Role Of Angiogenin Research Articles

Plasma Angiopoietin-2 as a Promising Biomarker for the Prognosis of Acute Pulmonary Embolism.

Endothelial damage is one of the pathogenic conditions of acute pulmonary embolism (APE). The essential role of angiogenin, ribonuclease A family, member 2 (Ang-2) in APE remains unclear. This study aimed to investigate the predictive value of Ang-2 in the clinical outcomes of patients with APE. Plasma Ang-2 levels were measured by an enzyme-linked immunosorbent assay kit using a DuoSet methodology in 118 APE patients and 53 healthy controls. Baseline data relevant to mortality over time were obtained from hospital databases or by patient's follow-up (median follow-up time: 25.0 ± 13.2 months). The main outcome was all-cause mortality. Plasma Ang-2 level was significantly higher in APE patients than in healthy controls (p < 0.001). Patients dying during the first 30 days presented higher baseline levels of Ang-2 than the survivors (p < 0.001). Patients dying during the follow-up also showed higher baseline levels of Ang-2 than the survivors (p < 0.001). The multi-variable logistic regression analysis showed that the N-terminal propeptide of B-type natriuretic peptide (NT-proBNP) [odds ratio (OR): 19.8; 95% CI: 1.5 - 255.8; p = 0.022] and Ang-2 (OR: 9.9; 95% CI: 1.4 - 70.5; p = 0.022) emerged as independent predictors of the 30-day mortality. Furthermore, the multivariable Cox's regression identified plasma Ang-2 [hazards ratio (HR): 1.35; 95% CI: 1.10 - 1.66; p = 0.004] as an independent predictor of long-term mortality in patients with APE. A high circulating level of Ang-2 can be considered as an independent predictor for the poor outcome of APE and may serve as a biomarker for the risk stratification in patients with APE.

A Possible Role of Angiogenin in Intergenerational Transmission of Diet-Induced Metabolic Stress

Abstract Objectives Epigenetic is one of the possible mechanisms of transmit parental metabolic stress to offspring. tRNA modification or fragmentation is a promising candidate. We investigated the molecular mechanism of intergeneration transmission of diet-induced metabolic stress. Methods Male mice fed with control diet (CD) or high-fat diet (HFD) for 9 weeks. Body weight, amount of food intake and organ weights were measured. Metabolism-related proteins and gene expression were measured in testis and liver. tRNA methylation in sperm was investigated by bisulfite conversion-based sequencing. We analyzed publicly available omics data to profile changes of high-fat diet feeding. To explain mTOR activity linked to angiogenin (ANG) gene expression, we treated compound C (CC) or rapamycin (RP) in cell lines. Results We showed mTOR negative regulators were down regulated in HFD from analysis of transcriptome data from liver and sperm. Consistently, analysis on sperm metabolome data revealed that free amino acid level and tRNA amino-acyl biosynthesis pathway was up-regulated in HFD. Increased a level of phospho-mTOR protein was confirmed in testis, but not phospho-AMPK protein. Next, we measured tRNA modification-related gene expression levels in testis and liver. Expression of Dnmt2 and NSun2 related in tRNA methylation was elevated in HFD in testis and liver. However, expression of ANG related with tRNA cleavage was only increased in testis. In addition, methylation status in sperm tRNA-Asp-GTC was no different between diets. The data suggested that tRNA cleavage with ANG, rather than tRNA methylation process, was more likely involved in transmit transgenerational effect to offspring. Finally, we investigated changing mTOR activity could affect to Angiogenin gene expression level. Treatment with CC showed increased Angiogenin gene expression level, but RP treatment showed no change. Conclusions Our data suggested that diet-induced alteration of mTOR activity led to upregulation of Angiogenin expression in sperm, which might be a key of transgenerational mechanism. Funding Sources This study was supported by the National Research Foundation of Korea the Korean National Cancer Center. EL is grateful for financial support from Hyundai Motor Chung Mong-Koo Foundation and BK21 FOUR (Fostering Outstanding Universities for Research).

