Beta-Arrestin1 Prevents Preeclampsia by Downregulation of Mechanosensitive AT1-B2 Receptor Heteromers.

Preeclampsia is the most frequent pregnancy-related complication worldwide with no cure. While a number of molecular features have emerged, the underlying causal mechanisms behind the disorder remain obscure. Here, we find that increased complex formation between angiotensin II AT1 and bradykinin B2, two G protein-coupled receptors with opposing effects on blood vessel constriction, triggers symptoms of preeclampsia in pregnant mice. Aberrant heteromerization of AT1-B2 led to exaggerated calcium signaling and high vascular smooth muscle mechanosensitivity, which could explain the onset of preeclampsia symptoms at late-stage pregnancy as mechanical forces increase with fetal mass. AT1-B2 receptor aggregation was inhibited by beta-arrestin-mediated downregulation. Importantly, symptoms of preeclampsia were prevented by transgenic ARRB1 expression or a small-molecule drug. Because AT1-B2 heteromerization was found to occur in human placental biopsies from pregnancies complicated by preeclampsia, specifically targeting AT1-B2 heteromerization and its downstream consequences represents a promising therapeutic approach.

Significant Association of Candidate Genes (AGTR1 and TGF-Β1) Polymorphism with Diabetic Nephropathy in Diabetes Mellitus Type 2 Patients.

BACKGROUND/AIMS: Diabetic nephropathy (DN) is one of the complications of diabetes mellitus (DM). This study aimed to investigate the association between genetic polymorphisms, specifically AGTR1 (rs5186) and TGF-ß1 (rs1800470), and the risk of developing Diabetic nephropathy (DN) in type 2 diabetes mellitus patients, compared to those without DN and healthy controls. METHODS: A case-control study was conducted on 165 diabetic patients (59 with diabetic nephropathy (DN) and 54 without DN (DM)), and 52 healthy controls (HC). The genotyping was done using amplification refractory mutation system method (ARMS-PCR). Age, gender, and duration of diabetes were matched across groups. Clinical parameters including FBS, RBS, HbA1C, creatinine, urea, SBP, DBP, total cholesterol, triglycerides, LDL, and BMI were assessed. RESULTS: Diabetic patients with nephropathy exhibited significantly higher levels of clinical parameters compared to those without nephropathy and healthy controls. The risk allele of AGTR1 , C (p <0.0001), and risk allele containing genotypes AC (p <0.0001) and CC (p - 0.0010) were significantly higher in DN patients compared to DM and HC groups. Similarly, the TGF-ß1 risk allele C (p - 0.0001), and corresponding genotypes TC (p - 0.0038) and CC (p - 0.0027) were significantly associated with increased risk of diabetic nephropathy compared to DM and HC groups. CONCLUSION: The data showed significant association of AGTR1 (rs5186) and TGF-ß1 (rs1800470) polymorphism with an increased risk of diabetic nephropathy in type 2 diabetes mellitus patients. More investigation will be required to disseminate the results, while increasing the samples size and using whole genome sequencing.

Associations of ACE I/D and AGTR1 rs5182 polymorphisms with diabetes and their effects on lipids in an elderly Chinese population.

BACKGROUND: Diabetes mellitus is generally accompanied by dyslipidaemia, but inconsistent relationships between lipid profiles and diabetes are noted. Moreover, genetic variations in insertion/deletion (I/D) polymorphisms at angiotensin-converting enzyme gene (ACE) and T/C polymorphisms in the angiotensin type 1 receptor gene (AGTR1) are related to diabetes and lipid levels, but the associations are controversial. Thus, the current research aimed to explore the effects of ACE I/D, AGTR1 rs5182 and diabetes mellitus on serum lipid profiles in 385 Chinese participants with an average age of 75.01 years. METHODS: The ACE I/D variant was identified using the polymerase chain reaction (PCR) method, whereas the AGTR1 rs5182 polymorphism was identified using the PCR-based restriction fragment length polymorphism (PCR-RFLP) method and verified with DNA sequencing. Total cholesterol (TC), triglyceride (TG), apolipoprotein A (ApoA), apolipoprotein B (ApoB), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were measured using routine methods, and the lipid ratios were calculated. RESULTS: ACE I/D, but not AGTR1 rs5182, was a predictor of TG/HDL-C for the whole study population. Both ACE I/D and AGTR1 rs5182 were predictors of HDL-C and LDL-C levels in females but not in males. Moreover, in females, diabetes mellitus and ACE I/D were identified as predictors of TG and TG/HDL-C, whereas AGTR1 rs5182 and diabetes mellitus were predictors of TG/HDL-C. Moreover, diabetes mellitus and the combination of ACE I/D and AGTR1 rs5182 variations were predictors of TG and TG/HDL-C exclusively in females. CONCLUSIONS: The results demonstrated the potential for gender-dependent interactions of ACE I/D, AGTR1 rs5182, and diabetes on lipid profiles. These findings may serve as an additional explanation for the inconsistent changes of blood lipids in individuals with diabetes mellitus, thereby offering a novel perspective for the clinical management of blood lipid levels in diabetic patients.

