|Year : 2019 | Volume
| Issue : 1 | Page : 22-28
Correlation between plasma-soluble angiotensin-converting enzyme 2, anti- angiotensin-converting enzyme 2, and angiotensin-(1–7) in patients with chronic heart failure
Yi Gu1, Xiao-Hui Yang1, Muhammad Nabeel Dookhun2, Jian-Song Zhou1, Si-Liang Xia1, Hui Zhang2, Xiao-Yi Qin2, Yu-Qing Yang2, Jia-Li Cao2, Hua-Yi-Yang Zou2, Xiao-Qian Xiao2, Xin Zheng Lu2
1 Department of Cardiology, Jiangbei People's Hospital, Nanjing, China
2 Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
|Date of Web Publication||28-Mar-2019|
Xin Zheng Lu
Department of Cardiology, The First Affiliated Hospital, Nanjing Medical University, Nanjing
Source of Support: None, Conflict of Interest: None
Background: Angiotensin-converting enzyme 2 (ACE2) is an ACE homolog that converts angiotensin II into angiotensin-(1–7) (Ang-[1–7]). Tumor necrosis factor α (TNF-α), interleukin-1 β, and interleukin-6 are plasma inflammatory cytokines that play a role in the development of hypertension and chronic heart failure (CHF). However, the relationship between soluble ACE2 (sACE2), Anti-ACE2, Ang-(1–7), and the plasma inflammatory cytokines during the development of CHF remains unclear. Methods and Results: A total of 135 patients with CHF were enrolled in this study (63 males and 72 females), with left ventricular ejection fraction (LVEF) <50%. The height and body weight of each patient was measured to calculate the body mass index. The plasma concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured using immunofluorescence. The patients were divided into four groups according to the quartiles of NT-proBNP levels. The plasma concentrations of sACE2, anti-ACE2, Ang-(1–7), and TNF-α were measured by enzyme-linked immunosorbent assay. The plasma ACE2, anti-ACE2, Ang-(1–7), and TNF-α levels in CHF patients increased with increasing NT-proBNP levels (P < 0.01). The plasma sACE2, anti-ACE2, Ang-(1–7), and TNF-α levels were positively correlated with NT-proBNP levels (r = 0.587, r = 0.949, r = 0.614, and r = 0.711, respectively; P < 0.01). Multiple linear regression analysis showed that TNF-α, Ang-(1–7), and LVEF are independent predictors for NT-proBNP in patients with CHF. Conclusions: The plasma sACE2, anti-ACE2, Ang-(1–7), and TNF-α levels increased in CHF patients with increasing NT-proBNP levels. The simultaneous detection of these markers is significant for diagnosing patients with CHF.
Keywords: Angiotensin-converting enzyme 2, angiotensin-(1–7), autoantibodies, chronic heart failure, N-terminal pro-brain natriuretic peptide, tumor necrosis factor α
|How to cite this article:|
Gu Y, Yang XH, Dookhun MN, Zhou JS, Xia SL, Zhang H, Qin XY, Yang YQ, Cao JL, Zou HY, Xiao XQ, Lu XZ. Correlation between plasma-soluble angiotensin-converting enzyme 2, anti- angiotensin-converting enzyme 2, and angiotensin-(1–7) in patients with chronic heart failure. Cardiol Plus 2019;4:22-8
|How to cite this URL:|
Gu Y, Yang XH, Dookhun MN, Zhou JS, Xia SL, Zhang H, Qin XY, Yang YQ, Cao JL, Zou HY, Xiao XQ, Lu XZ. Correlation between plasma-soluble angiotensin-converting enzyme 2, anti- angiotensin-converting enzyme 2, and angiotensin-(1–7) in patients with chronic heart failure. Cardiol Plus [serial online] 2019 [cited 2021 Mar 2];4:22-8. Available from: https://www.cardiologyplus.org/text.asp?2019/4/1/22/255073
*Yi Gu and Xiao-Hui Yang have contributed equally to this work.