Angiogenin maintains gut microbe homeostasis by balancing α-Proteobacteria and Lachnospiraceae

ObjectiveAntimicrobial peptides (AMPs) play essential roles in maintaining gut health and are associated with IBD. This study is to elucidate the effect of angiogenin (ANG), an intestine-secreted AMP, on gut...

Exosomal Angiogenin as a Potential Biomarker in Amyotrophic Lateral Sclerosis

Abstract—Exosomes are extracellular vesicles that represent an important mode of intercellular communication. It is thought that exosomes can carry biologically active molecules associated with the progressive spreading of amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disease characterized by the progressive death of motor neurons. Angiogenin is likely to be important in the pathogenesis of ALS. This paper analyzes the content of angiogenin in blood plasma, CSF, and exosome fractions obtained from blood plasma and CSF in ALS. The study included 30 patients with ALS and 26 age and gender matched healthy controls. The relative amount of angiogenin in plasma and CSF was significantly higher than in exosome fractions (p < 0.05). A comparison of angiogenin content in plasma and exosome fraction revealed lower angiogenin levels in patients with ALS compared to healthy volunteers (p < 0.05), which may indicate a protective role of angiogenin. Higher concentrations of angiogenin in plasma and its exosome fractions tended to correlate with better functional states in patients. Therefore, a reduction of angiogenin levels in plasma and the exosome fraction from plasma may be a marker of disease progression, but these data need to be confirmed in a larger cohort.

Angiogenin regulates PKD activation and COX-2 expression induced by TNF-α and bradykinin in the colonic myofibroblast

IntroductionThe myofibroblast is a gastrointestinal stromal cell that is a target of tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine strongly implicated in colitis-associated cancer. Crosstalk between TNF-α and other pro-inflammatory mediators amplify inflammatory signaling but the mechanism is unknown. Angiogenin (ANG) is a 14-kDa angiogenesis protein that is regulated in patients with inflammatory bowel disease. However, the role of ANG on inflammatory mediator crosstalk in the myofibroblast is unknown. MethodsThe human colonic myofibroblast cell line 18Co, as well as primary mouse and human colonic myofibroblasts, were exposed to TNF-α (10 ng/ml) and bradykinin (BK, 100 nM). ANG was quantified by ELISA. The expression of cyclo-oxygenase-2 (COX-2) and phosphorylation of PKD was assessed by Western Blot. ResultsPrimary mouse and human colonic myofibroblasts exposed to TNF-α/BK led to enhanced PKD phosphorylation and synergistic COX-2 expression. 18Co cells secrete high levels of ANG (24h, 265 ± 5 pg/ml). The monoclonal antibody 26-2F, which neutralizes ANG, inhibited TNF-α/BK-mediated PKD phosphorylation and synergistic COX-2 expression in primary human myofibroblasts. Likewise, in primary mouse myofibroblasts that do not express ANG (ANG-KO), TNF-α/BK failed to enhance PKD phosphorylation and COX-2 expression. ConclusionsTNF-α/BK enhance PKD phosphorylation and COX-2 expression in primary mouse and human colonic myofibroblasts. Angiogenin is produced by the myofibroblast, and inhibition of ANG signaling, either by its absence (ANG-KO) or by pharmacologic inhibition, blocks enhanced PKD phosphorylation and synergistic COX-2 expression induced by TNF-α/BK. ANG mediates crosstalk signaling between TNF-α/BK in the regulation of stroma-derived COX-2 and may be a novel therapeutic target for the management of colitis-associated cancer.

CSF angiogenin levels in amyotrophic lateral Sclerosis-Frontotemporal dementia spectrum