A loss-of-function AGTR1 variant in a critically-ill infant with renal tubular dysgenesis: case presentation and literature review.

BACKGROUND: Renal tubular dysgenesis (RTD) is a severe disorder with poor prognosis significantly impacting the proximal tubules of the kidney while maintaining an anatomically normal gross structure. The genetic origin of RTD, involving variants in the ACE, REN, AGT, and AGTR1 genes, affects various enzymes or receptors within the Renin angiotensin system (RAS). This condition manifests prenatally with oligohydramninos and postnatally with persistent anuria, severe refractory hypotension, and defects in skull ossification. CASE PRESENTATION: In this report, we describe a case of a female patient who, despite receiving multi vasopressor treatment, experienced persistent hypotension, ultimately resulting in early death at five days of age. While there was a history of parental consanguinity, no reported family history of renal disease existed. Blood samples from the parents and the remaining DNA sample of the patient underwent Whole Genome Sequencing (WGS). The genetic analysis revealed a rare homozygous loss of function variant (NM_000685.5; c.415C > T; p.Arg139*) in the Angiotensin II Receptor Type 1 (AGTR1) gene. CONCLUSION: This case highlights the consequence of loss-of-function variants in AGTR1 gene leading to RTD, which is characterized by high mortality rate at birth or during the neonatal period. Furthermore, we provide a comprehensive review of previously reported variants in the AGTR1 gene, which is the least encountered genetic cause of RTD, along with their associated clinical features.

Genetic Polymorphisms and Genetic Risk Scores Contribute to the Risk of Coronary Artery Disease (CAD) in a North Indian Population.

Coronary artery disease (CAD) is the leading cause of death in India. Many genetic polymorphisms play a role in regulating oxidative stress, blood pressure and lipid metabolism, contributing to the pathophysiology of CAD. This study examined the association between ten polymorphisms and CAD in the Jat Sikh population from Northern India, also considering polygenic risk scores. This study included 177 CAD cases and 175 healthy controls. The genetic information of GSTM1 (rs366631), GSTT1 (rs17856199), ACE (rs4646994), AGT M235T (rs699), AGT T174M (rs4762), AGTR1 A1166C (rs5186), APOA5 (rs3135506), APOC3 (rs5128), APOE (rs7412) and APOE (rs429358) and clinical information was collated. Statistical analyses were performed using SPSS version 27.0 and SNPstats. Significant independent associations were found for GST*M1, GST*T1, ACE, AGT M235T, AGT T174M, AGTR1 A1166C and APOA5 polymorphisms and CAD risk (all p < 0.05). The AGT CT haplotype was significantly associated with a higher CAD risk, even after controlling for covariates (adjusted OR = 3.93, 95% CI [2.39-6.48], p < 0.0001). The APOA5/C3 CC haplotype was also significantly associated with CAD (adjusted OR = 1.86, 95% CI [1.14-3.03], p < 0.05). A higher polygenic risk score was associated with increased CAD risk (adjusted OR = 1.98, 95% CI [1.68-2.34], p < 0.001). Seven polymorphisms were independently associated with an increase in the risk of CAD in this North Indian population. A considerable risk association of AGT, APOA5/C3 haplotypes and higher genetic risk scores is documented, which may have implications for clinical and public health applications.

Angiotensin II receptor type 1 blockade regulates Klotho expression to induce TSC2-deficient cell death.