| Introduction|| |
Heart failure is a complex condition involving several pathophysiological mechanisms. Overactivation of the renin-angiotensin system (RAAS) is one mechanism thought to contribute to the onset of heart failure, and may also induce chronic heart failure (CHF) or precipitate exacerbations of heart failure. Donoghue et al., isolated the first known human homolog of the angiotensin-converting enzyme (ACE) in 2000; and this RAS gene, named ACE2, has protective effects in CHF patients. ACE2 mediates the carboxylation of angiotensin II (AngII) into angiotensin-(1–7) (Ang-[1–7]), an endogenous antagonist of AngII. To date, ACE2 is known to stop the progression of CHF in animal (Sprague-Dawley rats), experimental models. Autoantibodies including myocardial anti-myosin heavy chain, have been detected in the plasma of patients with CHF., Takahashi et al. revealed that anti-ACE2 may be associated with constrictive vasculopathy in patients with connective tissue disease and that immunosuppressive therapy may markedly decrease the titer of autoantibodies against ACE2 (anti-ACE2) and restore plasma ACE2 activity. There is a strong evidence to suggest that high concentrations of tumor necrosis factor α (TNF-α) may induce cardiac damage,, and that TNF-α is associated with the progression of CHF. Plasma pro-BNP and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels are consistent with the clinical severity of heart failure according to the New York Heart Association (NYHA) classification. NT-proBNP is a useful diagnostic and prognostic biomarker for patients with heart failure. The current European Society of Cardiology guideline on heart failure recommends an NT-proBNP cutoff value of 125 pg/ml. Therefore, we hypothesized that the increasing NT-proBNP levels in CHF patients would change the endogenous regulation of RAS. Such changes would also alter the levels of sACE2, anti-ACE2, Ang-(1–7), and TNF-α.
| Methods|| |
A total of 135 patients with CHF were enrolled in this study (63 males and 72 females, with left ventricular ejection fraction [LVEF] <50%). The height and weight of each patient were measured, and the body mass index (BMI) was calculated. The plasma concentrations of NT-proBNP were measured using immunofluorescence, whereas those of ACE2, anti-ACE2, Ang-(1–7), and TNF-α were measured using enzyme-linked immunosorbent assay (ELISA). Given that the NYHA classification may be subjective, we used a novel method for grouping patients [Table 1]. Patients were divided into four groups based on quartiles of NT-proBNP levels: group 1 at <1674 ng/l), Group 2 at 1678 ng/l to 1818 ng/l, Group 3 at 1830 ng/l to 1980 ng/l, and Group 4 at >1988 ng/l).
|Table 1: Grouping patients based on quartiles of the N-terminal pro-brain natriuretic peptide levels|
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This study was approved by the Institutional Board. Plasma samples (n = 135; 63 males, 72 females; average age, 54.17 ± 12.15 years) of patients with CHF between July 2011 and March 2012 were obtained. The subjects included 50 patients with hypertensive disease, 46 with coronary heart disease, 20 with valvular heart disease, 11 with cardiomyopathy, and 8 with congenital heart disease. All patients met the following criteria: NYHA Level of II to IV, LVEF of <50% or LVEDd >55 mm. The biochemical characteristics and demographics were obtained before sample analysis. We excluded patients who had acute complications caused by diabetes mellitus, severe pulmonary diseases, diseases of the immune system, immunological deficiencies, malignant tumors, hematological diseases, acute or chronic infectious diseases, or serious liver and kidney dysfunction. All patients gave their informed consent to participate in this study.
Angiotensin-converting enzyme 2 enzymatic assay and anti-angiotensin-converting enzyme 2 assay
Fasting blood samples (4 ml) were collected in the early morning after a 30 min rest. The samples were immediately transferred into two glass tubes containing heparin as anticoagulant. The samples were centrifuged for 30 min at 604×g and tested using ELISA kits from American R and D Systems. The remaining samples were subsequently stored at −20°C or −80°C.
All reagents were prepared before the actual assay. Standard wells were prepared for testing the samples. In each well, 50 μl of the standard solution and 10 μl of the testing samples were added, followed by 40 μl of the respective diluted sample. The empty wells were covered with an adhesive strip and incubated for 30 min at 37°C. Each well was aspirated and washed five times. The washing steps were performed by filling each well with washing solution (400 μl) using a squirt bottle, manifold dispenser, or autowasher. The complete removal of liquid at each step is essential for effective quantification. The remaining washing solution was removed by aspiration or decanting. The plates were inverted and blotted against clean paper towels. Approximately 50 μl of the enzyme-detecting fluid was added to each well, except for the blank ones. The wells were covered with adhesive strips, and incubation was repeated for 30 min at 37°C. The suspensions in each well were aspirated and washed. Approximately 50 μl each of the chromogen solutions A and B were added to each well. The samples were gently mixed and incubated for 15 min at 37°C in the dark. The optical density at 450 nm (OD450 nm) was then defined using a microtiter plate reader.
