New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) II: Albumin Suppresses Angiotensin Converting Enzyme (ACE) Activity in Human

About 8% of the adult population is taking angiotensin-converting enzyme (ACE) inhibitors to treat cardiovascular disease including hypertension, myocardial infarction and heart failure. These drugs decrease mortality by up to one-fifth in these patients. We and others have reported previously that endogenous inhibitory substances suppress serum ACE activity, in vivo, similarly to the ACE inhibitor drugs. Here we have made an effort to identify this endogenous ACE inhibitor substance. ACE was crosslinked with interacting proteins in human sera. The crosslinked products were immunoprecipitated and subjected to Western blot. One of the crosslinked products was recognized by both anti-ACE and anti-HSA (human serum albumin) antibodies. Direct ACE-HSA interaction was confirmed by binding assays using purified ACE and HSA. HSA inhibited human purified (circulating) and human recombinant ACE with potencies (IC₅₀) of 5.7±0.7 and 9.5±1.1 mg/mL, respectively. Effects of HSA on the tissue bound native ACE were tested on human saphenous vein samples. Angiotensin I evoked vasoconstriction was inhibited by HSA in this vascular tissue (maximal force with HSA: 6.14±1.34 mN, without HSA: 13.54±2.63 mN), while HSA was without effects on angiotensin II mediated constrictions (maximal force with HSA: 18.73±2.17 mN, without HSA: 19.22±3.50 mN). The main finding of this study is that HSA was identified as a potent physiological inhibitor of the ACE. The enzymatic activity of ACE appears to be almost completely suppressed by HSA when it is present in its physiological concentration. These data suggest that angiotensin I conversion is limited by low physiological ACE activities, in vivo.     

New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) I: Endogenous Angiotensin Converting Enzyme (ACE) Inhibition

Angiotensin-converting enzyme (ACE) inhibitors represent the fifth most often prescribed drugs. ACE inhibitors decrease 5-year mortality by approximately one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors, which endogenous inhibitory effects are much less characterized than that for the clinically administered ACE inhibitors. Here we aimed to investigate this endogenous ACE inhibition in human sera. It was hypothesized that ACE activity is masked by an endogenous inhibitor, which dissociates from the ACE when its concentration decreases upon dilution. ACE activity was measured by FAPGG hydrolysis first. The specific (dilution corrected) enzyme activities significantly increased by dilution of human serum samples (23.2±0.7 U/L at 4-fold dilution, 51.4±0.3 U/L at 32-fold dilution, n = 3, p = 0.001), suggesting the presence of an endogenous inhibitor. In accordance, specific enzyme activities did not changed by dilution when purified renal ACE was used, where no endogenous inhibitor was present (655±145 U/L, 605±42 U/L, n = 3, p = 0.715, respectively). FAPGG conversion strongly correlated with angiotensin I conversion suggesting that this feature is not related to the artificial substrate. Serum samples were ultra-filtered to separate ACE (MW: 180 kDa) and the hypothesized inhibitor. Filtering through 50 kDa filters was without effect, while filtering through 100 kDa filters eliminated the inhibiting factor (ACE activity after <100 kDa filtering: 56.4±2.4 U/L, n = 4, control: 26.4±0.7 U/L, n = 4, p<0.001). Lineweaver-Burk plot indicated non-competitive inhibition of ACE by this endogenous factor. The endogenous inhibitor had higher potency on the C-terminal active site than N-terminal active site of ACE. Finally, this endogenous ACE inhibition was also present in mouse, donkey, goat, bovine sera besides men (increasing of specific ACE activity from 4-fold to 32-fold dilution: 2.8-fold, 1.7-fold, 1.5-fold, 1.8-fold, 2.6-fold, respectively). We report here the existence of an evolutionary conserved mechanism suppressing circulating ACE activity, in vivo, similarly to ACE inhibitory drugs.     

