA diameter with a cutoff value of 4.1cm predicted 13-year mortality with a sensitivity of 82% and specificity of 78%. Instead of the ACE genotype and activity, echocardiographic evaluation findings such as LV systolic and diastolic diameters, LV mass index, and particularly LA dimension may predict long-term mortality in patients with HCM. PAF has also significant importance in the long-term mortality in patients with HCM.

Does Plasma ACE Level Accurately Reflect the Occurrence of Exercise‐Induced Pulmonary Haemorrhage?

IntroductionExercise‐induced pulmonary haemorrhage (EIPH) is a highly prevalent airway disorder responsible for poor‐performance in horses. While various methodologies are available for diagnosing EIPH, no readily available systemic biomarker has to date been definitively validated. A recent study demonstrated that angiotensin‐converting enzyme (ACE) activity in plasma was increased in horses with higher degrees of haemorrhage, as assessed by post exercise tracheal endoscopy.AimsTo investigate plasma ACE activity in horses suffering previous episodes of EIPH and controls.MethodsVenous blood samples were collected at rest from 121 client‐owned, racing or race‐fit Standardbred racehorses. Bronchoalveolar lavage fluid (BALF) samples were collected from right and left lung, cytocentrifuged and stained with Perl's Prussian blue. Total haemosiderin scores (THS) were calculated for detecting EIPH. According to THS, 36 horses were diagnosed with EIPH and 85 were assigned as controls. The ACE levels were determined on an automated spectrophotometer, using FAPGG as a substrate.ResultsPlasma ACE levels in EIPH‐affected horses (85.1 ± 24.6 u/l) were lower than those of control horses (94.4 ± 24.0 u/l), even if the tendency was not statistically significant (P = 0.056). Within each group of horse (EIPH and control), no significant difference was found for THS between lungs; a significant correlation between right and left BALF being furthermore observed (R = 0.643; P&lt;0.001). No significant correlation was however found between plasma ACE levels and THS of BALF from either left or right lung.Conclusions and practical significanceThis is the first study determining plasma ACE activity in a large population of racehorses at training. Apart from acute pulmonary haemorrhage, these results highlight that previous episodes of EIPH might be associated with a moderate decrease of circulating ACE levels. Further studies are warranted to establish the precise implication of ACE in the physiopathology of EIPH and determine its relevance as a systemic biomarker.Ethical animal researchThis study has been approved by the Regional Animal Ethic Committee and all owners gave consent. Sources of funding: I.F.C.E. (French National Studs) and S.E.C.F. (French Trotters Racing Association). Competing interests: None.

NQO1 activation regulates angiotensin-converting enzyme shedding in spontaneously hypertensive rats

Angiotensin-converting enzyme (ACE) plays a key role in blood pressure (BP) homeostasis via regulation of angiotensin II. Active ACE ectodomain is enzymatically cleaved and released into body fluids, including plasma, and elevated plasma ACE levels are associated with increased BP. β-lapachone (βL) has been shown to increase cellular NAD(+)/NADH ratio via activation of NAD(P)H:quinone oxidoreductase 1 (NQO1). In this study, we evaluated whether NQO1 activation by βL modulates BP through regulation of ACE shedding in an animal model of hypertension. Spontaneously hypertensive rats (SHR) and a human ACE-overexpressing rat lung microvascular endothelial cell line (RLMVEC-hACE) were used to investigate the mechanism by which βL exerts a hypotensive effect. In vitro studies revealed that βL significantly increased intracellular Ca(2+) ([Ca(2+)]i) levels and CaMKII Thr(286) phosphorylation, followed by diminished ACE cleavage secretion into culture media. Inhibition of βL-induced [Ca(2+)]i level changes through intracellular Ca(2+) chelation, Nqo1-specific siRNA or ryanodine receptor blockade abolished not only βL-induced increase in [Ca(2+)]i levels and CaMKII phosphorylation, but also βL-mediated decrease in ACE shedding. The effect of βL on ACE shedding was also blocked by inhibition of CaMKII. In SHR, βL reduced BP following increase of CaMKII Thr(286) phosphorylation in the lung and decrease of ACE activity and angiotensin II levels in plasma. This is the first study demonstrating that ACE shedding is regulated by NQO1 activation, which is possibly correlated with relieving hypertension in SHR. These findings provide strong evidence suggesting that NQO1 might be a new target for ACE modulation and BP control.

Angiotensin-Converting Enzyme Insertion/Deletion Gene Polymorphism in Lung Cancer Patients

Lung cancer is a complex disease, and many factors, including environmental and occupational exposure, cigarette smoking, and genetics, contribute to its progression. Angiotensin-converting enzyme (ACE) is an important regulator of blood pressure and cardiovascular homeostasis. Plasma levels of ACE depend on an insertion/deletion (I/D) polymorphism in its gene. Current correlation data between lung cancer and the ACE I/D polymorphism are contradictory or insufficient. We investigated whether the ACE I/D polymorphism is associated with a risk for lung cancer development in the Croatian population, representing the first report in a population of Slavic origin. A total of 308 lung cancer patients and 353 control subjects were genotyped for the ACE I/D polymorphism by polymerase chain reaction. The observed distribution of genotypes and alleles showed no significant difference between total patients and controls (p>0.050). However, in a subgroup of nonsmall cell lung cancer patients with squamous cell carcinoma, a significantly higher frequency of the DD genotype (37.7% vs. 27.8%, p=0.030, OR=1.57, 95% CI=1.05-2.36) and D allele was observed compared with the control group (61.3% vs. 52.8%, p=0.015, OR=1.41, 95% CI=1.07-1.87). The DD genotype of ACE may contribute to a higher risk of developing squamous cell carcinoma in the Croatian population.