A standard curve was used to determine the amount of each substance in the unknown samples. The standard curve was generated by plotting the average OD450 nm of each standard concentration on the vertical (Y) axis versus the corresponding change in concentration on the horizontal (X) axis. First, the mean OD for each standard and sample was calculated. The OD values of all samples were subtracted by the mean value of the standards before interpreting the results. The amount of each substance in a sample was interpolated from the respective standard curve based on the OD. Variations in the results and experimental uncertainties may be present resulting from different persons performing the experiment, pipetting method, washing technique, incubation time, incubation temperature, and manufacturing date of the kit. Thus, the different person performing the experiment would have his own standard curve.
Plasma angiotensin-(1–7) and tumor necrosis factor α assay
Purified Ang-(1-–7)/TNF-α antibody was used to coat the wells and produce the solid-phase antibody. Ang-(1–7)/TNF-α was added to the wells in combination with the HRP-labeled Ang-(1–7) antibody to obtain an antibody-antigen enzyme-antibody complex. After washing each well, TMB was added to the substrate solution. The TMB substrate turns blue because of the HRP-catalyzed reaction. This was followed by the addition of a sulfuric acid solution. The color change was measured with a spectrophotometer at 450 nm. The Ang-(1–7) concentration of the samples was then determined by comparing their ODs to the standard curve.
Plasma N-terminal pro-brain natriuretic peptide assay
Plasma was collected from the blood samples using ethylenediaminetetraacetic acid as an anticoagulant. The plasma samples were centrifuged for 10 min at 3000 rpm, and NT-ProBNP was detected using an immunofluorescence method. This process was repeated thrice, and the average value was used as the final outcome of the assay.
The echocardiographic features of patients were determined. All patients were examined by ultrasound echocardiography (VIVID7; GE, USA). The measured parameters included LVEF, left ventricular fractional shortening, interventricular septal thickness, left ventricular posterior wall thickness, and left ventricular end-diastolic diameter.
The software SPSS version 16.0 (Chicago, SPSS Inc) was used for statistical analyses. All data were expressed as the mean ± standard deviation. The quantitative variables with a normal distribution were analyzed using the Student's t-test, whereas variables that were not normally distributed were analyzed using the two-tailed Mann–Whitney U-test. ANOVA was used for comparisons between and within treatment groups. Correlation analysis was performed through linear correlation and linear regression methods among the anti-ACE2, sACE2, Ang-(1–7), and TNF-α levels against the NT-proBNP levels. Multiple linear regression was used for multivariate analysis. P < 0.05 was considered statistically significant.
| Results|| |
The clinical characteristics of the patients in different NT-proBNP groups are listed in [Table 2]; these characteristics include gender, age, height, and weight. The table also includes the plasma levels of sACE2, anti-ACE2, Ang-(1–7), TNF-α, NT-proBNP, glucose, uric acid, urea nitrogen, as well as those of serum creatinine and lipid. With increasing NT-proBNP levels in patients with CHF, the plasma sACE2, anti-ACE2, Ang-(1–7), and TNF-α levels were noticeably and significantly increased between groups. No significant differences were found among the four groups based on their age, smoking history, drinking history, and heart rate, as well as the urea nitrogen, serum creatinine, uric acid, plasma glucose, cholesterol (total, high-density lipoprotein, and low-density lipoprotein), and triglycerides levels.
|Table 2: Clinical characteristics and plasma levels of soluble angiotensin converting enzyme 2, anti-angiotensin converting enzyme 2, Angiotensin-(1-7), and N-terminal pro-brain natriuretic peptide in patients with chronic heart failure (n=135)|
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Differential expression of soluble angiotensin-converting enzyme 2, anti-angiotensin converting enzyme 2, angiotensin-(1–7), and tumor necrosis factor α between different N-terminal pro-brain natriuretic peptide groups
A significant positive difference was found between groups [Figure 1], even after correction for patients' age, gender, LVEF, and BMI.
|Figure 1: Correlation of sACE2, anti-ACE2, Ang-(1–7), and TNF-α with the NT-proBNP groups. The apparent differences between groups continued to be significantly positive (a-d). Patients were divided into four groups according to the quartiles of the NT-proBNP levels. sACE2: Soluble angiotensin converting enzyme 2, Ang-(1–7): angiotensin-(1–7), TNF-α: Tumor necrosis factor α, NT-proBNP: N-terminal pro-brain natriuretic peptide|
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Linear regression analysis
The sACE2, anti-ACE2, Ang-(1–7), and TNF-α levels were positively correlated with NT-proBNP in patients with CHF [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d after correction for age, gender, LVEF, and BMI.