Objective: Angiogenin (ANG) is a pro-angiogenic and neurotrophic factor with an important role in stress-induced injury, by promoting neovascularization and neuronal survival. Identification of loss-of-function mutations and evidence of beneficial effect of ANG administration in transgenic SOD1G93A mice have linked ANG to the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), stimulating interest in considering circulating ANG levels as an ALS disease biomarker although robust evidence is still lacking. Aim of our study was to assess differences of ANG levels in the cerebrospinal fluid (CSF) of a large cohort of patients with ALS and frontotemporal dementia (FTD) compared to controls and to explore correlations between ANG content and disease-related clinical variables. Methods: ANG levels were measured in CSF samples using a commercially available ELISA kit in 88 patients affected with ALS and/or FTD and 46 unrelated individuals (control group). Results: ANG levels didn’t differ significantly between cases and controls. Patients with FTD or ALS-FTD showed significantly increased CSF concentration of ANG compared to ALS patients without dementia and controls in a multivariate regression model (p < 0.001). No correlations were found in ALS/FTD patients between ANG levels and clinical parameters, including age, presence of C9orf72 repeat expansion, body mass index (BMI). Conclusions: our findings highlight a role of ANG as CSF biomarker useful to identify ALS patients with concurrent FTD and suggest that it should be further explored as potential biomarker for FTD.

Expression of Angiogenin is inversely correlated to Progression of Gastric Tumors

Objective: Angiogenin (ANG) is upregulated in a variety of cancers including those of prostate, cervix, pancreas, liver, oral cavity, skin, and etc., however, the role of ANG in gastric cancer has not been fully elucidated yet. We use tissue microarray (TMA) to examine ANG expression to investigate the role of ANG in the progression of gastric cancer. Method: Immunohistochemistry was used to evaluate ANG expression in TMA with 208 spots from 104 patients diagnosed with gastric cancer and the corresponding adjacent tissue. Results: In normal adjacent tissue, ANG was expressed mainly in cytoplasm at basal gland of the gastric mucus where gastric stem cells are reserved, and also sparsely expressed in the nucleus of gastric mucosal gland cells at isthmus where gastric stem cells are gathered. In cancer tissues, ANG was very sparsely expressed in the nucleus of gastric glandular cells. ANG expression in the cytoplasm was found to be significantly associated with pathological types (p&lt;0.001) and malignancy (p&lt;0.001). ANG expression in the nucleus was inversely correlated with malignancy (p=0.019), differentiation status (p&lt; 0.001), and tumor stage (p= 0.048).Conclusion: ANG might play an important role in gastric cancer development.

Nailfold capillary changes in adult new-onset dermatomyositis: a prospective cross-sectional study.

It is to prospectively analyze nailfold capillaroscopy (NC) findings in new-onset dermatomyositis (DM) and to correlate NC findings with serum angiogenic cytokines and DM clinical and laboratory features. Twenty-three patients with DM who experienced < 12months of symptoms were included in the study. To assess serum cytokine levels, 23 age-, sex-, and ethnicity-matched healthy volunteers were used. NC characteristics and DM activity parameters were analyzed. Significantly higher serum angiogenin (ANG) and vascular endothelial growth factor-1 (VEGF1) levels were observed in DM patients than in controls. Capillary density and avascular areas correlated positively and negatively, respectively, with serum levels of ANG. Moreover, the capillary density correlated inversely with the number of enlarged and giant capillaries and avascular areas. The number of enlarged capillaries correlated positively with patient and physician visual analogue scales (VAS), the presence of a facial rash, giant capillaries, and microhemorrhages. Giant capillaries had a positive correlation with physician and cutaneous VAS, enlarged capillaries, avascular areas, microhemorrhages and bushy capillaries, and a negative correlation with capillary density. Microhemorrhages correlated positively with the "V-neck" sign and physician VAS. VEGF1 showed no relationship with the NC parameters with DM-related clinical and laboratory features. Additionally, 15 out of 23 patients were assessed prospectively after 3.21years. All patients had a major clinical response with significant improvement in all NC parameters, except for enlarged and bushy capillaries. The NC may be a useful tool to assess disease activity in recent-onset DM, and it can also reinforce the role of ANG in the angiogenesis of this myopathy.