New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) III: Endogenous Inhibition of Angiotensin Converting Enzyme (ACE) Provides Protection against Cardiovascular Diseases

ACE inhibitor drugs decrease mortality by up to one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors. Here we investigated the clinical significance of this potential endogenous ACE inhibition.ACE concentration and activity was measured in patient''s serum samples (n = 151). ACE concentration was found to be in a wide range (47–288 ng/mL). ACE activity decreased with the increasing concentration of the serum albumin (HSA): ACE activity was 56±1 U/L in the presence of 2.4±0.3 mg/mL HSA, compared to 39±1 U/L in the presence of 12±1 mg/mL HSA (values are mean±SEM). Effects of the differences in ACE concentration were suppressed in human sera: patients with ACE DD genotype exhibited a 64% higher serum ACE concentration (range, 74–288 ng/mL, median, 155.2 ng/mL, n = 52) compared to patients with II genotype (range, 47–194 ng/mL, median, 94.5 ng/mL, n = 28) while the difference in ACE activities was only 32% (range, 27.3–59.8 U/L, median, 43.11 U/L, and range 15.6–55.4 U/L, median, 32.74 U/L, respectively) in the presence of 12±1 mg/mL HSA. No correlations were found between serum ACE concentration (or genotype) and cardiovascular diseases, in accordance with the proposed suppressed physiological ACE activities by HSA (concentration in the sera of these patients: 48.5±0.5 mg/mL) or other endogenous inhibitors.Main implications are that (1) physiological ACE activity can be stabilized at a low level by endogenous ACE inhibitors, such as HSA; (2) angiotensin II elimination may have a significant role in angiotensin II related pathologies.     

Growth Hormone Therapy in Congestive Heart Failure Due to Left Ventricular Systolic Dysfunction: a Meta-Analysis

ObjectiveTo examine the efficacy and safety of recombinant human growth hormone (rhGH) therapy in congestive heart failure (CHF) by conducting a meta-analysis of clinical studies.MethodsWe searched 3 literature databases (MEDLINE, EMBASE, and the Cochrane Register) for clinical studies of rhGH therapy in CHF due to systolic dysfunction and conducted a meta-analysis.ResultsTherapy with rhGH appears to have beneficial clinical effects (weighted mean difference [95% confidence interval]) in CHF including improved exercise duration (1.9 min [1.1-2.7]), maximum oxygen consumption (2.1 mL·kg^–1·min^–1 [1.2-3.0]), and New York Heart Association class (–0.9 [–1.5 to –0.3]). There were salutary hemodynamic effects of rhGH therapy, including increased cardiac output (0.4 L·min^–1 [0.1-0.6]) and decreased systemic vascular resistance (–177 dyn·s·cm^–5 [–279 to –74]). Among rhGH–treated patients, left ventricular (LV) ejection fraction improved (4.3% [2.2-6.4]). Despite increases in LV mass and wall thickness, there were no adverse effects on diastolic function. Subgroup analyses suggest that study design and treatment duration may influence some of the treatment effects. Most of the beneficial effects were driven by either uncontrolled or longer duration studies. Administration of rhGH therapy slightly increased the risk for ventricular arrhythmia; however, this finding was driven by a single small study.ConclusionrhGH therapy may have beneficial cardiovascular effects in CHF caused by LV systolic dysfunction. The possibility of proarrhythmia associated with rhGH therapy requires further study. Larger randomized trials with longer treatment duration are needed to fully elucidate the efficacy and safety of rhGH therapy in this patient population. (Endocr Pract. 2008;14:40-49)     

Human Pentraxin 3 (PTX3) as a Novel Biomarker for the Diagnosis of Pulmonary Arterial Hypertension

Background

Although inflammation is an important feature of pulmonary arterial hypertension (PAH), the usefulness of local inflammatory markers as biomarkers for PAH is unknown. In this study, we tested whether plasma concentrations of human pentraxin 3 (PTX3), a local inflammatory marker, would be a useful biomarker for detecting PAH.

Methods

Plasma PTX3 concentrations were evaluated in 50 PAH patients (27 with idiopathic PAH, 17 with PAH associated with connective tissue disease (CTD-PAH), and six with congenital heart disease), 100 age and sex-matched healthy controls, and 34 disease-matched CTD patients without PAH. Plasma concentrations of B-type natriuretic peptide (BNP) and C-reactive protein (CRP) were also determined.

Results

Mean PTX3 levels were significantly higher in all PAH patients than in the healthy controls (4.40±0.37 vs. 1.94±0.09 ng/mL, respectively; P<0.001). Using a threshold level of 2.84 ng/mL, PTX3 yielded a sensitivity of 74.0% and a specificity of 84.0% for the detection of PAH. In CTD-PAH patients, mean PTX3 concentrations were significantly higher than in CTD patients without PAH (5.02±0.69 vs. 2.40±0.14 ng/mL, respectively; P<0.001). There was no significant correlation between plasma levels of PTX3 and BNP or CRP. Receiver operating characteristic (ROC) curves for screening PAH in patients with CTD revealed that PTX3 (area under the ROC curve 0.866) is superior to BNP. Using a PTX3 threshold of 2.85 ng/mL maximized true-positive and false-negative results (sensitivity 94.1%, specificity 73.5%).

