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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
SUMMARY OBJECTIVE: The delayed increase in serum creatinine levels poses challenges in the timely diagnosis of acute kidney injury. This study aimed to investigate the relationship between serum angiotensinogen and urinary angiotensinogen levels and the prognosis of renal function in patients diagnosed with acute kidney injury. METHODS: A total of 79 newly diagnosed acute kidney injury patients aged 18 years and older were enrolled. Serum angiotensinogen and urinary angiotensinogen levels were measured at the onset of the disease, as well as on the 15th and 30th days of follow-up. After 3 months, renal function was evaluated by measuring serum creatinine levels. RESULTS: Among the acute kidney injury patients, those in Kidney Disease: Improving Global Outcomes stage 3 exhibited significantly higher urinary angiotensinogen/urine creatinine levels compared with stages 1 and 2 patients at the time of diagnosis (p<0.05). Furthermore, a positive correlation was observed between the urinary angiotensinogen/urine creatinine level at the time of diagnosis and the serum creatinine level at the third month (r=0.408, p=0.048). CONCLUSION: The findings suggest that urinary angiotensinogen levels can serve as an indicator of the severity of acute kidney injury. Monitoring urinary angiotensinogen levels could potentially contribute to the prognosis assessment and management of acute kidney injury patients.
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Background: A large research portfolio indicates that an activated renal renin-angiotensin system or a deficit on melatonin is associated with several cardiovascular pathologies. In this observational clinical study, we hypothesized that alterations in urinary melatonin or angiotensinogen levels may be altered in two common conditions, preeclampsia and gestational diabetes. Our study's primary objective was to assess melatonin and angiotensinogen as novel disease biomarkers detectable and quantifiable in the urine of pregnant women with or without pregnancy complications. Methods: This was a concurrent cohort study of pregnant women with selected obstetric pathologies (gestational diabetes, preeclampsia, hypertension and obesity with hypertension). A group of healthy controls was also included. Urinary 6-sulfatoxymelatonin and angiotensinogen were measured by sensitive and specific ELISAs in first morning void urine samples. The patients were included in the cohort consecutively, and the diagnosis was blinded at the level of urine collection. Urinary 6-sulfatoxymelatonin and angiotensinogen levels were investigated in the patients included in the cohort. Results: Urinary levels of angiotensinogen were significantly higher in the gestational diabetes [angiotensinogen/creatinine ratio median (25th, 75th): 0.11 (0.07, 0.18)] and preeclampsia [0.08 (0.06, 0.18)] groups than in those with healthy pregnancy [0.05(0.04, 0.06]; 6-sulfatoxymelatonin levels were significantly lower in the gestational diabetes [ug/h: median (25th, 75th): 0.12(0.08, 0.17)] and preeclampsia [0.12 (0.09, 0.15)] groups than in those with healthy pregnancy [0.20 (0.15, 0.27]. Neither morning void protein/creatinine ratio nor 24-h urine protein estimate were significantly different between the study groups. Conclusion: These results suggest that urinary angiotensinogen levels may indicate an intrarenal RAS activation while melatonin production appears to be defective in gestational diabetes or hypertension. An angiotensinogen/melatonin ratio is suggested as an early biomarker for identification of gestational diabetes or hypertension. This report provides a basis for the potential use of melatonin for the treatment of preeclampsia. A prospective study in a larger number of patients to determine the operative characteristics of these markers as potential diagnostic tests is justified.