L-mimosine and hypoxia can increase angiogenin production in dental pulp-derived cells

BackgroundAngiogenin is a key molecule in the healing process which has been successfully applied in the field of regenerative medicine. The role of angiogenin in dental pulp regeneration is unclear. Here we aimed to reveal the impact of the hypoxia mimetic agent L-mimosine (L-MIM) and hypoxia on angiogenin in the dental pulp.MethodsHuman dental pulp-derived cells (DPC) were cultured in monolayer and spheroid cultures and treated with L-MIM or hypoxia. In addition, tooth slice organ cultures were applied to mimic the pulp-dentin complex. We measured angiogenin mRNA and protein levels using qPCR and ELISA, respectively. Inhibitor studies with echinomycin were performed to reveal the role of hypoxia-inducible factor (HIF)-1 signaling.ResultsBoth, L-MIM and hypoxia increased the production of angiogenin at the protein level in monolayer cultures of DPC, while the increase at the mRNA level did not reach the level of significance. The increase of angiogenin in response to treatment with L-MIM or hypoxia was reduced by echinomycin. In spheroid cultures, L-MIM increased angiogenin at protein levels while the effect of hypoxia was not significant. Angiogenin was also expressed and released in tooth slice organ cultures under normoxic and hypoxic conditions and in the presence of L-MIM.ConclusionsL-MIM and hypoxia modulate production of angiogenin via HIF-1 differentially and the response depends on the culture model. Given the role of angiogenin in regeneration the here presented results are of high relevance for pre-conditioning approaches for cell therapy and tissue engineering in the field of regenerative endodontics.

Angiogenin is upregulated during the alloreactive immune response and has no effect on the T-cell expansion phase, whereas it affects the contraction phase by inhibiting CD4+ T-cell apoptosis.

Under growth conditions, angiogenin is translocated into the nucleus, where it enhances ribosomal RNA transcription, facilitating increased protein synthesis and cellular proliferation. During stress conditions, angiogenin is sequestered in the cytoplasm, where it cleaves transfer RNA (tRNA) to produce tRNA-derived, stress-induced small RNAs (tiRNAs) that inhibit global protein synthesis, but increase the translation of anti-apoptotic factors. In the present study, the role of angiogenin in the human alloreactive immune response was evaluated using mixed lymphocyte reactions (MLRs) and neamine, an inhibitor of angiogenin nuclear translocation. In MLRs, angiogenin production was significantly (P<0.001) increased compared with resting peripheral blood mononuclear cells. The addition of neamine had no effect on cell proliferation, but did significantly (P<0.001) increase expression of Bcl-2-associated X protein and protein levels of activated caspase-3 in CD4+ T-cells isolated from the MLRs, indicating that angiogenin reduces apoptosis. In conclusion, angiogenin is upregulated during the alloreactive immune response, in which it does not affect the T-cell expansion phase, but inhibits the T-cell contraction phase by protecting against CD4+ T-cell apoptosis.

Abstract A05: Angiogenin contributes to bladder cancer tumorigenesis by facilitating p53/DNMT3b-mediated activation of MMP2