Lymphangioleiomyomatosis (LAM) is a multisystem disease occurring in women of child-bearing age manifested by uncontrolled proliferation of smooth muscle-like "LAM" cells in the lungs. LAM cells bear loss-of-function mutations in tuberous sclerosis complex (TSC) genes TSC1 and/or TSC2, causing hyperactivation of the proliferation promoting mammalian/mechanistic target of Rapamycin complex 1 pathway. Additionally, LAM-specific active renin-angiotensin system (RAS) has been identified in LAM nodules, suggesting this system potentially contributes to neoplastic properties of LAM cells; however, the role of this renin-angiotensin signaling is unclear. Here, we report that TSC2-deficient cells are sensitive to the blockade of angiotensin II receptor type 1 (Agtr1). We show that treatment of these cells with the AGTR1 inhibitor losartan or silencing of the Agtr1 gene leads to increased cell death in vitro and attenuates tumor progression in vivo. Notably, we found the effect of Agtr1 blockade is specific to TSC2-deficient cells. Mechanistically, we demonstrate that cell death induced by Agtr1 inhibition is mediated by an increased expression of Klotho. In TSC2-deficient cells, we showed overexpression of Klotho or treatment with recombinant (soluble) Klotho mirrored the cytocidal effect of angiotensin blockade. Furthermore, Klotho treatment decreased the phosphorylation of AKT, potentially leading to this cytocidal effect. Conversely, silencing of Klotho rescued TSC2-deficient cells from cell death induced by Agtr1 inhibition. Therefore, we conclude that Agtr1 and Klotho are important for TSC2-deficient cell survival. These findings further illuminate the role of the RAS in LAM and the potential of targeting Agtr1 inhibition in TSC2-deficient cells.

High-risk HPV infection-associated hypermethylated genes in oropharyngeal squamous cell carcinomas.

BACKGROUND: HPV-positive oropharyngeal squamous cell carcinomas (OPSCCs) are sensitive to chemo-radiation therapy and have favorable survival outcomes compared with HPV-negative cancers. These tumors are usually not related to tobacco and alcohol exposure. Therefore, diagnosing HPV-positive OPSCCs for the appropriate disease management is crucial, and no suitable markers are available for detecting early malignancies in HPV-infected tissues. In this study, we attempt to find HPV-specific epigenetic biomarkers for OPSCCs. METHODS: A total of 127 surgical samples were analyzed for HPV positivity and promoter methylation of a panel of genes. HPV detection was performed by PCR detection of HPV E6 and E7 viral oncoproteins. In addition, promoter methylation of a total of 8 genes (DAPK, FHIT, RASSF1A, TIMP3, AGTR1, CSGALNACT2, GULP1 and VGF) was analyzed by quantitative-methylation specific PCR (QMSP), and their associations with HPV positivity or RB/p16 expressions were evaluated. RESULTS: AGTR1 and FHIT were frequently methylated in HPV-positive OPSCC samples with a good area under the curve (AUC over 0.70). In addition, these genes' promoter methylation was significantly associated with p16 positive and RB negative cases, which were the characteristics of OPSCC cases with favorable survival outcomes. Either AGTR1 or FHIT methylated cases were significantly associated with HPV-positive cancers with 92.0% sensitivity (P < 0.001). Also, they had significantly better overall survival (P = 0.047) than both unmethylated cases. CONCLUSIONS: A combination of AGTR1 and FHIT methylation demonstrated a suitable detection marker of OPSCCs derived from the HPV-infected field, familiar with p16-positive and RB-negative phenotypes.

Association between AT1 receptor gene polymorphism and left ventricular hypertrophy and arterial stiffness in essential hypertension patients: a prospective cohort study.

BACKGROUND: AT1 receptor gene (AGTR1) is related to essential hypertension (EH), and left ventricular hypertrophy (LVH) and arterial stiffness are common complications of EH. This study aimed to explore the association between AGTR1 genotype and LVH and arterial stiffness in EH patients. METHODS: A total of 179 EH patients were recruited in this study. Oral exfoliated cells were collected from each patient, and the genetic polymorphism of AGTR1(rs4524238) was assessed using a gene sequencing platform. The outcomes were LVH and arterial stiffness. RESULTS: Among 179 patients, 114 were with AGTR1 genotype of GG (57 males, aged 59.54 ± 13.49 years) and 65 were with AGTR1 genotype of GA or AA (36 males, aged 61.28 ± 12.79 years). Patients with AGTR1 genotype of GG were more likely to have LVH (47 [41.23%] vs. 14 [21.54%], P = 0.006) and arterial stiffness (30 [26.32%] vs. 8 [12.31%], P = 0.036). The AGTR1 polymorphism frequency was in accordance with Hardy-Weinberg equilibrium (P = 0.291). The multivariate logistic regression showed that AGTR1 genotype of GA or AA was independently associated with lower risk of LVH (OR = 0.344, 95%CI 160~0.696, P = 0.003) and arterial stiffness (OR = 0.371, 95%CI 0.155~0.885, P = 0.025) after adjusting for gender, age, and diabetes. CONCLUSION: EH patients with the AGTR1 genotype of GA or AA were at lower risk for LVH and arterial stiffness than those with the GG genotype.

