RESUMO
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.
Assuntos
Angiotensinogênio , Apolipoproteína A-V , Apolipoproteínas E , Doença da Artéria Coronariana , Estratificação de Risco Genético , Glutationa Transferase , Polimorfismo de Nucleotídeo Único , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Angiotensinogênio/genética , Apolipoproteína A-V/genética , Apolipoproteína C-III , Apolipoproteínas E/genética , Estudos de Casos e Controles , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/epidemiologia , Frequência do Gene , Estudos de Associação Genética , Glutationa Transferase/genética , Haplótipos , Índia/epidemiologia , Peptidil Dipeptidase A/genética , Receptor Tipo 1 de Angiotensina/genética , Fatores de RiscoRESUMO
Activation of the renin-angiotensin-aldosterone system (RAAS) plays an important pathophysiological role in hypertension. Increased mRNA levels of the angiotensinogen angiotensin-converting enzyme, angiotensin type 1 receptor gene, Agtr1a, and the aldosterone synthase gene, CYP11B2, have been reported in the heart, blood vessels, and kidneys in salt-sensitive hypertension. However, the mechanism of gene regulation in each component of the RAAS in cardiovascular and renal tissues is unclear. Epigenetic mechanisms, which are important for regulating gene expression, include DNA methylation, histone post-translational modifications, and microRNA (miRNA) regulation. A close association exists between low DNA methylation at CEBP-binding sites and increased AGT expression in visceral adipose tissue and the heart of salt-sensitive hypertensive rats. Several miRNAs influence AGT expression and are associated with cardiovascular diseases. Expression of both ACE and ACE2 genes is regulated by DNA methylation, histone modifications, and miRNAs. Expression of both angiotensinogen and CYP11B2 is reversibly regulated by epigenetic modifications and is related to salt-sensitive hypertension. The mineralocorticoid receptor (MR) exists in cardiovascular and renal tissues, in which many miRNAs influence expression and contribute to the pathogenesis of hypertension. Expression of the 11beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) gene is also regulated by methylation and miRNAs. Epigenetic regulation of renal and vascular HSD11B2 is an important pathogenetic mechanism for salt-sensitive hypertension.
Assuntos
Metilação de DNA , Epigênese Genética , Hipertensão , Sistema Renina-Angiotensina , Sistema Renina-Angiotensina/genética , Hipertensão/genética , Hipertensão/metabolismo , Animais , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismoRESUMO
Adenocarcinoma of the pancreas (PAAD) is one of the deadliest malignant tumors, and messenger ribonucleic acid vaccines, which constitute the latest generation of vaccine technology, are expected to lead to new ideas for the treatment of pancreatic cancer. The Cancer Genome Atlas-PAAD and Genotype-Tissue Expression data were merged and analyzed. Weighted gene coexpression network analysis was used to identify gene modules associated with tumor mutational burden among the genes related to both immunity and oxidative stress. Differentially expressed immune-related oxidative stress genes were screened via univariate Cox regression analysis, and these genes were analyzed via nonnegative matrix factorization. After immune infiltration analysis, least absolute shrinkage and selection operator regression combined with Cox regression was used to construct the model, and the usefulness of the model was predicted based on the receiver operating characteristic curve and decision curve analysis curves after model construction. Finally, metabolic pathway enrichment was analyzed using gene set enrichment analysis combined with Kyoto Encyclopedia of Genes and Genomes and gene ontology biological process analyses. This model consisting of the ERAP2, mesenchymal-epithelial transition factor (MET), CXCL9, and angiotensinogen (AGT) genes can be used to help predict the prognosis of pancreatic cancer patients more accurately than existing models. ERAP2 is involved in immune activation and is important in cancer immune evasion. MET binds to hepatocyte growth factor, leading to the dimerization and phosphorylation of c-MET. This activates various signaling pathways, including MAPK and PI3K, to regulate the proliferation, invasion, and migration of cancer cells. CXCL9 overexpression is associated with a poor patient prognosis and reduces the number of CD8â +â cytotoxic T lymphocytes in the PAAD tumor microenvironment. AGT is cleaved by the renin enzyme to produce angiotensin 1, and AGT-converting enzyme cleaves angiotensin 1 to produce angiotensin 2. Exposure to AGT-converting enzyme inhibitors after pancreatic cancer diagnosis is associated with improved survival. The 4 genes identified in the present study - ERAP2, MET, CXCL9, and AGT - are expected to serve as targets for messenger ribonucleic acid vaccine development and need to be further investigated in depth.