Abstract Epigenetic-mediated gene activation/silencing plays a crucial role in human tumorigenesis. Eliciting the underlying mechanism behind certain epigenetic changes is essential for understanding tumor biology. An important epigenetic process that is implicated in mammalian development is the methylation of cytosine within the context of a simple dinucleotide site, CpG. Deregulated DNA methylation can be a major driver of pathologic conditions such as neurological and autoimmune diseases, as well as cancers Previous studies in human cancers revealed an unrecognized interplay between Angiogenin (ANG)-MAPK/ERK- matrix metalloproteinase-2 (MMP2) leading to pronounced tumorigenesis. Specifically, we showed that forced ANG expression in a benign human bladder UROtsa cell line induced cellular survival, proliferation, endothelial tube formation and xenograft angiogenesis and growth by mediating the MAPK/ERK-MMP2 axis. Here we provide multiple lines of evidence indicating ANG oncogenic potential and how ANG regulates MMP2 expression. Here we have shown that deletion and site-directed mutagenesis analysis of the MMP2 promoter demonstrated that the p53-binding site is critical for ANG-induced MMP2 promoter activity. To further determine whether ANG facilitates the recruitment of p53 to its targets in cells, we used a ChIP assay to examine p53 binding to the promoter region of the MMP2 gene in UROtsaEmpty, UROtsaANG, RT112 Scr and RT112 KD-ANG. Overexpression of ANG greatly enriched p53 association with the MMP2 promoter and ANG depletion decreased enrichment of p53 with MMP2 promoter. To further explore the mechanism by which ANG regulates MMP2 expression, we investigated whether ANG is also functionally linked to DNA methylation-based transcriptional repression. First, we quantitatively assessed the methylation status of the MMP2 promoter. Overexpression of ANG was associated with a reduction in methylation status of the MMP2 promoter, which led to increased gene expression of MMP2. The alteration of genome-wide DNA methylation in these cells was then analyzed using Illumina whole genome methylation array. ANG expression was noted to be associated with a change in global DNA methylation levels compared to control cells. Mechanistically, ANG negatively regulated DNA methyltransferase 3b (DNMT3b) enzymatic activity by down-regulating its expression and inhibiting its recruitment to the MMP2 promoter. To further define the role of ANG, p53 and MMP2 in tumorigenesis, we collected 78 fresh bladder cancer samples from bladder cancer patients and extracted DNA and RNA for analysis. Muscle invasive bladder cancer specimens had increased levels of ANG, p53 and MMP2 compared to non-muscle invasive bladder cancer. More importantly, disease free survival was adversely and significantly effected if ANG, p53 and MMP2 were overexpressed. In this study we demonstrate that ANG is overexpressed in approximately 45% of bladder tumors resulting in overexpression of p53 and MMP2, a reduction in DNMT3b and deep changes in the methylation status genome wide. Such molecular alterations are associated with higher rates of muscle invasive bladder cancers as well as a reduction in disease specific survival, thus attesting to ANG, p53 and MMP2 ability to further risk stratify patients that may require a more aggressive, even personalized, management plan. Therefore, the study provides novel evidence that ANG plays an important role in the promoter activation of the tumor oncogenic gene MMP2, which likely contributes to ANG oncogenic activity. Citation Format: Rafael Peres, Hideki Furuya, Ian Pagano, Yoshiko Shimizu, Kanani Hokutan, Joanna Gawecka, Charles Joel Rosser. Angiogenin contributes to bladder cancer tumorigenesis by facilitating p53/DNMT3b-mediated activation of MMP2. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A05.

Abstract A087: Angiogenin (ANG) localized at the leading edges of breast cancer cells regulates plasmin formation by plasminogen activation complex (PAC) and cell migration

Abstract Angiogenin (ANG), a 14-kDa pro-angiogenic protein, had been shown to play a role in cell migration and tumor invasion processes, which involve proteolytic cleavage of plasminogen to generate plasmin. However, the mechanism by which ANG regulates plasmin formation and cell migration was not known. Our studies detected elevated levels of secreted ANG and cell surface-bound ANG in highly invasive metastatic breast cancer cells. By immunofluorescence and immunoprecipitation analysis, ANG was detected at leading edges of the cell surfaces where it colocalized and interacted with members of the plasminogen activation complex (PAC) such as Annexin A2 (A2), Calpactin (S100A10) and Urokinase plasminogen receptor (uPAR). Analysis of lipid raft (LR) and non-lipid raft (NLR) regions of the cell membranes showed the predominance of ANG, A2 and S100A10 in the LR regions. In contrast, uPAR was detected only in the NLR fractions, suggesting that ANG interacts with uPAR at junctions of LR and NLR regions. ANG knockdown in T47D and MDA-MB-231 breast cancer cell lines did not affect the cellular expression of A2, S100A10 and uPAR but decreased cell migration and plasmin formation. Neutralization of ANG with monoclonal antibodies similarly decreased the migration of MDA-MB-231 cells. In the presence of ANG on cell surfaces, uPAR was observed to interact with UPA, which is known to be necessary for proteolytic cleavage of plasminogen by UPA to form plasmin. However, in the absence of ANG, uPAR interacted exclusively with PAI, which is known to inhibit plasmin formation by blocking UPA mediated proteolytic cleavage of plasminogen. Assessment of phosphorylation states of cellular FAK and Src kinases under these conditions further showed that both FAK and Src are dephosphorylated in the absence of ANG. Taken together, our results identified a novel regulatory role of ANG as a bridging protein that facilitates the interaction of uPAR with UPA, which leads to plasmin formation and cell migration necessary for tumor invasion and metastasis of breast cancer cells. These studies also suggest that ANG could serve as a bio-marker for identifying the leading edges of metastatic breast cancer cells and targeting ANG could be a novel method to block breast cancer invasiveness. Citation Format: Sujoy Dutta, Chirosree Bandyopadhyay, Lydia Wilson, Case Warshall, Virginie Bottero, Karen E. Johnson, Bala Chandran. Angiogenin (ANG) localized at the leading edges of breast cancer cells regulates plasmin formation by plasminogen activation complex (PAC) and cell migration. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A087.