Conclusion

Plasma concentrations of PTX3 may be a better biomarker of PAH than BNP, especially in patients with CTD.     

感觉神经损伤性盐敏感性高血压大鼠心、肾ACE和ACE2的表达

目的研究肾素-血管紧张素系统（RAS）基因血管紧张素转换酶（ACE）和血管紧张素转换酶2（ACE2）在感觉神经损伤性盐敏感性高血压大鼠心肌和肾脏中的表达情况,探讨ACE、ACE2在盐敏感性高血压发生发展中的作用。方法用乳鼠皮下注射辣椒辣素法建立模型。哺乳期后,大鼠被随机分成4组：对照＋正常盐饮食组（CON-NS）、对照＋高盐饮食组（CON-HS）、辣椒辣素＋正常盐饮食组（CAP-NS）、辣椒辣素＋高盐饮食组（CAP-HS）。四组大鼠分别接受4周不同的处理。至7周龄（分组饲养后第4周）处死大鼠,免疫组化检测大鼠心肌和肾脏ACE和ACE2蛋白的表达,反转录-聚合酶链式反应（RT-PCR）检测大鼠心肌和肾脏ACE和ACE2mRNA的表达。结果①至7周龄（分组饲养后第4周）各组动物体重差异无显著性（P〉0.05）。②各组动物在分组时（0周）鼠尾收缩压差异无显著性（P=0.583）,至7周龄（分组饲养后第4周）,CAP-HS组鼠尾收缩压明显高于其它三组（P〈0.01）。③心肌和肾脏ACE蛋白表达均升高。心肌组织,CAP-HS组与CON-NS比较,P〈0.01,与CON-HS和CAP-NS比较,P〈0.05;肾脏组织,CAP-HS组与其它三组比较,P〈0.01。④心肌和肾脏ACE2蛋白表达均降低。心肌和肾脏组织,CAP-HS组与CON-NS和CAP-NS比较,P〈0.01,与CON-HS比较,P〈0.05。⑤心肌和肾脏ACE mRNA表达均升高。心肌组织,CAP-HS组与CON-NS比较,P〈0.01,与CON-HS和CAP-NS比较,P〈0.05;肾脏组织,CAP-HS组与其它三组比较,P〈0.01。⑥心肌和肾脏ACE2 mRNA表达均降低。心肌和肾脏组织,CAP-HS组与CON-NS和CAP-NS比较,P〈0.01,与CON-HS比较,P〈0.05。结论感觉神经损伤性盐敏感性高血压大鼠心、肾ACE表达升高的同时有ACE2表达的降低,ACE和ACE2表达水平的差异可能与盐敏感性高血压的形成有关。     

Characterization of Angiotensin Converting Enzyme-2 (ACE2) in Human Urine

Angiotensin converting enzyme-2 (ACE2) is a recently described membrane-bound carboxypeptidase identified by its homology to ACE, the enzyme responsible for the formation of the potent vasoconstrictor angiotensin II (Ang II). ACE2 inactivates Ang II and is thus thought to act in a counter-regulatory fashion to ACE. ACE2 is highly expressed in epithelial cells of distal renal tubules, and recent evidence indicates that expression is increased in a range of renal diseases. A soluble form of ACE, generated by proteolytic cleavage of the membrane-bound form, has been shown to be present in urine; although evidence for a similar release of ACE2 has been reported in cell culture, it is not yet known whether this occurs in vivo. The present study has identified ACE2 in human urine, both by a sensitive fluorescence-based activity assay and by Western immunoblot. Levels of ACE2 were surprisingly higher than ACE, which may reflect preferential targeting of the enzyme to the luminal surface of the renal epithelium. Future studies will determine whether increased expression of ACE2 in renal diseases are reflected in higher urinary levels of this novel enzyme.Australian Peptide Conference Issue.     