THE EFFECT OF NOS3 AND AGTR1 GENOTYPES ON THE COURSE OF THE ARTERIAL HYPERTENSION FOR THE OVERWEIGHT OR OBESE PATIENTS.

OBJECTIVE: The aim: Objective of the research is to determine the effect of NOS3 and AGTR1 genotypes of patients with arterial hypertension and high body mass index in the course of the disease. PATIENTS AND METHODS: Materials and methods: 58 patients (22 men and 36 women) with AH and high BMI were examined. The average age of the examined patients was 53.6±8.7 years. The analysis of rs1799983 polymorphisms of the NOS3 gene (localization 7q36.1; 7:150999023) and AGTR1 (type 1 receptor for angiotensin 2 1166 A>C) was performed using TaqMan assay (Thermo Fisher Scientific, USA) by real-time PCR (Applied Biosystems, USA) using TaqMan probe amplification products. Genomic DNA samples were isolated from stabilized blood using a Genomic DNA Mini Kit reagent (Invitrogen, USA). The Statistica 10 program (StatSoft Inc.) was used for statistical processing of the obtained data, USA). The independent samples were compared using the Mann-Whitney (U) criterion. In all cases of statistical evaluation, the reliability of differences was taken into account at a value of p<0.05. CONCLUSION: Results and conclusions: Polymorphism of the NOS3 and AGTR1 genes is associated with early development and complicated course of cardiovascular pathology. The combination of NOS3 and AGTR1 gene polymorphism in patients with the high body mass index increases the risk of complications in hypertension. Using a mathematical model to predict the probability (95%) of genetic mutations in two genes (NOS3 and AGTR1) increases the effectiveness of diagnosis for patients with the high risk of developing cardiovascular complications.

LINC00852 promotes the proliferation and invasion of ovarian cancer cells by competitively binding with miR-140-3p to regulate AGTR1 expression.

BACKGROUND: Dysregulation of long non-coding RNAs (lncRNAs) has been identified in ovarian cancer. However, the expression and biological functions of LINC00852 in ovarian cancer are not understood. METHODS: The expressions of LINC00852, miR-140-3p and AGTR1 mRNA in ovarian cancer tissues and cells were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay. Gain- and loss-of-function assays were performed to explore the biological functions of LINC00852 and miR-140-3p in the progression of ovarian cancer in vitro. The bindings between LINC00852 and miR-140-3p were confirmed by luciferase reporter gene assay, RNA immunoprecipitation (RIP) assay and RNA pull-down assay. RESULTS: We found that LINC00852 expression was significantly up-regulated in ovarian cancer tissues and cells, whereas miR-140-3p expression was significantly down-regulated in ovarian cancer tissues. Functionally, LINC00852 knockdown inhibited the viability, proliferation and invasion of ovarian cancer cells, and promoted the apoptosis of ovarian cancer cells. Further investigation showed that LINC00852 interacted with miR-140-3p, and miR-140-3p overexpression suppressed the viability, proliferation and invasion of ovarian cancer cells. In addition, miR-140-3p interacted with AGTR1 and negatively regulated its level in ovarian cancer cells. Mechanistically, we found that LINC00852 acted as a ceRNA of miR-140-3p to promote AGTR1 expression and activate MEK/ERK/STAT3 pathway. Finally, LINC00852 knockdown inhibited the growth and invasion ovarian cancer in vivo. CONCLUSION: LINC00852/miR-140-3p/AGTR1 is an important pathway to promote the proliferation and invasion of ovarian cancer.

Distributive characteristics of the CYP2C9 and AGTR1 genetic polymorphisms in Han Chinese hypertensive patients: a retrospective study.