|Figure 2: Correlation of the sACE2, anti-ACE2, Ang-(1–7), and TNF-α levels with NT-proBNP, EF%, sACE2, anti-ACE2, and Ang-(1–7). The sACE2, anti-ACE2, Ang-(1–7), and TNF-α levels were positively correlated with NT-proBNP were observed in patients with CHF (a-d) after correction for age, gender, LVEF and BMI. The sACE2, anti-ACE2, Ang-(1–7), and TNF-α levels were positively correlated with eachothers (e-j). The sACE2, anti-ACE2, Ang-(1–7), and TNF-α levels were negatively correlated with EF% (k-n). sACE2: Soluble angiotensin converting enzyme 2, Ang-(1–7): Angiotensin-(1–7), TNF-α: Tumor necrosis factor α, NT-proBNP: N-terminal pro-brain natriuretic peptide|
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Multiple linear regression analysis
NT-proBNP was considered the dependent variable, whereas sACE2, anti-ACE2, Ang-(1–7), TNF-α, and LVEF were independent variables. Multiple linear regression analysis found the coefficient of determination (r2) ranging from 0.628 to 0.617. The levels of TNF-α (β = 0.494; P = 0.000) and Ang-(1–7) (β =0.235; P = 0.001) and LVEF (β = −0.349; P = 0.000) were included in the analysis. TNF-α, Ang-(1–7) and LVEF were found to be independent predictors of NT-proBNP levels in patients with CHF.
| Discussion|| |
The RAAS consists of renin, angiotensin, ACE, and aldosterone and it has a crucial role in the pathophysiology of CHF., ACE is a core enzyme of RAAS. Its substrate is Angiotensin I and its product is AngII, which is a key peptide of the so-called ACE–AngII axis. In addition to the already mentioned ACE–AngII axis, the ACE–Ang-(1–7) axis has also been observed. ACE2 was initially identified from 5' sequencing of a failed ventricle of human heart. ACE2 is a carboxypeptidase that degrades AngII to Ang-(1–7). AngII is a vasoconstrictive agent, whereas the vasoprotective Ang-(1–7) has vasodilating, antiproliferative, and antithrombotic properties that antagonize the action of AngII.,, Previous studies have demonstrated that Ang-(1–7) inhibits inflammation and oxidative stress activates phosphatases, promotes renal natriuresis and vasodilation, as well as mediates myocardial remodeling and fibrosis, vascular remodeling in hypertension, vascular smooth muscle cell proliferation and inflammation, regulation of endothelial cell function, and other pathophysiological processes. Theoretically, ACE2 can overcome the effects of AngII in relation to cardiac remodeling.
We observed that the plasma levels of sACE2, anti-ACE2, Ang-(1–7), and TNF-α were significantly increased in patients with CHF [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d. The upregulation of these factors in patients with CHF was associated with the marked activation of the ACE2–Ang-(1–7) axis in RAAS, as well as that of the inflammatory cascade [Figure 2]g, [Figure 2]i and [Figure 2]j. As NT-proBNP level increased, the plasma ACE2, anti-ACE2, Ang-(1–7), and TNF-α levels also increased. The levels of sACE2, Anti-ACE2, Ang-(1–7), and TNF-α levels were positively correlated with the NT-proBNP level after correction for patients' age, gender, and BMI. Inflammatory biomarkers are commonly seen in heart failure, which is consistent with the observation of our study [Figure 2]c and [Figure 2]n.