Assuntos
Estresse Oxidativo , Neoplasias Pancreáticas , Vacinas de mRNA , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Humanos , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Angiotensinogênio/genética , Regulação Neoplásica da Expressão Gênica , PrognósticoRESUMO
BACKGROUND: Autosomal recessive renal tubular dysgenesis is a rare, usually fatal inherited disorder of the renin-angiotensis system (RAS). Herein, we report an adolescent individual experiencing an unknown chronic kidney disease and aim to provide novel insights into disease mechanisms. METHODS: Exome sequencing for a gene panel associated with renal disease was performed. The RAS was assessed by comprehensive biochemical analysis in blood. Renin expression was determined in primary tubular cells by quantitative polymerase chain reaction and in situ hybridization on kidney biopsy samples. Allele frequencies of heterozygous and biallelic deleterious variants were determined by analysis of the Genomics England 100,000 Genomes Project. RESULTS: The patient was delivered prematurely after oligohydramnios was detected during pregnancy. Postnatally, he recovered from third-degree acute kidney injury but developed chronic kidney disease stage G3b over time. Exome sequencing revealed a previously reported pathogenic homozygous missense variant, p.(Arg375Gln), in the AGT (angiotensinogen) gene. Blood AGT concentrations were low, but plasma renin concentration and gene expression in kidney biopsy, vascular, and tubular cells revealed strong upregulation of renin. Angiotensin II and aldosterone in blood were not abnormally elevated. CONCLUSIONS: Renal tubular dysgenesis may present as chronic kidney disease with a variable phenotype, necessitating broad genetic analysis for diagnosis. Functional analysis of the RAS in a patient with AGT mutation revealed novel insights regarding compensatory upregulation of renin in vascular and tubular cells of the kidney and in plasma in response to depletion of AGT substrate as a source of Ang II (similarly observed with hepatic AGT silencing for the treatment of hypertension).
Assuntos
Angiotensinogênio , Humanos , Angiotensinogênio/genética , Masculino , Adolescente , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologia , Progressão da Doença , Renina/genética , Renina/sangue , Renina/metabolismo , Mutação de Sentido Incorreto/genética , Sequenciamento do Exoma/métodos , Feminino , Túbulos Renais Proximais/anormalidades , Anormalidades UrogenitaisRESUMO
OBJECTIVES: To analyze the gene variants of the renin-angiotensin-aldosterone system and determine their association with the severity and outcome of COVID-19. METHODS: A total of 104 patients were included in the study: 34 asymptomatic patients with COVID-19 as controls and 70 symptomatic patients as cases. The genetic variants ACE rs4343, ACE2 rs2074192, AGTR1 rs5182, and AGT rs4762 were identified using TaqMan genotyping tests. RESULTS: Patients with the T/T genotype of AGTR1 rs5182 have a higher probability of developing symptomatic COVID-19 (odds ratio [OR] 12.25, 95% confidence interval [CI] 1.34-111.9, P ≤0.001) and a higher risk of hospitalization because of disease (OR 14.00, 95% CI 1.53-128.49, P = 0.012). The haplotype CTG (AGTR1 rs5182, ACE2 rs2074192, ACE rs4343) decreased the odds of death related to COVID-19 in the study population (OR 0.03, 95% CI 0.0-0.06, P = 0.026). CONCLUSIONS: The T/T genotype of the AGTR1 rs5182 variant increased the probability of symptomatic COVID-19 and hospitalization, whereas the haplotype CTG (consisting of AGTR1 rs5182, ACE2 rs2074192, and ACE rs4343) decreased the odds of death related to COVID-19 by 97% in the hospitalized patients with COVID-19. These results support the participation of renin-angiotensin-aldosterone system gene variants as modifiers of the severity of symptoms associated with SARS-CoV-2 infection and the outcome of COVID-19.
Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Hospitalização , Peptidil Dipeptidase A , Receptor Tipo 1 de Angiotensina , Sistema Renina-Angiotensina , SARS-CoV-2 , Índice de Gravidade de Doença , Humanos , COVID-19/genética , COVID-19/mortalidade , COVID-19/virologia , Masculino , Feminino , Pessoa de Meia-Idade , Receptor Tipo 1 de Angiotensina/genética , Sistema Renina-Angiotensina/genética , Enzima de Conversão de Angiotensina 2/genética , SARS-CoV-2/genética , Peptidil Dipeptidase A/genética , Adulto , Polimorfismo de Nucleotídeo Único , Idoso , Angiotensinogênio/genética , Genótipo , Predisposição Genética para Doença , Haplótipos , Estudos de Casos e ControlesRESUMO
BACKGROUND: Small-interfering RNA (siRNA) targeting hepatic AGT (angiotensinogen) mRNA depletes AGT, lowering blood pressure for up to 6 months. However, certain situations may require a rapid angiotensin increase. The REVERSIR (RVR) - reverse siRNA silencing technology a potential approach to counteract siRNA effects. METHODS: Spontaneously hypertensive rats received 10 mg/kg AGT siRNA, and 3 weeks later were given AGT-RVR (1, 10, or 20 mg/kg). One week after AGT-RVR dosing, a redose of AGT siRNA assessed its post-AGT-RVR effectiveness for 2 weeks. Additionally, the impact of AGT-RVR after an equihypotensive dose of valsartan (4 mg/kg per day) was examined. RESULTS: Baseline mean arterial pressure (MAP) was 144±1 mmâ Hg. AGT siRNA reduced MAP by ≈16 mmâ Hg and AGT by >95%, while renin increased 25-fold. All AGT-RVR doses restored MAP to baseline within 4 to 7 days. Notably, 10 and 20 mg/kg restored AGT and renin to baseline, while 1 mg/kg allowed ≈50% AGT restoration, with renin remaining above baseline. A second AGT siRNA treatment, following 1 mg/kg AGT-RVR, reduced MAP to the same degree as the initial dose, while following 10 mg/kg AGT-RVR, it resulted in ≈50% of the first dose's MAP effect at 2 weeks. The valsartan-induced MAP reduction was unaffected by AGT-RVR. CONCLUSIONS: In spontaneously hypertensive rats, angiotensinogen-RVR dose-dependently reversed AGT siRNA-induced AGT reduction, normalizing MAP. MAP normalization persisted even with 50% recovered AGT levels, likely due to upregulated renin maintaining adequate angiotensin generation. Post-AGT-RVR dosing, a second AGT siRNA dose lowered MAP again.
Assuntos
Angiotensinogênio , Anti-Hipertensivos , Hipertensão , RNA Interferente Pequeno , Ratos Endogâmicos SHR , Animais , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/genética , Ratos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Hipertensão/metabolismo , Anti-Hipertensivos/farmacologia , Masculino , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Valsartana/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
Alamandine is a peptide hormone belonging to the renin-angiotensin system (RAS). It acts through the Mas-related G-protein coupled receptor type D, MrgD, which is expressed in different tissues, including the brain. In the present study, we hypothesize that a lack of alamandine, through MrgD, could cause the anxiety-like behavior in transgenic rats with low brain angiotensinogen [TGR(ASrAOGEN)680]. Adult male transgenic rats exhibited a significant increase in the latency to feeding time in the novelty suppressed feeding test and a decrease in the percentage of time and entries in the open arms in the elevated plus maze. These effects were reversed by intracerebroventricular infusion of alamandine. Pretreatment with D-Pro7-Ang-(1-7), a Mas and MrgD receptor antagonist, prevented the anxiolytic effects induced by this peptide. However, its effects were not altered by the selective Mas receptor antagonist, A779. In conclusion, our data indicates that alamandine, through MrgD, attenuates anxiety-like behavior in male TGR(ASrAOGEN)680, which reinforces the importance of the counter-regulatory RAS axis as promising target for the treatment of neuropsychiatric disorders.