BACKGROUND: There is an individual variation in response to antihypertensive effect of the angiotensin II receptor antagonist. This study aimed to determine the allele and genotype frequencies of CYP2C9 and AGTR1 genetic polymorphisms and explore the potential role of these polymorphisms in guiding the selection of angiotensinIIreceptor antagonist in Han Chinese hypertensive patients. METHODS: Totally 2419 Han Chinese hypertensive patients and 126 normotensive controls were recruited in this study. Venous blood samples were collected from each patient, and the genetic polymorphisms of CYP2C9 and AGTR1 were assessed using a gene chip platform. The allele and genotype frequency of each gene and the combined genotypes in this study were analyzed respectively. RESULTS: The gene chip analysis identified an allelic frequency of 96.51% for CYP2C9*1 and 3.49% for CYP2C9*3 in the cohort of Han Chinese hypertensive patients. Statistical analysis showed that the frequency of wild-type homozygous for CYP2C9*1/*1 was 93.30%, while the frequency of heterozygous for *1/*3 or mutant homozygous for *3/*3 was 6.41% or 0.29%. Meanwhile, we detected allelic frequencies of 95.06% and 4.94% for the A and C allele of AGTR1, respectively. While the genotype frequency of wild-type homozygous for AA was 90.41%, the frequency of heterozygous for AC or mutant homozygous for CC was 9.30% or 0.29%. Notably, we observed that 84.66% (2048/2419) of the subjects exhibited a combined genotype of CYP2C9 and AGTR1 as *1/*1 + AA, while the combined genotypes *3/*3 + AC or *3/*3 + CC were not detected in hypertension patients. Besides, no significant association was found between normotensive controls and hypertensive patients, or among the three grades of hypertensive patients. CONCLUSIONS: These data revealed the polymorphisms characteristics of CYP2C9 and AGTR1 in Han Chinese hypertensive patients, providing valuable information for genotype-based antihypertension therapy in prospective clinical studies in the future.

Functional tests to guide management in an adult with loss of function of type-1 angiotensin II receptor.

BACKGROUND: Genetic loss of function of AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), or AGTR1 (type-1 angiotensin II receptor) leads to renal tubular dysgenesis (RTD). This syndrome is almost invariably lethal. Most surviving patients reach stage 5 chronic kidney disease at a young age. METHODS: Here, we report a 28-year-old male with a homozygous truncating mutation in AGTR1 (p.Arg216*), who survived the perinatal period with a mildly impaired kidney function. In contrast to classic RTD, kidney biopsy showed proximal tubules that were mostly normal. During the subsequent three decades, we observed evidence of both tubular dysfunction (hyperkalemia, metabolic acidosis, salt-wasting and a urinary concentrating defect) and glomerular dysfunction (reduced glomerular filtration rate, currently ~30 mL/min/1.73 m2, accompanied by proteinuria). To investigate the recurrent and severe hyperkalemia, we performed a patient-tailored functional test and showed that high doses of fludrocortisone induced renal potassium excretion by 155%. Furthermore, fludrocortisone lowered renal sodium excretion by 39%, which would have a mitigating effect on salt-wasting. In addition, urinary pH decreased in response to fludrocortisone. Opposite effects on urinary potassium and pH occurred with administration of amiloride, further supporting the notion that a collecting duct is present and able to react to fludrocortisone. CONCLUSIONS: This report provides living proof that even truncating loss-of-function mutations in AGTR1 are compatible with life and relatively good GFR and provides evidence for the prescription of fludrocortisone to treat hyperkalemia and salt-wasting in such patients.

Stearoyl-CoA Desaturase (SCD) Induces Cardiac Dysfunction with Cardiac Lipid Overload and Angiotensin II AT1 Receptor Protein Up-Regulation.

Heart failure is a major cause of death worldwide with insufficient treatment options. In the search for pathomechanisms, we found up-regulation of an enzyme, stearoyl-CoA desaturase 1 (Scd1), in different experimental models of heart failure induced by advanced atherosclerosis, chronic pressure overload, and/or volume overload. Because the pathophysiological role of Scd1/SCD in heart failure is not clear, we investigated the impact of cardiac SCD upregulation through the generation of C57BL/6-Tg(MHCSCD)Sjaa mice with myocardium-specific expression of SCD. Echocardiographic examination showed that 4.9-fold-increased SCD levels triggered cardiac hypertrophy and symptoms of heart failure at an age of eight months. Tg-SCD mice had a significantly reduced left ventricular cardiac ejection fraction of 25.7 ± 2.9% compared to 54.3 ± 4.5% of non-transgenic B6 control mice. Whole-genome gene expression profiling identified up-regulated heart-failure-related genes such as resistin, adiponectin, and fatty acid synthase, and type 1 and 3 collagens. Tg-SCD mice were characterized by cardiac lipid accumulation with 1.6- and 1.7-fold-increased cardiac contents of saturated lipids, palmitate, and stearate, respectively. In contrast, unsaturated lipids were not changed. Together with saturated lipids, apoptosis-enhancing p53 protein contents were elevated. Imaging by autoradiography revealed that the heart-failure-promoting and membrane-spanning angiotensin II AT1 receptor protein of Tg-SCD hearts was significantly up-regulated. In transfected HEK cells, the expression of SCD increased the number of cell-surface angiotensin II AT1 receptor binding sites. In addition, increased AT1 receptor protein levels were detected by fluorescence spectroscopy of fluorescent protein-labeled AT1 receptor-Cerulean. Taken together, we found that SCD promotes cardiac dysfunction with overload of cardiotoxic saturated lipids and up-regulation of the heart-failure-promoting AT1 receptor protein.