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AIMS: Since angiotensinogen has a pivotal role in the renin-angiotensin-aldosterone system, the analysis of polymorphisms of the angiotensinogen (AGT) gene could help explain its potential involvement in hypertension and diabetic nephropathy (DN) pathogenesis. For that reason, we investigated 1) the association of AGT rs4762 with blood pressure (BP) and kidney function-related traits and 2) the interaction effect of AGT rs4762 with DN on BP and kidney function-related traits in 546 Mexican adults with type 2 diabetes (T2D). METHODS: We enrolled 546 unrelated Mexican patients with T2D (350 cases with DN and 196 controls without DN). AGT rs4762 was genotyped in all participants using TaqMan technology (effect allele: A). BP and kidney function-related traits, including serum urea and creatinine, urinary albumin, urine albumin to urine creatinine ratio (ACR), and glomerular filtration rate, were studied. DN was defined as having a previous diagnosis of T2D and an ACRâ¯≥â¯30â¯mg/g. The association between these parameters was investigated using logistic regression with adjustment for covariates. RESULTS: AGT rs4762 A allele was significantly associated with diastolic blood pressure (Nâ¯=â¯546, ßâ¯=â¯1.243 ± 0.918, p = 0.029). A significant interaction between DN and AGT rs4762 was also observed in relation to diastolic blood pressure (DBP) (Nâ¯=â¯546, ßâ¯=â¯0.930 ± 0.433, p=0.032). A follow-up analysis of simple effects particularly revealed a positive association between AGT rs4762 A allele and DBP only in patients with diabetic nephropathy (Nâ¯=â¯350, ßâ¯=â¯2.837⯱â¯1.267, pâ¯=â¯0.026). CONCLUSION: Our results evidence that, although AGT rs4762 is not associated with DN, the AGT rs4762 A allele is positively associated with DBP in the Mexican population with DN.
Assuntos
Angiotensinogênio , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Adulto , Albuminas , Angiotensinogênio/genética , Pressão Sanguínea , Creatinina , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/genética , Humanos , México , Sistema Renina-Angiotensina/genéticaRESUMO
Alamandine (Ala1-Arg2-Val3-Tyr4-Ile5-His6-Pro7), a heptapeptide hormone of the renin-angiotensin system (RAS), exerts its effects through the Mas-related G-protein coupled receptor of the type D, MrgD, which is expressed in different tissues, including the brain. In the present study, we tested the hypothesis that alamandine could attenuate the depression-like behavior observed in transgenic rats with low brain angiotensinogen, TGR (ASrAOGEN)680. Transgenic rats exhibited a significant increase in the immobility time in forced swim test, a phenotype reversed by intracerebroventricular infusion of alamandine. Pretreatment with D-Pro7-Ang-(1-7), a Mas/MrgD receptor antagonist, prevented the antidepressant-like effect induced by this peptide demonstrating, for the first time, that alamandine through MrgD receptor, can modulate depression-like behavior in TGR (ASrAOGEN)680. This result shows an action of alamandine which strengthens the importance of the counter-regulatory arms of the RAS in fight and treatment of neuropsychiatric diseases.
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Angiotensinogênio/genética , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Proteínas do Tecido Nervoso/fisiologia , Oligopeptídeos/farmacologia , Receptores Acoplados a Proteínas G/fisiologia , Angiotensina I/farmacologia , Angiotensinogênio/metabolismo , Animais , Encéfalo/metabolismo , Injeções Intraventriculares , Masculino , Proteínas do Tecido Nervoso/antagonistas & inibidores , Oligopeptídeos/administração & dosagem , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Pathologies linked to the renin-angiotensin system are frequent, and the drugs used in them are numerous and show great variability in therapeutic effects and adverse reactions. Genetic variants have been detected in the angiotensinogen gene (6), angiotensin-converting enzyme (9), angiotensinconverting enzyme 2 (1), and angiotensin receptor Type 1 (4) among others. However, the large number of studies that have analyzed each of them makes it complex and almost impossible to consider all the existing information. This manuscript aims to review the effects of the different known variants on the expected response of different drugs as a basis for the future development of therapeutic guidelines that seek to implement therapeutic individualization strategies on the renin-angiotensin system.