Assuntos
Angiotensinogênio , Ansiolíticos , Ansiedade , Encéfalo , Ratos Transgênicos , Receptores Acoplados a Proteínas G , Animais , Masculino , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Ratos , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Ansiolíticos/farmacologia , Angiotensinogênio/metabolismo , Angiotensinogênio/genética , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Receptores dos Hormônios Gastrointestinais/metabolismo , Oligopeptídeos/farmacologia , Proteínas do Tecido NervosoRESUMO
AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention compared to many other renin-angiotensin system components. Focus on AGT has increased recently, particularly with the evolution of drugs to target the synthesis of the protein. AGT is a noninhibitory serpin that has several conserved domains in addition to the angiotensin II sequences at the N terminus. Increased study is needed on the structure-function relationship to resolve many unknowns regarding AGT metabolism. Constitutive whole-body genetic deletion of Agt in mice leads to multiple developmental defects creating a challenge to use these mice for mechanistic studies. This has been overcome by creating Agt-floxed mice to enable the development of cell-specific deficiencies that have provided considerable insight into a range of cardiovascular and associated diseases. This has been augmented by the recent development of pharmacological approaches targeting hepatocytes in humans to promote protracted inhibition of AGT synthesis. Genetic deletion or pharmacological inhibition of Agt has been demonstrated to be beneficial in a spectrum of diseases experimentally, including hypertension, atherosclerosis, aortic and superior mesenteric artery aneurysms, myocardial dysfunction, and hepatic steatosis. This review summarizes the findings of recent studies utilizing AGT manipulation as a therapeutic approach.
Assuntos
Angiotensinogênio , Doenças Cardiovasculares , Doenças Metabólicas , Animais , Humanos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/genética , Angiotensinogênio/metabolismo , Angiotensinogênio/genética , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Doenças Metabólicas/genética , Sistema Renina-Angiotensina/efeitos dos fármacos , Terapia de Alvo MolecularRESUMO
Sepsis induced myocardial dysfunction (SIMD) is a serious complication of sepsis. There is increasing evidence that the renin-angiotensin system (RAS) is activated in SIMD. Angiotensinogen (AGT) is a precursor of the RAS, and the inhibition of AGT may have significant cardiovascular benefits. But until now, there have been no reports of small molecule drugs targeting AGT. In this study, we designed a promoter-luciferase based system to screen for novel AGT inhibitors to alleviate SIMD. As a result of high-throughput screening, a total of 5 compounds from 351 medicinal herb-derived natural compounds were found inhibiting AGT. 18ß-glycyrrhetinic acid (18ßGA) was further identified as a potent suppressor of AGT. In vitro experiments, 18ßGA could inhibit the secretion of AGT by HepG2 cells and alleviate the elevated level of mitochondrial oxidative stress in cardiomyocytes co-cultured with HepG2 supernatants. In vivo, 18ßGA prolonged the survival rate of SIMD mice, enhanced cardiac function, and inhibited the damage of mitochondrial function and inflammation. In addition, the results showed that 18ßGA may reduce AGT transcription by downregulating hepatocyte nuclear factor 4 (HNF4) and that further alleviated SIMD. In conclusion, we provided a more efficient screening strategy for AGT inhibitors and expanded the novel role of 18ßGA as a promising lead compound in rescuing cardiovascular disease associated with RAS overactivation.
Assuntos
Ácido Glicirretínico/análogos & derivados , Ensaios de Triagem em Larga Escala , Sepse , Camundongos , Animais , Lipopolissacarídeos , Angiotensinogênio/genéticaRESUMO
Coronary artery disease (CAD) is the third most common cause of mortality globally (with 17.8 million deaths annually). Angiotensinogen (AGT) and polymorphisms in this gene can be considered as susceptibility factors for CAD. We performed a retrospective case-control study to determine the correlation of AGT rs5051 and rs699 polymorphisms with CAD in an Iranian population. We genotyped 310 CAD patients and 310 healthy subjects using polymerase chain reaction-based methods. To confirm the accuracy of the screening approach, 10% of genotyped subjects were validated using gold-standard Sanger Sequencing. To evaluate the effect of the candidate polymorphisms, white blood cells were randomly purified from the subjects and AGT expression was measured by quantitative reverse transcriptase-polymerase chain reaction. Sex stratification indicated a significant correlation between CAD and male sex (Pâ =â .0101). We found a significant association between the rs5051 A allele (Pâ =â .002) and the rs699 C allele, and CAD (Pâ =â .0122) in recessive and dominant models. Moreover, our findings showed a significant association of the haplotype, including the rs5051 A/A and rs699 T/C genotypes, with CAD (Pâ =â .0405). Finally, AGT mRNA levels were significantly decreased in patients harboring the candidate polymorphisms (Pâ =â .03). According to our findings The AGT rs5051 A and AGT rs699 C alleles are predisposing variants of CAD risk and severity in the Iranian population.