Circulating Interleukin-18 as a Biomarker of Total-Body Radiation Exposure in Mice,Minipigs, and Nonhuman Primates (NHP)

We aim to develop a rapid, easy-to-use, inexpensive and accurate radiation dose-assessment assay that tests easily obtained samples (e.g., blood) to triage and track radiological casualties, and to evaluate the radioprotective and therapeutic effects of radiation countermeasures. In the present study, we evaluated the interleukin (IL)-1 family of cytokines, IL-1β, IL-18 and IL-33, as well as their secondary cytokines’ expression and secretion in CD2F1 mouse bone marrow (BM), spleen, thymus and serum in response to γ-radiation from sublethal to lethal doses (5, 7, 8, 9, 10, or 12 Gy) at different time points using the enzyme-linked immune sorbent assay (ELISA), immunoblotting, and cytokine antibody array. Our data identified increases of IL-1β, IL-18, and/or IL-33 in mouse thymus, spleen and BM cells after total-body irradiation (TBI). However, levels of these cytokines varied in different tissues. Interestingly, IL-18 but not IL-1β or IL-33 increased significantly (2.5–24 fold) and stably in mouse serum from day 1 after TBI up to 13 days in a radiation dose-dependent manner. We further confirmed our finding in total-body γ-irradiated nonhuman primates (NHPs) and minipigs, and demonstrated that radiation significantly enhanced IL-18 in serum from NHPs 2–4 days post-irradiation and in minipig plasma 1–3 days post-irradiation. Finally, we compared circulating IL-18 with the well known hematological radiation biomarkers lymphocyte and neutrophil counts in blood of mouse, minipigs and NHPs and demonstrated close correlations between these biomarkers in response to radiation. Our results suggest that the elevated levels of circulating IL-18 after radiation proportionally reflect radiation dose and severity of radiation injury and may be used both as a potential biomarker for triage and also to track casualties after radiological accidents as well as for therapeutic radiation exposure.     

Probiotics (VSL#3) Prevent Endothelial Dysfunction in Rats with Portal Hypertension: Role of the Angiotensin System

Aims

Portal hypertension characterized by generalized vasodilatation with endothelial dysfunction affecting nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) has been suggested to involve bacterial translocation and/or the angiotensin system. The possibility that ingestion of probiotics prevents endothelial dysfunction in rats following common bile duct ligation (CBDL) was evaluated.

Methods

Rats received either control drinking water or the probiotic VSL#3 solution (50 billion bacteria.kg body wt⁻¹.day⁻¹) for 7 weeks. After 3 weeks, rats underwent surgery with either resection of the common bile duct or sham surgery. The reactivity of mesenteric artery rings was assessed in organ chambers, expression of proteins by immunofluorescence and Western blot analysis, oxidative stress using dihydroethidium, and plasma pro-inflammatory cytokine levels by flow cytometry.

Results

Both NO- and EDH-mediated relaxations to acetylcholine were reduced in the CBDL group compared to the sham group, and associated with a reduced expression of Cx37, Cx40, Cx43, IK_Ca and SK_Ca and an increased expression of endothelial NO synthase (eNOS). In aortic sections, increased expression of NADPH oxidase subunits, angiotensin converting enzyme, AT1 receptors and angiotensin II, and formation of ROS and peroxynitrite were observed. VSL#3 prevented the deleterious effect of CBDL on EDH-mediated relaxations, vascular expression of connexins, IK_Ca, SK_Ca and eNOS, oxidative stress, and the angiotensin system. VSL#3 prevented the CBDL-induced increased plasma TNF-α, IL-1α and MCP-1 levels.

Conclusions

These findings indicate that VSL#3 ingestion prevents endothelial dysfunction in the mesenteric artery of CBDL rats, and this effect is associated with an improved vascular oxidative stress most likely by reducing bacterial translocation and the local angiotensin system.     

Effects of Exercise Training on Circulating and Skeletal Muscle Renin-Angiotensin System in Chronic Heart Failure Rats

Background

Accumulated evidence shows that the ACE-AngII-AT1 axis of the renin-angiotensin system (RAS) is markedly activated in chronic heart failure (CHF). Recent studies provide information that Angiotensin (Ang)-(1–7), a metabolite of AngII, counteracts the effects of AngII. However, this balance between AngII and Ang-(1–7) is still little understood in CHF. We investigated the effects of exercise training on circulating and skeletal muscle RAS in the ischemic model of CHF.