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Medicina de Precisão/métodos , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/genética , Aminopeptidases/genética , Enzima de Conversão de Angiotensina 2/genética , Angiotensinogênio/genética , Animais , Humanos , Peptidil Dipeptidase A/genética , Receptor Tipo 1 de Angiotensina/genéticaRESUMO
Muscle damage is one of the most important factors that affect muscle fatigue during endurance exercise. Recent evidence suggests that the renin-angiotensin system impacts on skeletal muscle wasting. The aim of this study was to determine association between the AGT Met235Thr, ACE I/D and BDKRB2 -9/+9 polymorphisms with inflammation, myocardial and muscle injury induced by endurance exercise. Eighty-one Brazilian male runners participated in this study and completed the International Marathon of Sao Paulo. Muscle and myocardial damage markers (alanine transaminase, ALT, aspartate transaminase, AST, lactic dehydrogenase, LDH, creatine kinase, CK, Troponin, pro BNP, myoglobin, and CK-MB) and inflammatory mediators (IL-6, IL-8, IL-10, IL12p70, IL1ß, and TNF-α) were determined one day before, immediately after, one day after, and three days after the event. Muscle damage was also determined fifteen days after race and angiotensinogen (AGT) Met235Thr, angiotensin-converting enzyme (ACE) I/D, and Bradykinin B2 receptor (BDKRB2) -9/+9 polymorphisms were determined. Marathon race participation induced an increase in all muscle damage and inflammatory markers evaluated (p < 0.0001). The muscle damage markers, troponin and pro BNP, CK and LDH and inflammatory markers, IL-6, IL-8, IL-1ß and IL-10 were also higher in ACE II genotype immediately after race, compared to DD genotype. The percentage of runners higher responders (>500U/I) to CK levels was higher for II genotypes (69%) compared to DD and ID genotypes (38% and 40%, respectively) immediately after. Troponin, pro BNP and IL-1ß, IL-8 levels were also elevated in AGT MM genotype compared to TT genotype athletes after and/or one day after race. BDKRB2 -9/-9 had pronounced response to LDH, CK, CK-MB and ALT and AST activities, myoglobin, troponin, IL-6, IL-8 levels immediately, one day and/or three days after race. The percentage of runners higher responders (>500U/I) to CK levels was greater for -9-9 and -9+9 genotypes (46 and 48%, respectively) compared to +9+9 genotypes (31%) immediately after. ACE II, AGT MM, and BDKRB2 -9-9 genotypes may increase the susceptibility to inflammation, muscle injury after endurance exercise and could be used to predict the development of clinical conditions associated with muscle damage and myocardial injury.
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Gliomas are the most common primary intrinsic tumor in the brain and are classified as low- or high-grade according to the World Health Organization (WHO). Patients with high-grade gliomas (HGG) who undergo surgical resection with adjuvant therapy have a mean overall survival of 15 months and 100% recurrence. The renin-angiotensin system (RAS), the primary regulator of cardiovascular circulation, exhibits local action and works as a paracrine system. In the context of this local regulation, the expression of RAS peptides and receptors has been detected in different kinds of tumors, including gliomas. The dysregulation of RAS components plays a significant role in the proliferation, angiogenesis, and invasion of these tumors, and therefore in their outcomes. The study and potential application of RAS peptides and receptors as biomarkers in gliomas could bring advantages against the limitations of current tumoral markers and should be considered in the future. The targeting of RAS components by RAS blockers has shown potential of being protective against cancer and improving immunotherapy. In gliomas, RAS blockers have shown a broad spectrum for beneficial effects and are being considered for use in treatment protocols. This review aims to summarize the background behind how RAS plays a role in gliomagenesis and explore the evidence that could lead to their use as biomarkers and treatment adjuvants.
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Angiotensinas/uso terapêutico , Biomarcadores/metabolismo , Neoplasias Encefálicas/terapia , Glioma/terapia , Sistema Renina-Angiotensina/fisiologia , Angiotensinas/química , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Humanos , Fragmentos de Peptídeos/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
AIM: To elucidate the profile of the salivary proteome. METHODS: Unstimulated whole mouth saliva was collected from 30 volunteers [15 proliferative verrucous leukoplakia (PVL) patients and 15 controls] and proteins were submitted for mass spectrometry-based proteomics using the discovery approach, followed by analyses of variance and logistic regression tests. RESULTS: A total of two hundred and eighty-three proteins were confidently identified in saliva. By combining two low abundance proteins from the PVL group, angiotensinogen (AGT) and dipeptidyl peptidase 1 (DPP1), a model for group differentiation was built with a concordance index of 94.2%, identifying both proteins as potential etiologic biomarkers for PVL. CONCLUSION: This study suggests that both AGT and DPP1 may be involved in developmental mechanisms of PVL.