ACE2 is an integral membrane protein like ACE. The cleavage of membrane ACE2 into its soluble form is partially dependent on the TNF-α convertase ADAM17 (a disintegrin and metalloprotease 17) [Figure 2]g, which is an up-regulated protease in CHF., The up-regulation of pro-inflammatory cytokines and activation of proteases during CHF has been implicated as a pathological mechanism in cardiac remodeling., The cleavage of membrane ACE2 may be due to the up-regulation of protease, thereby inducing a relative decrease in ACE2 levels and subsequently leading to cardiac dysfunction. Alternatively, the cleavage of membrane ACE2 and the release of its soluble form may be a compensatory mechanism during HF. Ang-(1–7) has a very short half-life (<9 s). Thus, the release of sACE2 from the vascular endothelium may alter the systemic Ang-(1–7) concentrations and the relative balance of peripheral ACE2/ACE [Figure 2]h. During CHF, RAAS is excessively activated, ACE mRNA expression is upregulated in the heart, and local AngII levels are correspondingly increased. Thus, cardiac remodeling occurs, which ultimately leads to heart failure. Simultaneously, ACE2 mRNA level is significantly increased in the heart, thereby reducing AngII levels and producing Ang-(1–7) [Figure 2]h. sACE2 and Ang-(1–7) levels are correspondingly increased with the progression of heart failure [Figure 2]a, [Figure 2]d, [Figure 2]k and [Figure 2]m. Thus, these substances may be necessary for the systemic activation of an endogenous counter-regulatory pathways in RAAS. Nevertheless, anti-ACE2 may gradually interfere with such a mechanism. Under certain conditions, the innate immune system will induce an autoimmune response and generate auto-reactive antibodies [Figure 2]e, [Figure 2]f and [Figure 2]i. Previous studies have shown that several circulating autoantibodies are crucial for the progression and induction of heart failure. Cardiac autoantibodies are expressed in the plasma of patients with hypertension, viral myocarditis, myocardial infarction, dilated cardiomyopathy, and other heart diseases. Basic and clinical research efforts have demonstrated that immune adsorption may improve cardiac function., These cardiac autoantibodies have been suggested to contribute toward myocardial cell injury, which cause the deterioration of heart function and myocardial remodeling [Figure 2]l. Accordingly, these immune mechanisms may be involved in the pathological process of heart disease. Anti-ACE2 may be associated with constrictive vasculopathy in patients with connective tissue diseases; immunosuppressive therapy markedly decreases the titer of autoantibodies against ACE2 and restores plasma ACE2 activity. Continuous auto-antigen exposure occurs during ventricular remodeling, with progressive changes in the myocardial structure. The generation of inflammatory cytokines promotes the autoimmune reaction in affected tissues, thereby producing anti-ACE2 [Figure 2]i.
Anti-ACE2 was observed in the plasma of patients with heart failure at different stages in this study [Figure 2]b and [Figure 2]l. Moreover, with increasing NT-proBNP levels, the plasma anti-ACE2 levels had a tendency to increase as well [Figure 2]b. This result indicates that immune dysfunction occurs in the development of CHF with the production of anti-ACE2 [Figure 2]e and [Figure 2]f. Simultaneously, other pathological factors may induce an immune response. The presence of various cardiac tissue-specific autoantibodies and other related biologic markers reveals that further immune-mediated myocardial injury occurs after heart failure. Autoantibodies can influence cardiac function by inducing negative chronotropic and/or negative inotropic effects. Furthermore, these autoantibodies could induce cardiomyocyte apoptosis and activate their complementary antigens.,,, In a prospective study, Caforio et al. showed that circulating anti-cardiac autoantibodies may precede disease manifestation, as independent predictors of disease development. The activity and ACE2 expression in cardiovascular tissue is normally low. Infusion of AngII (40 pmol/min) and/or recombinant human ACE2 (rhACE2) (1 mg/kg) was performed on mice for three consecutive days via a permeable micro-pump. It was observed that ACE2 activity was increased in the mice after infusion of AngII, whereas rhACE2 treatment decreased the concentration of AngII. rhACE2 has antihypertensive and cardiovascular protective effects by effectively degrading AngII and upregulating ACE2/Ang-(1–7). This observation implies that an exogenous increase in the expression and/or activity of ACE2 may be a novel method for improving cardiovascular fibrosis.
However, the exact mechanism of the generation of sACE2 and its autoantibody still remains unclear. Similarly, the biological significance of increased concentrations of sACE2 and its antibody requires further study. The regulation of immune function may be a novel therapeutic target for CHF treatment. Meanwhile, these results demonstrate the presence of functionally significant interactions between RAAS and PIC. Therefore, PIC indirectly participates in the development and progression of CHF by regulating RAAS.
| Conclusion|| |
The regulation of immune function may be a novel therapeutic target for CHF treatment. Meanwhile, our results demonstrate the presence of functionally significant interactions between RAAS and PIC. Therefore, PIC indirectly participates in the development and progression of CHF by regulating RAAS.
Financial support and sponsorship
This study was supported by the Jiangsu six human source foundations, 2015-WSN-004.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]