Improvements of symptoms of Alzheimer`s disease by inhibition of the angiotensin system.

With ageing of the global society, the frequency of ageing-related neurodegenerative diseases such as Alzheimer`s disease (AD) is on the rise worldwide. Currently, there is no cure for AD, and the four drugs approved for AD only have very small effects on AD symptoms. Consequently, there are enormous efforts worldwide to identify new targets for treatment of AD. Approaches that interfere with classical neuropathologic features of AD, such as extracellular senile plaques formed of aggregated amyloid-beta (Abeta), and intracellular neurofibrillary tangles of hyperphosphorylated tau have not been successful so far. In search for a treatment approach of AD, we found that inhibition of the angiotensin-converting enzyme (ACE) by a centrally acting ACE inhibitor retards symptoms of neurodegeneration, Abeta plaque formation and tau hyperphosphorylation in experimental models of AD. Our approach is currently being investigated in a clinical setting. Initial evidence with AD patients shows that a brain-penetrating ACE inhibitor counteracts the process of neurodegeneration and dementia. Moreover, centrally acting ACE inhibitors given in addition to the standard therapy, cholinesterase inhibition, can improve cognitive function of AD patients for several months. This is one of the most promising results for AD treatment since more than a decade.

[Study on mechanism of Tibetan medicine Zuomua Decoction in treatment of hypertension based on network pharmacology and molecular docking technology].

Hypertension is a kind of chronic cardiovascular system disease caused by a series of factors and carriers dysfunction, which belongs to the category of Tibetan medicine "Chalong disease", and has a high rate of disability and mortality. Zuomua Decoction is a classical Tibetan medicine for Chalong disease, but its mechanism is not clear. Therefore, in this paper we explored the multi-components, multi-targets and multi-channels mechanism of Zuomua Decoction in the treatment of hypertension based on network pharmacology and molecular docking technology. First of all, the chemical components of Zuomua Decoction were obtained in the retrieval of traditional Chinese medicine systems pharmacology database(TCMSP), China National Knowledge Infrastructure(CNKI) and Wanfang database. The potential targets of Zuomua Decoction were predicted by BATMAN-TCM database, and the targets of hypertension were obtained by using DisGeNET database. The intersection of these two targets set was taken to obtain the potential targets of Zuomua Decoction in the treatment of hypertension, and then the chemical compositions-targets network was constructed. Secondly, the intersection targets were imported into STRING database to obtain the interaction relationship of intersection targets, and the protein interaction network of Zuomua Decoction in the treatment of hypertension was constructed in Cytoscape. Topological, GO, and KEGG enrichment analysis were used to construct the key targets-signal pathways-biological processes network diagram and explore the mechanism of Zuomua Decoction in the treatment of hypertension. Finally, the key targets were selected to construct the pharmacodynamic identification models to verify the effect mode of Zomua Decoction in treating hypertension. The results showed that there were 61 chemical components and 90 potential targets in the compounds-targets network. We obtained 21 key targets, 154 signal pathways, and 382 biological processes in topological, GO, and KEGG enrichment analysis of the protein interaction network, and in the comprehensive analysis, it was found that Zuomua Decoction could reduce blood pressure by regulating renin angiotension aldosterone system, balancing the concentration of intracellular calcium and sodium ions and regulating vasoconstriction and relaxation. ACE, AGTR1, and ADRB2 were used as the carriers for molecular docking study on the components of Zuoma Decoction, and the results showed that the chemical components of Zuomua Decoction had a good binding activity with key targets. The purpose of this study is to provide ideas for the in-depth study of Zuoma Decoction in the treatment of hypertension, and provide scientific basis for its clinical rational application.

Angiotensin-converting enzyme insertion/deletion (rs106180) and angiotensin type 1 receptor A1166 C (rs106165) genotypes and psoriasis: Correlation with cellular immunity, lipid profile, and oxidative stress markers.