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Uterine natural killer cells are important for uteroplacental development and pregnancy maintenance. Their role in pregnancy disorders, such as preeclampsia, is unknown. We reduced the number of natural killer cells by administering rabbit anti-asialo GM1 antiserum in an established rat preeclamptic model (female human angiotensinogen×male human renin) and evaluated the effects at the end of pregnancy (day 21), compared with preeclamptic control rats receiving normal rabbit serum. In 100% of the antiserum-treated, preeclamptic rats (7/7), we observed highly degenerated vessel cross sections in the mesometrial triangle at the end of pregnancy. This maternal uterine vasculopathy was characterized by a total absence of nucleated/living cells in the vessel wall and perivascularly and prominent presence of fibrosis. Furthermore, there were no endovascular trophoblast cells within the vessel lumen. In the control, normal rabbit serum-treated, preeclamptic rats, only 20% (1/5) of the animals displayed such vasculopathy. We confirmed the results in healthy pregnant wild-type rats: after anti-asialo GM1 treatment, 67% of maternal rats displayed vasculopathy at the end of pregnancy compared with 0% in rabbit serum-treated control rats. This vasculopathy was associated with a significantly lower fetal weight in wild-type rats and deterioration of fetal brain/liver weight ratio in preeclamptic rats. Anti-asialo GM1 application had no influence on maternal hypertension and albuminuria during pregnancy. Our results show a new role of natural killer cells during hypertensive pregnancy in maintaining vascular integrity. In normotensive pregnancy, this integrity seems important for fetal growth.
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Células Matadoras Naturais/citologia , Circulação Placentária/fisiologia , Pré-Eclâmpsia/fisiopatologia , Prenhez , Trofoblastos/citologia , Análise de Variância , Angiotensinogênio/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Feminino , Desenvolvimento Fetal/imunologia , Desenvolvimento Fetal/fisiologia , Idade Gestacional , Interleucina-15/metabolismo , Células Matadoras Naturais/imunologia , Circulação Placentária/imunologia , Pré-Eclâmpsia/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Estatísticas não Paramétricas , Trofoblastos/metabolismoRESUMO
AIM: The renal renin-angiotensin system (RAS) has been implicated in the pathogenesis of diabetic nephropathy. The aim of this study was to investigate sex differences in renal renin-angiotensin system (RAS) and the roles of androgens in diabetes-associated renal injury. METHODS: Renal injury and fibrosis were studied in streptozotocin-induced diabetic rats by albuminuria and by gene expression of collagen I and fibronectin. RAS was investigated by analysing the plasma angiotensinogen (AOGEN) and renin activity (PRA) and their renal gene expression. Also, a group of diabetic rats was treated with the anti-androgen flutamide. RESULTS: Albuminuria was significantly lower in diabetic females than in males (1.2 [0.8-1.5] versus 4.4 [2.2-6.1] mg/24 h, data are median [IQR] values, P < 0.05). Renal AOGEN mRNA levels were increased by diabetes in males (8.1 ± 0.8% in diabetes versus 0.8 ± 0.2% in control, P < 0.001) but not in females (1.0 ± 0.1% in diabetes versus 0.8 ± 0.1% in control, P > 0.05), as were collagen I and fibronectin mRNAs. Furthermore, AOGEN mRNA levels were strongly correlated with albuminuria (Spearman r = 0.64, 95% [CI] 0.36-0.81, P < 0.0001). Diabetes decreased PRA, renal renin mRNA and plasma AOGEN in both females and males. Anti-androgen treatment decreased albuminuria only in diabetic males without affecting the endocrine or renal RAS. CONCLUSIONS: These data indicate that renal but not hepatic AOGEN or renin is positively associated with diabetic albuminuria and contribute to the sex-dependent differences in renal injury. Androgens may contribute to albuminuria in male independently of the RAS.