Assuntos
Angiotensinogênio , Doença da Artéria Coronariana , Humanos , Masculino , Angiotensinogênio/genética , Estudos de Casos e Controles , Doença da Artéria Coronariana/genética , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Irã (Geográfico) , Estudos Retrospectivos , Fatores de RiscoRESUMO
PURPOSE OF REVIEW: The primary goal of this review article was to determine whether the three RAAS-associated SNPs, Renin-rs16853055, AGT-rs3789678 and ACE-rs4305 are genetically linked to the development of hypertension in preeclampsia. The secondary goal was to establish if there was a link between these SNPs and HIV infection. RECENT FINDINGS: There is a paucity of findings related to the aforementioned SNPs and preeclampsia. There are no recent findings on the rs16853055 renin polymorphism. The rs3789678 angiotensinogen polymorphism correlated significantly with gestational hypertension. The rs4305 ACE polymorphism showed no significant association with the development of pregnancy-induced hypertension. There are conflicting findings when determining the relationship between ethnicity and the predisposition of preeclampsia and hypertension in relation to the discussed RAAS-associated SNPs. To date, the association between RAAS-associated SNPs and preeclamptic women co-morbid with HIV in South Africa has revealed that certain alleles of the AGT gene are more prominent in HIV-infected PE compared to normotensive pregnant HIV-infected women.
Assuntos
Angiotensinogênio , Infecções por HIV , Peptidil Dipeptidase A , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia , Sistema Renina-Angiotensina , Renina , Humanos , Gravidez , Feminino , Pré-Eclâmpsia/genética , Infecções por HIV/genética , Infecções por HIV/complicações , Polimorfismo de Nucleotídeo Único/genética , Angiotensinogênio/genética , Sistema Renina-Angiotensina/genética , Renina/genética , Peptidil Dipeptidase A/genética , Predisposição Genética para Doença , Complicações Infecciosas na Gravidez/genética , Complicações Infecciosas na Gravidez/virologiaRESUMO
There is little data regarding the impact of renin-angiotensin system (RAS) gene polymorphisms on tuberculosis. The current study designed to survey the possible association between RAS polymorphisms and the risk of pulmonary tuberculosis (PTB) in a sample of the southeast Iranian population. This case-control study was done on 170 PTB patients and 170 healthy subjects. The AGT rs699 C>T, ACE rs4341 C>G and AT1R rs5186 C>A variants were genotyped using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and ACE rs4646994 (287bp I/D) variant by PCR method. Regarding AT1R rs5186 A>C polymorphism, the findings revealed that AC genotype and C allele significantly decreased the risk of PTB (OR=0.39, 95% CI=0.22-0.67, p=0.001, and OR=0.53, 95% CI=0.25-0.72, p=0.002, C vs. A, respectively). The TC genotype and C allele of AGT rs699 T>C significantly associated with decreased the risk of PTB (OR=0.45, 95% CI=0.28-0.74, p=0.002, TC vs. TT and OR=0.51, 95% CI=0.32-0.80, p=0.005, C vs. T, respectively). The ID genotype of ACE 287bp I/D significantly increased the risk of PTB (OR=1.88, 95% CI=1.12-3.17, p=0.017). Our finding did not support an association between ACE rs4341 C>G variant and the risk of PTB. In summary, the findings revealed an association between AT1R rs5186 A>C, AGT rs699 T>C and ACE 287bp I/D polymorphisms and the risk of PTB in a sample of the southeast Iranian population. Further investigation with higher sample sizes and diverse ethnicities are required to confirm our findings.