Methods/Main Results

Male Wistar rats underwent left coronary artery ligation or a Sham operation. They were divided into four groups: 1) Sedentary Sham (Sham-S), 2) exercise-trained Sham (Sham-Ex), sedentary CHF (CHF-S), and exercise-trained CHF (CHF-Ex). Angiotensin concentrations and ACE and ACE2 activity in the circulation and skeletal muscle (soleus and plantaris) were quantified. Skeletal muscle ACE and ACE2 protein expression, and AT1, AT2, and Mas receptor gene expression were also evaluated. CHF reduced ACE2 serum activity. Exercise training restored ACE2 and reduced ACE activity in CHF. Exercise training reduced plasma AngII concentration in both Sham and CHF rats and increased the Ang-(1–7)/AngII ratio in CHF rats. CHF and exercise training did not change skeletal muscle ACE and ACE2 activity and protein expression. CHF increased AngII levels in both soleus and plantaris muscle, and exercise training normalized them. Exercise training increased Ang-(1–7) in the plantaris muscle of CHF rats. The AT1 receptor was only increased in the soleus muscle of CHF rats, and exercise training normalized it. Exercise training increased the expression of the Mas receptor in the soleus muscle of both exercise-trained groups, and normalized it in plantaris muscle.

Conclusions

Exercise training causes a shift in RAS towards the Ang-(1–7)-Mas axis in skeletal muscle, which can be influenced by skeletal muscle metabolic characteristics. The changes in RAS circulation do not necessarily reflect the changes occurring in the RAS of skeletal muscle.     

Angiotensin Converting Enzyme-2 (ACE2) and its Possible Roles in Hypertension, Diabetes and Cardiac Function

Angiotensin converting enzyme-2 (ACE2) is a recently described homologue of the vasoactive peptidase, angiotensin converting enzyme (ACE). Like ACE, ACE2 is an integral (type I) membrane zinc metallopeptidase, which exists as an ectoenzyme. ACE2 is less widely distributed than ACE in the body, being expressed at highest concentrations in the heart, kidney and testis. ACE2 also differs from ACE in its substrate specificity, functioning exclusively as a carboxypeptidase rather than a peptidyl dipeptidase. A key role for ACE2 appears to be emerging in the conversion of angiotensin II to angiotensin (1–7), allowing it to act as a counter-balance to the actions of ACE. ACE2 has been localised to the endothelial and epithelial cells of the heart and kidney where it may have a role at the cell surface in hydrolysing bioactive peptides such as angiotensin II present in the circulation. A role for ACE2 in the metabolism of other biologically active peptides also needs to be considered. ACE2 also serendipitously appears to act as a receptor for the severe acute respiratory syndrome (SARS) coronavirus. Studies using ace2 ^-/- mice, and other emerging studies in vivo and in vitro, have revealed that ACE2 has important functions in cardiac regulation and diabetes. Together with its role as a SARS receptor, ACE2 is therefore likely to be an important therapeutic target in a diverse range of disease states.     

SERCA2a in Heart Failure: Role and Therapeutic Prospects

Ca²⁺ is a key molecule controlling several cellular processes, from fertilization to cell death, in all cell types. In excitable and contracting cells, such as cardiac myocytes, Ca²⁺ controls muscle contractility. The spatial and temporal segregation of Ca²⁺ concentrations are central to maintain its concentration gradients across the cells and the cellular compartments for proper function. SERCA2a is a cornerstone molecule for maintaining a balanced concentration of Ca²⁺ during the cardiac cycle, since it controls the transport of Ca²⁺ to the sarcoplasmic reticulum (SR) during relaxation. Alterations of the activity of this pump have been widely investigated, emphasizing its central role in the control of Ca²⁺ homeostasis and consequently in the pathogenesis of the contractile defect seen with heart failure. This review focuses on the molecular characteristics of the pump, its role during the cardiac cycle and the prospects derived from the manipulation of SERCA2a for heart failure treatment.     

Cognitive Function in Ambulatory Patients with Systolic Heart Failure: Insights from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial

We sought to determine whether cognitive function in stable outpatients with heart failure (HF) is affected by HF severity. A retrospective, cross-sectional analysis was performed using data from 2, 043 outpatients with systolic HF and without prior stroke enrolled in the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial. Multivariable regression analysis was used to assess the relationship between cognitive function measured using the Mini-Mental Status Exam (MMSE) and markers of HF severity (left ventricular ejection fraction [LVEF], New York Heart Association [NYHA] functional class, and 6-minute walk distance). The mean (SD) for the MMSE was 28.6 (2.0), with 64 (3.1%) of the 2,043 patients meeting the cut-off of MMSE <24 that indicates need for further evaluation of cognitive impairment. After adjustment for demographic and clinical covariates, 6-minute walk distance (β-coefficient 0.002, p<0.0001), but not LVEF or NYHA functional class, was independently associated with the MMSE as a continuous measure. Age, education, smoking status, body mass index, and hemoglobin level were also independently associated with the MMSE. In conclusion, six-minute walk distance, but not LVEF or NYHA functional class, was an important predictor of cognitive function in ambulatory patients with systolic heart failure.     