Genes of the RNASE5 pathway contain SNP associated with milk production traits in dairy cattle

BackgroundIdentification of the processes and mutations responsible for the large genetic variation in milk production among dairy cattle has proved challenging. One approach is to identify a biological process potentially involved in milk production and to determine the genetic influence of all the genes included in the process or pathway. Angiogenin encoded by angiogenin, ribonuclease, RNase A family 5 (RNASE5) is relatively abundant in milk, and has been shown to regulate protein synthesis and act as a growth factor in epithelial cells in vitro. However, little is known about the role of angiogenin in the mammary gland or if the polymorphisms present in the bovine RNASE5 gene are associated with lactation and milk production traits in dairy cattle. Given the high economic value of increased protein in milk, we have tested the hypothesis that RNASE5 or genes in the RNASE5 pathway are associated with milk production traits. First, we constructed a “RNASE5 pathway” based on upstream and downstream interacting genes reported in the literature. We then tested SNP in close proximity to the genes of this pathway for association with milk production traits in a large dairy cattle dataset.ResultsThe constructed RNASE5 pathway consisted of 11 genes. Association analysis between SNP in 1 Mb regions surrounding these genes and milk production traits revealed that more SNP than expected by chance were associated with milk protein percent (P < 0.05 significance). There was no significant association with other traits such as milk fat content or fertility.ConclusionsThese results support a role for the RNASE5 pathway in milk production, specifically milk protein percent, and indicate that polymorphisms in or near these genes explain a proportion of the variation for this trait. This method provides a novel way of understanding the underlying biology of lactation with implications for milk production and can be applied to any pathway or gene set to test whether they are responsible for the variation of complex traits.

The relationship between serum levels of angiogenin, bFGF, VEGF, and ocular involvement in patients with Behçet’s disease

The aim of this study was to investigate the possible role of angiogenin, vascular endothelial growth factor, (VEGF) and basic fibroblast growth factor (bFGF) in the pathogenesis of BD. Sixty-five patients with BD and 21 healthy control subjects were included in the study, and serum angiogenin, bFGF, and VEGF concentrations were measured by using in-vitro enzyme immunoassay (ELISA) kits according to the manufacturer's instructions. The median serum angiogenin level was significantly higher in patients with BD (391.8; range:151.6-594.8pg/ml) than controls (298.8; range:241.9-449.6pg/ml) (p = 0.001). The levels were similar in both ocular and non-ocular BD patients (p = 0.537). The mean serum bFGF level was higher in patients with BD (38.8 ± 12.3pg/ml) than controls (33.2 ± 11.3pg/ml); the median serum VEGF level was also higher in BD patients (239.7; range:53-991.3pg/ml) than controls (189.4; range:53.6-357.9pg/ml). But these differences were not statistically significant. Serum bFGF and VEGF levels were also not different statistically in ocular and non-ocular Behçet's patients. There was no statistically significant relationship between serum angiogenin, bFGF, and VEGF levels and the presence of active eye disease or anatomic location of uveitis. While there was a correlation of borderline significance in angiogenin levels between the patients with anterior uveitis and panuveitis (p = 0.053), we did not obtain any correlation between serum angiogenin, bFGF, and VEGF levels and the duration of BD. This study suggests that angiogenin may be associated with pathophysiology of BD, and highlights the need of further investigation of the role of angiogenin, bFGF, and VEGF serum levels in BD susceptibility and its clinical manifestations.