Assuntos
Peptidil Dipeptidase A , Tuberculose Pulmonar , Humanos , Angiotensinogênio/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Irã (Geográfico)/epidemiologia , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Receptor Tipo 1 de Angiotensina/genética , Tuberculose Pulmonar/genéticaRESUMO
Due to the inconsistent findings from various studies, the role of gene polymorphisms in the renin-angiotensin system in influencing the development of cardiomyopathy remains unclear. In this study, we conducted a systematic review and meta-analysis to summarize the findings regarding the impact of angiotensin converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T, and angiotensin II Type 1 receptor (AGTR1) A1166C gene polymorphisms in patients with cardiomyopathy. We performed a comprehensive search of several electronic databases, including PubMed, Embase, the Cochrane Library, and Web of Science, covering articles published from the time of database creation to April 17, 2023. Studies on the assessment of genetic polymorphisms in genes related to the renin-angiotensin system in relation to cardiomyopathy were included. The primary outcome was cardiomyopathy. Risk of bias was assessed using the Newcastle-Ottawa Scale scale. The meta-analysis includes 19 studies with 4,052 cases and 5,592 controls. The ACE I/D polymorphisms were found to be associated with cardiomyopathy (allelic model D vs I: OR = 1.29, 95CI% = 1.08-1.52; dominant model DD+ID vs II: OR = 1.43, 95CI% = 1.01-2.02; recessive model DD vs ID+II: OR = 0.79, 95CI% = 0.64-0.98). AGT M235T polymorphism and cardiomyopathy were not significantly correlated (allelic model T vs M: OR = 1.26, 95CI% = 0.96-1.66; dominant model TT+MT vs MM: OR = 1.30, 95CI% = 0.98-1.73; recessive model TT vs MT+MM: OR = 0.63, 95CI% = 0.37-1.07). AGTR1 polymorphism and cardiomyopathy were not significantly associated under allelic model A vs C (OR = 0.69, 95CI% = 0.46-1.03) and recessive model AA vs CA+CC (OR = 0.89, 95CI% = 0.34-2.30), but under the dominant model AA+CA vs CC (OR = 0.51, 95CI% = 0.38-0.68). The current meta-analysis reveals that polymorphisms in ACE I/D may be a genetic risk factor for cardiomyopathy. There is an association between AGTR1 gene polymorphisms and risk of cardiomyopathy under the specific model.
Assuntos
Cardiomiopatias , Sistema Renina-Angiotensina , Humanos , Sistema Renina-Angiotensina/genética , Fatores de Risco , Polimorfismo Genético , Peptidil Dipeptidase A/genética , Angiotensinogênio/genética , Cardiomiopatias/genética , Receptor Tipo 1 de Angiotensina/genéticaRESUMO
It has been previously shown that clinical cardiovascular manifestations can be caused by mild changes in thyroid function. However, the implication of angiotensinogen (Agt) and vascular smooth muscle cells (VSMCs) dysfunction in the pathophysiology of cardiovascular manifestations in hypothyroidism have not yet been investigated. We induced experimental hypothyroidism in Psammomys obesus by administering carbimazole for five months. At the end of the experiment, the animals were sacrificed and histopathological analysis was performed using Masson's trichrome staining of the aorta and thyroid gland. The expression of the Agt gene and the genes implicated in cholesterol metabolism regulation in the liver and VSMCs was determined by qRT-PCR. Histological observations revealed profound remodeling of the aorta structure in animals with hypothyroidism. In addition, Agt gene expression in the liver was significantly increased. In vitro study, showed that VSMCs from hypothyroid animals overexpressed 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr) and Acyl CoA:cholesterol acyltransferase (Acat) 1, with failure to increase the efflux pathway genes (ATP-binding cassette subfamily G member (Abcg) 1 and 4). These results suggest that hypothyroidism leads to vascular alterations, including structural remodeling, VSMCs cholesterol metabolism dysfunction, and their switch to a synthetic phenotype, together with hepatic Agt gene overexpression.