Predicting the angiotensin converting enzyme 2 (ACE2) utilizing capability as the receptor of SARS-CoV-2

SARS-CoV-2, the newly identified human coronavirus causing severe pneumonia pandemic, was probably originated from Chinese horseshoe bats. However, direct transmission of the virus from bats to humans is unlikely due to lack of direct contact, implying the existence of unknown intermediate hosts. Angiotensin converting enzyme 2 (ACE2) is the receptor of SARS-CoV-2, but only ACE2s of certain species can be utilized by SARS-CoV-2. Here, we evaluated and ranked the receptor-utilizing capability of ACE2s from various species by phylogenetic clustering and sequence alignment with the currently known ACE2s utilized by SARS-CoV-2. As a result, we predicted that SARS-CoV-2 tends to utilize ACE2s of various mammals, except murines, and some birds, such as pigeon. This prediction may help to screen the intermediate hosts of SARS-CoV-2.     

Quantification of a Cardiac Biomarker in Human Serum Using Extraordinary Optical Transmission (EOT)

Nanoimprinting lithography (NIL) is a manufacturing process that can produce macroscale surface areas with nanoscale features. In this paper, this technique is used to solve three fundamental issues for the application of localized surface plasmonic resonance (LSPR) in practical clinical measurements: assay sensitivity, chip-to-chip variance, and the ability to perform assays in human serum. Using NIL, arrays of 140 nm square features were fabricated on a sensing area of 1.5 mm x 1.5 mm with low cost. The high reproducibility of NIL allowed for the use of a one-chip, one-measurement approach with 12 individually manufactured surfaces with minimal chip-to-chip variations. To better approximate a real world setting, all chips were modified with a biocompatible, multi-component monolayer and inter-chip variability was assessed by measuring a bioanalyte standard (2.5−75 ng/ml) in the presence of a complex biofluid, human serum. In this setting, nanoimprinted LSPR chips were able to provide sufficient characteristics for a ‘low-tech’ approach to laboratory-based bioanalyte measurement, including: 1) sufficient size to interface with a common laboratory light source and detector without the need for a microscope, 2) high sensitivity in serum with a cardiac troponin limit of detection of 0.55 ng/ml, and 3) very low variability in chip manufacturing to produce a figure of merit (FOM) of 10.5. These findings drive LSPR closer to technical comparability with ELISA-based assays while preserving the unique particularities of a LSPR based sensor, suitability for multiplexing and miniaturization, and point-of-care detections.     

Macro- and Microelement Status in Animal and Human Hypertension: the Role of the ACE Gene I/D Polymorphism

Growth hormone (GH) and zinc (Zn) were evaluated for their potential to prevent radiation injury using a rat model of radiation-induced skin injury. Sprague–Dawley rats were divided into five groups: a control group not receiving Zn, GH, or irradiation: a radiation (RT) group receiving a single 30 Gy dose of gamma irradiation to the right hind legs; a radiation + GH group (RT + GH) receiving a single 30 Gy dose of gamma irradiation plus the subcutaneous administration of 0.01 IU kg d^?1 GH; a radiation + Zn group (RT + Zn) receiving a single 30 Gy dose plus 5 mg kg d^?1 Zn po; and a radiation + GH + Zn group (RT + GH + Zn) group receiving a single 30 Gy dose plus subcutaneous 0.01 IU kg d^?1 GH and 5 mg kg d^?1 Zn po. Acute skin reactions were assessed every 3 days by two radiation oncologists grouping. Light microscopic findings were assessed blindly by two pathologists. Groups receiving irradiation were associated with dermatitis as compared to the control group (P < 0.05). The severity of radiodermatitis in the RT + GH, RT + Zn, and RT + GH + Zn groups was significantly lower than that in the RT group (P < 0.05). Furthermore, radiodermatitis was observed earlier in the RT group than in the other treatment groups (P < 0.05). GH and Zn effectively prevented epidermal atrophy, dermal degeneration, and hair follicle atrophy. The highest level of protection against radiation dermatitis was observed in the combination group.