Correlation of serum angiogenin level with various vascular complications in type 2 diabetic patients

Abstract Introduction Premature development of microvascular and macrovascular disease is the most frequent complication of diabetes. It is responsible for diabetic retinopathy, nephropathy, and neuropathy. Moreover, diabetes leads to reduced collateralization in ischemic tissues, which causes a three- to four-fold increase in cardiac mortality in diabetic individuals compared with nondiabetic individuals. The pathophysiological mechanisms responsible for impaired angiogenic activity in diabetes remain unknown. The role of angiogenin in the physiological revascularization process has not been clarified. Purpose This work was carried out to determine the serum angiogenin level in type 2 diabetic patients and to determine its correlation with various microangiopathies, cardiovascular complications, and the duration in type 2 diabetic patients. Patients and methods This work was carried out on 88 individuals, 68 type 2 diabetic patients and 20 apparently healthy controls. All individuals were subjected to the following assessments: medical history taking; clinical examination including measurement of BMI; estimation of levels of fasting blood sugar, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, urea, low-density lipoprotein, and creatinine; determination of the albumin/creatinine ratio and complete lipid profile (total cholesterol, triglyceride, high-density lipoproteins); serum angiogenin estimation by enzyme linked immunosorbent assay; fundus examination; ECG and transthoracic echocardiography; and abdominal ultrasonography. Results Our results indicated a significant decrease in the serum angiogenin level in diabetic patients compared with the control group; an insignificantly low serum angiogenin level in diabetic patients with retinopathy and nephropathy compared with those without retinopathy and nephropathy, respectively; a significant decrease in the serum angiogenin level in patients with coronary artery disease (CAD) compared with diabetic patients without CAD; an insignificant inverse correlation of angiogenin with fasting blood sugar, duration of diabetes mellitus with urea, and creatinine with albumin/creatinine ratio; and an insignificant proportional correlation of angiogenin with ejection fraction in diabetic patients with complications of retinopathy, nephropathy, and CAD in each group separately. Conclusion This work concluded that the serum angiogenin level is lower in type 2 diabetic patients compared with the control group and it decreases with prolonged duration of diabetes, especially in uncontrolled patients and patients with microangiopathic and cardiovascular complications. As angiogenin is one of most powerful angiogenic factors, we recommend further studies to evaluate the diagnostic, prognostic, and therapeutic value of angiogenin in various microangiopathic and cardiovascular complications of type 2 diabetes.

Angiogenin levels are increased in lesional skin and sera in patients with erythrodermic cutaneous T cell lymphoma

Angiogenin is a member of the ribonuclease superfamily that is associated with the angiogenic process. Angiogenesis is regarded as an important step to support primary and metastatic tumor growth. In cutaneous T cell lymphoma (CTCL), angiogenesis in lesional skin is increased, suggesting that interaction between tumor cells and their microvasculature are likely to occur during progression of CTCL. Patients with hematological malignancies show increased serum angiogenin levels, which are related with poor overall survival. To investigate possible roles of angiogenin in development of CTCL, we measured serum angiogenin levels in 36 patients with CTCL and 21 healthy controls by enzyme-linked immunosorbent assay. We also investigated angiogenin mRNA and protein expression in lesional skin of CTCL by quantitative RT-PCR and immunohistochemistry. Serum angiogenin levels in patients with CTCL were significantly higher than those in healthy controls. When classified with types of skin lesions, serum angiogenin levels were elevated only in erythrodermic CTCL patients. Angiogenin mRNA expression levels in lesional skin were significantly elevated in erythrodermic CTCL compared to normal skin. Immunohistochemical study revealed that angiogenin was expressed by keratinocytes, endothelial cells, and infiltrating lymphocytes in CTCL. Our results suggest that enhanced angiogenin expression may be related with a poor prognosis of erythrodermic CTCL. As angiogenin acts as an inhibitor of polymorphonuclear leukocyte degranulation, angiogenin may also be linked to impaired host defense in erythrodermic CTCL.