Assuntos
Hipotireoidismo , Músculo Liso Vascular , Animais , Gerbillinae , Músculo Liso Vascular/metabolismo , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Colesterol/metabolismo , Hipotireoidismo/genética , Hipotireoidismo/metabolismo , Aorta/metabolismo , Expressão Gênica , Miócitos de Músculo Liso/metabolismoRESUMO
INTRODUCTION: Hypertension is the main global risk factor for cardiovascular disease. Despite this, less than half of treated hypertensive patients are controlled. One reason for this is nonadherence, a major unmet need in hypertension pharmacotherapy. Small interfering RNA (small interfering ribonucleic acid) therapies inhibit protein translation, and, when linked to N-acetylgalactosamine, allow liver-specific targeting, and durability over several months. Targeted knockdown of hepatic angiotensinogen, the source of all angiotensins, offers a precision medicine approach. AREAS COVERED: This article describes the molecular basis for durability over months and the 24-h tonic target inhibition observed after one administration. We present an analysis of the published phase I trials using zilebesiran, a siRNA targeting hepatic angiotensinogen, which reduces blood pressure (BP) by up to 20 mmHg, lasting 24 weeks. Finally, we examine data evaluating reversibility of angiotensinogen knockdown and its relevance to the future clinical utility of zilebesiran. EXPERT OPINION: Further studies should assess safety, efficacy, and outcomes in larger, more broadly representative groups. An advantage of zilebesiran is the potential for bi-annual dosing, thereby reducing nonadherence and improving control rates. It may also reduce nighttime BP due to 24-h tonic control. The provision of adherence assessment services will maximize the clinical value of zilebesiran.
Assuntos
Angiotensinogênio , Hipertensão , Humanos , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Angiotensinogênio/uso terapêutico , RNA Interferente Pequeno , Hipertensão/tratamento farmacológico , Pressão Sanguínea , Fígado/metabolismoRESUMO
Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or the so-called RAS escape phenomenon, elicited by the compensatory renin elevation upon RAS blockade. Recently, evidence points toward targeting hepatic AGT (angiotensinogen) as a novel approach to block the RAS pathway that could circumvent the RAS escape phenomenon. Removing AGT, from which all angiotensins originate, should prevent further angiotensin generation, even when renin rises. Furthermore, by making use of a trivalent N-acetylgalactosamine ligand-conjugated small interfering RNA that specifically targets the degradation of hepatocyte-produced mRNAs in a highly potent and specific manner, it may be possible in the future to manage hypertension with therapy that is administered 1 to 2× per year, thereby supporting medication adherence. This review summarizes all current findings on AGT small interfering RNA in preclinical models, making a comparison versus classical RAS blockade with either ACE (angiotensin-converting enzyme) inhibitors or AT1 (angiotensin II type 1) receptor antagonists and AGT suppression with antisense oligonucleotides. It ends with discussing the first-in-human study with AGT small interfering RNA.
Assuntos
Angiotensinogênio , Hipertensão , Humanos , Acetilgalactosamina , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Pressão Sanguínea , Hipertensão/terapia , Hipertensão/tratamento farmacológico , Renina/metabolismo , Sistema Renina-Angiotensina/fisiologia , RNA Interferente Pequeno/farmacologiaAssuntos
Angiotensinogênio , Hipertensão , RNA Interferente Pequeno , Humanos , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Pressão Sanguínea/genética , Hipertensão/genética , Hipertensão/terapia , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêuticoRESUMO
Hypertension remains the leading cause of cardiovascular disease and premature death globally, affecting half of US adults. A high proportion of hypertensive patients exhibit uncontrolled blood pressure (BP), associated with poor adherence, linked to pill burden and adverse effects. Novel pharmacological strategies are urgently needed to improve BP control. Dysregulation of the renin-angiotensin system increases BP through its primary effector, Ang II (angiotensin II), which results in tissue remodeling and end-organ damage. Silencing liver angiotensinogen (the sole source of Ang II) has been achieved using novel RNA therapeutics, including the antisense oligonucleotide, IONIS-AGT (angiotensinogen)-LRX, and the small-interfering RNA, zilebesiran. Conjugation to N-acetylgalactosamine enables targeted delivery to hepatocytes, where endosomal storage, slow leakage, and small-interfering RNA recycling (for zilebesiran) result in knockdown over several months. Indeed, zilebesiran has an impressive and durable effect on systolic BP, reduced by up to 20 mm Hg and sustained for 6 months after a single administration, likely due to its very effective knockdown of angiotensinogen, without causing acute kidney injury or hyperkalemia. By contrast, IONIS-AGT-LRX caused less knockdown and marginal effects on BP. Future studies should evaluate any loss of efficacy relating to antidrug antibodies, safety issues associated with long-term angiotensinogen suppression, and broader benefits, especially in the context of common comorbidities such as type 2 diabetes and chronic kidney disease.