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Angiotensinogênio/sangue , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/etiologia , Rim/metabolismo , Sistema Renina-Angiotensina , Albuminúria/sangue , Albuminúria/etiologia , Antagonistas de Androgênios/farmacologia , Angiotensinogênio/genética , Animais , Biomarcadores/sangue , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Diabetes Mellitus Experimental/sangue , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Feminino , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrose , Flutamida/farmacologia , Rim/efeitos dos fármacos , Rim/patologia , Masculino , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Renina/sangue , Renina/genética , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/genética , Fatores de Risco , Fatores SexuaisRESUMO
A single or repeated exposure to psychostimulants induces long-lasting neuroadaptative changes. Different neurotransmitter systems are involved in these responses including the neuropeptide angiotensin II. Our study tested the hypothesis that the neuroadaptative changes induced by amphetamine produce alterations in brain RAS components that are involved in the expression of the locomotor sensitization to the psychostimulant drug. Wistar male rats, pretreated with amphetamine were used 7 or 21 days later to study AT1 receptors by immunohistochemistry and western blot and also angiotensinogen mRNA and protein in caudate putamen and nucleus accumbens. A second group of animals was used to explore the possible role of Ang II AT1 receptors in the expression of behavioral sensitization. In these animals treated in the same way, bearing intra-cerebral cannula, the locomotor activity was tested 21 days later, after an amphetamine challenge injection and the animals received an AT1 blocker, losartan, or saline 5min before the amphetamine challenge. An increase of AT1 receptor density induced by amphetamine was found in both studied areas and a decrease in angiotensinogen mRNA and protein only in CPu at 21 days after treatment; meanwhile, no changes were established in NAcc. Finally, the increased locomotor activity induced by amphetamine challenge was blunted by losartan administration in CPu. No differences were detected in the behavioral sensitization when the AT1 blocker was injected in NAcc. Our results support the hypothesis of a key role of brain RAS in the neuroadaptative changes induced by amphetamine.
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Anfetamina/farmacologia , Encéfalo/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Angiotensinogênio/metabolismo , Animais , Encéfalo/fisiologia , Losartan/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/fisiologiaRESUMO
Transgenic rats with low brain angiotensinogen, TGR(ASrAOGEN)680, expressing an antisense RNA against angiotensinogen in glial cells, provide an interesting tool to evaluate the role of brain angiotensins in different behavior responses. The present study was conducted to test the hypothesis that angiotensin-(1-7) [Ang-(1-7)] and serotonin can modulate anxiety and depression-related behaviors in the TGR(ASrAOGEN)680 rats. Therefore, the effect of acute intracerebroventricular administration of Ang-(1-7) and intraperitoneal administration of the selective serotonin reuptake inhibitor fluoxetine was evaluated in TGR(ASrAOGEN) rats subjected to the elevated plus maze (EPM) and forced swimming (FST) tests. Transgenic rats spent a lower percentage of time in the open arms of EPM and showed a significant increase in the immobility time in FST, indicating that a low angiotensinogen level in the brain leads to anxiety-like behavior accompanied by a depression-like state. Administration of both, Ang-(1-7) and fluoxetine reversed the anxiety- and depressive-like behavior of transgenic rats with low brain angiotensinogen, suggesting that this may be, at least in part, related to a decreased level of Ang-(1-7) and serotonin in the brain of these animals.
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Angiotensina I/uso terapêutico , Angiotensinogênio/metabolismo , Ansiedade/tratamento farmacológico , Encéfalo/metabolismo , Depressão/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Psicotrópicos/uso terapêutico , Angiotensinogênio/genética , Animais , Ansiedade/genética , Encéfalo/efeitos dos fármacos , Depressão/genética , Modelos Animais de Doenças , Vias de Administração de Medicamentos , Fluoxetina/uso terapêutico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , RNA Antissenso/genética , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Natação/psicologiaRESUMO
Renin-angiotensin and kallikrein-kinin systems are interconnected, regulating blood pressure homeostasis. We have demonstrated the interactions among polymorphisms of the angiotensinogen (AGT) and endothelial nitric oxide synthase (NOS3) genes and conventional risk factors affecting the hypertension occurrence. Individuals were recruited (n=192) and classified into hypertensive (HG; n=140) and normotensive (NG; n=52) groups. The genotypic distribution of the Met235Thr (AGT) and Glu298Asp (NOS3) polymorphisms demonstrated that both are independent risk factors of hypertension (p=0.02 and p=0.008, respectively). The concomitant presence of these polymorphisms in the HG group was significantly different (p=0.001) from the NG. Both gene polymorphisms presented an additive effect for the unfavourable alleles T and A, respectively, and 95% of the double mutant homozygotes were classified into the HG. Specific interactions among certain conventional factors and the presence of at least one unfavourable allele presented significant odds towards hypertension. Blood pressure homeostasis was affected by genetic polymorphisms conditioned by the T and A alleles of the AGT and NOS3 genes, respectively, which acted independently. However, their interaction with smoking, sedentariness, age and total cholesterol may have increased the predisposition to hypertension, which may explain most of the hypertension cases.