Psoriasis is a chronic inflammatory skin condition and angiotensin-converting enzyme (ACE) is a key circulating enzyme converting angiotensin (Ang) I to the vasoactive peptide Ang II. The exact role of ACE insertion (I)/deletion (D) polymorphism (rs106180) in psoriasis is not clear. We aimed to examine whether the ACE I/D and Ang II type 1 receptor (AT1R) A1166 C-polymorphisms (rs106165), lipid profile, and stress oxidative are associated with susceptibility to psoriasis. One hundred patients with psoriasis and 100 sex- and age-matched unrelated healthy controls were recruited for this case-control study. ACE I/D and AT1R A1166 C polymorphisms were identified by the polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism, respectively, malondialdehyde (MDA) was detected by the high-performance liquid chromatography, serum arylesterase (ARE) activity of paraoxonase and catalase activities were detected by the spectrophotometry, superoxide dismutase (SOD) activity and vascular adhesion protein (VAP)-1 were measured by ELISA. The presence of C allele of AT1R A1166 C and I allele of ACE considerably increased the risk of psoriasis by 6.42-fold (P < 0.001). The distribution of II-genotype of ACE was significantly higher in psoriasis patients than in control group and increased the risk of disease by 3.11-times (P = 0.023). The higher levels of MDA in patients and the higher activity of SOD, ARE, and CAT was observed in healthy controls with I/D+I/I-genotype of ACE I/D. This study for the first time demonstrated that the ACE I/D and AT1R A 1166 C genes polymorphisms robustly increases the risk of developing psoriasis in population from west of Iran. In addition, these individuals had significantly higher VAP-1 and MDA concentration and lower enzymatic and nonenzymatic antioxidant-status, suggesting that psoriatic patients carrying C allele of AT1R1166 polymorphism may be more susceptible to cardiovascular disease and myocardial infarction compared with A allele.

Angiotensin I-converting enzyme inhibitors/angiotensin II receptor blockers may reduce tumor recurrence in left-sided and early colorectal cancers.

BACKGROUND: Angiotensin signaling is suggested to be involved in tumorigenesis, tumor proliferation, and metastases. In colorectal cancer (CRC), it was demonstrated that angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) may reduce the risk of CRC; however, their impact on tumor recurrence remains unknown. Therefore, in this study, we evaluated the impact of ACEIs/ARBs on tumor recurrence in CRC patients. PATIENTS AND METHODS: We retrospectively investigated the clinicopathological data of 461 stage I-III CRC patients. We divided the patients into those who took an ACEI and/or ARB (the ACEI/ARB+ group) and those who did not (the ACEI/ARB- group), and we compared the two groups' recurrence-free survival (RFS) using a Kaplan-Meier curve analysis and log rank test. We also examined the impact of AGTR1 expression on tumor recurrence, using two public CRC datasets. RESULTS: The Kaplan-Meier curves showed a trend toward improved RFS in the ACEI/ARB+ group versus the ACEI/ARB- group (p = 0.063). Subgroup analyses demonstrated that the RFS was significantly better in the ACEI/ARB+ group versus the ACEI/ARB- group in the patients with left-sided CRC (p = 0.030) and those with stage I CRC (p = 0.009). Consistent with these findings, the AGTR1 expression was higher in the left-sided versus right-sided colon (p = 0.048). High AGTR1 expression levels were associated with poor RFS in the GSE39582 dataset's stage I-III CRC patients (p < 0.001), and this finding was also validated in the GSE17536 dataset (p = 0.023). CONCLUSION: ACEI/ARB treatment may reduce tumor recurrence in left-sided CRC and early-stage CRC.

Genetic polymorphisms associated with the prevalence of retinal vein occlusion in a Greek population.