Molecular Mechanisms in Amyotrophic Lateral Sclerosis: The Role of Angiogenin, a Secreted RNase

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease caused by the loss of motoneurons. The precise molecular and cellular basis for neuronal death is not yet well established, but the contemporary view is that it is a culmination of multiple aberrant biological processes. Among the proposed mechanisms of motoneuron degeneration, alterations in the homeostasis of RNA binding proteins (RBP) and the consequent changes in RNA metabolism have received attention recently. The ribonuclease, angiogenin was one of the first RBPs associated with familial and sporadic ALS. It is enriched in motoneurons under physiological conditions, and is required for motoneuron survival under stress conditions. Furthermore, delivery of angiogenin protects cultured motoneurons against stress-induced injury, and significantly increases the survival of motoneurons in SODG93A mice. In this overview on the role of angiogenin in RNA metabolism and in the control of motoneuron survival, we discuss potential pathogenic mechanisms of angiogenin dysfunction relevant to ALS and other neurodegenerative disorders. We also discuss recent evidence demonstrating that angiogenin secreted from stressed motoneurons may alter RNA metabolism in astrocytes.

Angiogenin loss‐of‐function mutations in amyotrophic lateral sclerosis

Heterozygous missense mutations in the coding region of angiogenin (ANG), an angiogenic ribonuclease, have been reported in amyotrophic lateral sclerosis (ALS) patients. However, the role of ANG in motor neuron physiology and the functional consequences of these mutations are unknown. We searched for new mutations and sought to define the functional consequences of these mutations. We sequenced the coding region of ANG in an independent cohort of North American ALS patients. Identified ANG mutations were then characterized using functional assays of angiogenesis, ribonucleolysis, and nuclear translocation. We also examined expression of ANG in normal human fetal and adult spinal cords. We identified four mutations in the coding region of ANG from 298 ALS patients. Three of these mutations are present in the mature protein. Among the four mutations, P(-4)S, S28N, and P112L are novel, and K17I has been reported previously. Functional assays show that these ANG mutations result in complete loss of function. The mutant ANG proteins are unable to induce angiogenesis because of a deficiency in ribonuclease activity, nuclear translocation, or both. As a correlate, we demonstrate strong ANG expression in both endothelial cells and motor neurons of normal human spinal cords from the developing fetus and adult. We provide the first evidence that ANG mutations, identified in ALS patients, are associated with functional loss of ANG activity. Moreover, strong ANG expression, in normal human fetal and adult spinal cord neurons and endothelial cells, confirms the plausibility of ANG dysfunction being relevant to the pathogenesis of ALS.

Low Serum Angiogenin Concentrations in Patients With Type 2 Diabetes

Premature development of microvascular and macrovascular disease is the most frequent complication of diabetes. It is responsible for diabetic retinopathy, nephropathy, and neuropathy (1). Moreover, diabetes leads to reduced collateralization in ischemic tissues, which causes impaired wound healing, exacerbation of peripheral limb ischemia, and a three- to fourfold increase in cardiac mortality in comparison with nondiabetic patients (2,3). The pathophysiological mechanisms responsible for impaired angiogenic activity in diabetes remain unknown. Although angiogenesis impairment has been attributed to alterations in the gene regulatory network, which can be involved in the physiological revascularization process, the role of angiogenin in this process has not been clarified (2,4). The aim of this study therefore was to compare angiogenin serum levels in healthy and type 2 diabetic age-matched individuals. The cutaneous angiogenesis in vivo (serum-induced angiogenesis [SIA]) test in mice was performed in parallel to determine the functional differences between the groups examined. A total of 43 patients with type 2 diabetes and 43 age-matched healthy control subjects volunteered for the study. Patients suffering from acute and chronic infections and neoplastic diseases were excluded. Diabetes was defined according to American Diabetes Association criteria (5). All patients had blood glucose levels …

Dysregulation of the host-commensal relationship in IBD: Exploring the role of angiogenin and ribonuclease 4 polymorphisms as candidate genes

Dysregulation of the host-commensal relationship in IBD: Exploring the role of angiogenin and ribonuclease 4 polymorphisms as candidate genes