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Angiotensinogênio/genética , Predisposição Genética para Doença , Hipertensão/enzimologia , Hipertensão/genética , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Frequência do Gene , Humanos , Razão de Chances , Análise de Regressão , Fatores de RiscoRESUMO
FUNDAMENTO: O polimorfismo AGT*M235T tem sido associado a elevados níveis séricos de angiotensinogênio (AGT), hipertensão arterial sistêmica e disfunção cardíaca (DC). OBJETIVO: Testar a hipótese de haver associação entre polimorfismo AGT*M235T e o risco de desenvolver disfunção cardíaca (insuficiência cardíaca ou disfunção sistólica ventricular esquerda assintomática) pós-síndrome coronariana aguda (SCA), durante o período de internação hospitalar. MÉTODOS: Foram estudados 363 pacientes (idade média 62 ± 12 anos), sendo 233 (64 por cento) homens e 130 (36 por cento) mulheres, todos da mesma coorte, internados por SCA. Compararam-se dados clínicos e genéticos dos 117 (32,2 por cento) que evoluíram com disfunção cardíaca (grupo caso) com os dos 246 (67,8 por cento), que não desenvolveram tal condição (grupo controle). O polimorfismo AGT*M235T foi determinado por análise de sequenciamento e estava em equilíbrio de Hardy-Weinberg. RESULTADOS: Houve diferença significativa na distribuição dos genótipos nas mulheres, com predomínio do genótipo *235MM no grupo controle (p = 0,001) e do alelo *235T no grupo caso. Em ambos os sexos, nos modelos de regressão logística, o diagnóstico de infarto de parede anterior na admissão foi fator de incremento no risco de DC, enquanto angina instável na admissão, ausência do alelo *235T, glicemia < 100 mg/dl, uso de betabloqueador, creatinina sérica < 1,5 mg/dl, faixa de frequência cardíaca > 60 e < 90 bpm e tabagismo atual foram fatores de redução do risco de DC. CONCLUSÃO: Este estudo sugere que a ausência do alelo *235T do AGT contribui para a redução do risco de disfunção cardíaca pós-síndrome coronariana aguda.
BACKGROUND: AGT*M235T polymorphism has been associated with high serum angiotensinogen (AGT) levels, systemic hypertension and cardiac dysfunction (CD). OBJECTIVE: To test the hypothesis of AGT*M235T polymorphism being associated with the risk of developing cardiac dysfunction (heart failure or asymptomatic left ventricular systolic dysfunction) after acute coronary syndrome (ACS) during hospitalization. METHODS: A total of 363 patients (mean age of 62 ± 12 years), of whom 233 (64 percent) were men and 130 (36 percent) were women, all from the same cohort and hospitalized for ACS, were studied. Clinical and genetic data from the 117 (32.2 percent) patients who developed cardiac dysfunction (case group) were compared to those of the 246 (67.8 percent) who did not develop this condition (control group). The AGT*M235T polymorphism was determined by sequence analysis and was in Hardy-Weinberg equilibrium. RESULTS: There was a significant difference in the distribution of genotypes among women, with a predominance of the *235MM genotype in the control group (p = 0.001) and of the *235T allele in the case group. In the logistic regression models, the diagnosis of anterior wall myocardial infarction at admission was related to an increased risk of CD in both genders, whereas unstable angina at admission.; absence of the *235T allele; blood glucose <100 mg/dl; use of betablocker; serum creatinine level < 1.5 mg/dl;heart rate range > 60 and < 90 bpm; and current cigarette smoking were related to a lower risk of CD. CONCLUSION: This study suggests that the absence of the AGT *235T allele contributes to a reduced risk of cardiac dysfunction after acute coronary syndrome.