Assuntos
Diabetes Mellitus Tipo 2 , Hipertensão , Humanos , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Hipertensão/genética , Pressão Sanguínea/fisiologia , Sistema Renina-Angiotensina , Angiotensina II/farmacologia , RNA Interferente Pequeno/farmacologiaRESUMO
BACKGROUND: Kidney angiotensin (Ang) II is produced mainly from liver-derived, glomerular-filtered angiotensinogen (AGT). Podocyte injury has been reported to increase the kidney Ang II content and induce Na + retention depending on the function of megalin, a proximal tubular endocytosis receptor. However, how megalin regulates the renal content and action of Ang II remains elusive. METHODS: We used a mass spectrometry-based, parallel reaction-monitoring assay to quantitate Ang II in plasma, urine, and kidney homogenate of kidney-specific conditional megalin knockout (MegKO) and control (Ctl) mice. We also evaluated the pathophysiological changes in both mouse genotypes under the basal condition and under the condition of increased glomerular filtration of AGT induced by administration of recombinant mouse AGT (rec-mAGT). RESULTS: Under the basal condition, plasma and kidney Ang II levels were comparable in the two mouse groups. Ang II was detected abundantly in fresh spot urine in conditional MegKO mice. Megalin was also found to mediate the uptake of intravenously administered fluorescent Ang II by PTECs. Administration of rec-mAGT increased kidney Ang II, exerted renal extracellular signal-regulated kinase 1/2â(ERK1/2) signaling, activated proximal tubular Na + -H + exchanger 3 (NHE3), and decreased urinary Na + excretion in Ctl mice, whereas these changes were suppressed but urinary Ang II was increased in conditional MegKO mice. CONCLUSION: Increased glomerular filtration of AGT is likely to augment Ang II production in the proximal tubular lumen. Thus, megalin-dependent Ang II uptake should be involved in the ERK1/2 signaling that activates proximal tubular NHE3 in vivo , thereby causing Na + retention.
Assuntos
Angiotensina II , Angiotensinogênio , Animais , Camundongos , Angiotensina II/farmacologia , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Túbulos Renais Proximais , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Sistema de Sinalização das MAP Quinases , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Sódio/metabolismo , Trocador 3 de Sódio-Hidrogênio/metabolismoRESUMO
Background and purpose: Hypertension (HTN) is a multifactorial chronic disease that poses a significant global health burden and is associated with increased mortality rates. It often coexists with other conditions, such as cardiovascular, liver, and renal diseases, and has a strong association with diabetes mellitus. Insulin resistance and endothelial dysfunction commonly occur in individuals with both HTN and type 2 diabetes mellitus (T2DM). Genetic factors, along with environmental and pathological factors, play a role in the development of HTN. Recent studies have revealed the influence of single nucleotide polymorphisms (SNPs) in various genes on HTN. In this study, we aimed to investigate the genetic polymorphism of angiotensinogen (AGT) T174M (rs4762) and its association with HTN in diabetic patients. Methods: A total of 300 participants were enrolled in this study and divided into three groups: control, hypertensive, and hypertensive diabetic. Blood samples were collected, and predetermined biochemical parameters were assessed. Genotyping of the AGT T174M (rs4762) gene was conducted using Tetra ARMS PCR with specific primers. Results: The study findings revealed a significant association between AGT T174M (rs4762) genotype and HTN in diabetic patients within the Pakistani population. The C/T genotype of AGT T174M (rs4762) was found to be significant in both the hypertensive and hypertensive diabetic participants compared to the control group. This genotype was identified as a risk factor for developing HTN in both the hypertensive and hypertensive diabetic participants. Conclusion: This study demonstrates a significant association between AGT T174M (rs4762) genetic polymorphism and HTN in diabetic patients. The C/T genotype of AGT T174M (rs4762) may serve as a potential marker for identifying individuals at risk of developing HTN, specifically in the hypertensive and hypertensive diabetic populations. Further research is warranted to elucidate the underlying mechanisms and validate these findings in larger cohorts.