PURPOSE: To investigate possible associations of single-nucleotide polymorphisms (SNPs) from five genes with branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO). METHODS: A total of 69 patients with retinal vein occlusion-RVO (24 with BRVO and 45 with CRVO), and 82 controls, were enrolled in this study. All subjects were screened for hypertension, diabetes mellitus, hyperlipidemia, glaucoma, anticoagulant medication, smoking status and history of stroke. The genotyping of AGTR1-A1166C, adiponectin + 276 G/T, MMP2-1306C/T, Gpla/lla-C807T/G873A and VKORC1-G1639A polymorphisms was performed using restriction fragment length polymorphism or allele-specific polymerase chain reaction. RESULTS: The percentage of the AGTR1-A1166C C allele carriers and Gpla/lla-C807T/G873A T/A carriers was significantly higher in the CRVO patients than in the controls (P = 0.00001 and P = 0.0004, respectively). At the multiple logistic regression analysis, the AGTR1-A1166C C allele carrier status and the Gpla/lla-C807T/G873A T/A allele carrier status were found to be associated with an increased risk of CRVO. Moreover, adiponectin + 276 G/T T allele carriers had a significantly increased risk of RVO in subjects ≥ 75 years old. There was no significant difference between the BRVO patients and controls concerning the genotype or the allele frequency distributions of these SNPs. The genotype distributions or allelic frequencies of the other evaluated polymorphisms did not significantly differ between the patients with RVO and the control subjects. CONCLUSIONS: AGTR1 A1166C and Gpla/lla C807T/G873A polymorphisms are likely to be risk factors for CRVO. Adiponectin + 276 G/T SNP is likely to predispose to RVO in older subjects.

Qiliqiangxin Rescues Mouse Cardiac Function by Regulating AGTR1/TRPV1-Mediated Autophagy in STZ-Induced Diabetes Mellitus.

BACKGROUND/AIMS: To explore the potential role of qiliqiangxin (QLQX) A traditional Chinese medicine and the involvement of angiotensin II receptor type 1 (AGTR1) and transient receptor potential vanilloid 1 (TRPV1) in diabetic mouse cardiac function. METHODS: Intragastric QLQX was administered for 5 weeks after streptozotocin (STZ) treatment. Additionally, Intraperitoneal injections of angiotensin II (Ang II) or intragastric losartan (Los) were administered to assess the activities of AGTR1 and TRPV1. Two-dimensional echocardiography and tissue histopathology were used to assess cardiac function Western blot was used to detect the autophagic biomarkers Such as light chain 3 P62 and lysosomal-associated membrane protein 2 And transmission electron microscopy was used to count the number of autophagosomes. RESULTS: Decreased expression of TRPV1 and autophagic hallmarks and reduced numbers of autophagolysosomes as well as increased expression of angiotensin converting enzyme 1 and AGTR1 were observed in diabetic hearts. Blocking AGTR1 with Los mimicked the QLQX-mediated improvements in cardiac function Alleviated myocardial fibrosis and enabled autophagy Whereas Ang II abolished the beneficial effects of QLQX in wild type diabetic mice but not in TRPV1-/- diabetic mice. CONCLUSIONS: QLQX may improve diabetic cardiac function by regulating AGTR1/ TRPV1-mediated autophagy in STZ-induced diabetic mice.

Post-Transcriptional Control of Angiotensin II Type 1 Receptor Regulates Osteosarcoma Cell Death.

BACKGROUND/AIMS: MicroRNAs (miRNAs) play an essential role in the tumorigenesis of osteosarcoma (OS). However, the effects of miR-1248 on chemo-resistant potential of OS have not been studied. Here, we addressed this question. METHODS: The levels of miR-1248 and apoptotic protein angiotensin II type 1 receptor (AGTR1) in OS specimens were examined by RT-qPCR and Western blotting, respectively. The relationship between miR-1248 and AGTR1 was determined by analysis of Spearman's Rank Correlation Coefficients. The patient survival was determined with Kaplan-Meier curves. Bioinformatics analyses were done to predict microRNAs (miRNAs) that target AGTR1. The functional binding of miRNAs to AGTR1 mRNA was examined by a dual luciferase reporter assay. Cell viability was determined by an CCK-8 assay. Apoptosis was determined by a fluorescence-based apoptosis assay. RESULTS: The levels of miR-1248 were significantly elevated while the levels of AGTR1 were significantly decreased in OS specimens than in paired adjacent normal tissue. The levels of miR-1248 were negatively correlated to the levels of AGTR1. Moreover, the patients with high miR-1248 levels had poorer survival than those with low MiR-1248 levels, and the patients with low AGTR1 levels had poorer survival than those with high AGTR1 levels. MiR-1248 inhibited protein translation of AGTR1, through binding to the 3'-UTR of the AGTR1 mRNA. The AGTR1-mediated cell apoptosis was suppressed by overexpressing miR-1248, and was augmented by depleting miR-1248. CONCLUSION: Increased miR-1248 expression in OS may inhibit AGTR1-mediated cancer cell death in chemotherapy. The outcome of chemotherapy may be improved by the suppression of miR-1248 in OS cells.