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2.
Arch Endocrinol Metab ; 63(4): 402-410, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365628

RESUMO

OBJECTIVE: The increased prevalence of obesity and associated comorbidities, such as cardiovascular and metabolic diseases, has gained attention worldwide, and the renin-angiotensin system (RAS) has been pointed out as a possible link. Thus, the present study aimed to verify the possible association between angiotensinogen (AGT) or angiotensin-converting enzyme (ACE) polymorphisms with overweight and obesity in adults. SUBJECTS AND METHODS: The present investigation was a population-based cross-sectional study including 1,567 individuals from an urban area in Brazil. Anthropometric, clinical and biochemical parameters were evaluated, and all individuals were genotyped for the ACE I/D and AGT M/T polymorphisms. RESULTS: The prevalence of overweight was higher among men, whereas obesity was more prevalent among women. However, the frequency of ACE or AGT polymorphisms was similar among body mass index (BMI) categories. In addition, the mean age-adjusted BMI averages did not change significantly for ACE or AGT polymorphisms, regardless of sex or BMI category. The age-adjusted BMI average for the combination of ACE and AGT genotypes evidenced no significant differences regardless of sex or BMI categories. Results were similar when BMI was replaced by waist circumference (WC). CONCLUSIONS: We were not able to find any associations between BMI and WC (overweight/obesity) and ACE and AGT polymorphisms, indicating that the RAS system might not be involved in overweight and obesity, at least based on genetic backgrounds. However, further studies must measure RAS components to elucidate this question.


Assuntos
Obesidade/genética , Sobrepeso/genética , Polimorfismo Genético/genética , Sistema Renina-Angiotensina/genética , Adulto , Distribuição por Idade , Angiotensinogênio/genética , Pressão Sanguínea , Índice de Massa Corporal , Brasil , Estudos Transversais , Feminino , Frequência do Gene/genética , Humanos , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/genética , Distribuição por Sexo , Circunferência da Cintura
3.
Ther Adv Cardiovasc Dis ; 13: 1753944719868134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31401939

RESUMO

Since the launch of the first orally available angiotensin II (AngII) type 1 receptor (AT1R) blocker (ARB) losartan (Cozaar) in the late 1990s, the class of ARBs (or 'sartans', short for Angiotensin-RecepTor-ANtagonistS) quickly expanded to include candesartan, eprosartan, irbesartan, valsartan, telmisartan, and olmesartan. All ARBs have high affinity for the AT1 receptor, expressed in various tissues, including smooth muscle cells, heart, kidney, and brain. Since activation of AT1R, the target of these drugs, leads, among other effects, to vascular smooth muscle cell growth, proliferation and contraction, activation of fibroblasts, cardiac hypertrophy, aldosterone secretion from the adrenal cortex, thirst-fluid intake (hypervolemia), etc., the ARBs are nowadays one of the most useful cardiovascular drug classes used in clinical practice. However, significant differences in their pharmacological and clinical properties exist that may favor use of particular agents over others within the class, and, in fact, two of these drugs, candesartan and valsartan, continuously appear to distinguish themselves from the rest of the 'pack' in recent clinical trials. The reason(s) for the potential superiority of these two agents within the ARB class are currently unclear but under intense investigation. The present short review gives an overview of the clinical properties of the ARBs currently approved by the United States Food and Drug Administration, with a particular focus on candesartan and valsartan and the areas where these two drugs seem to have a therapeutic edge. In the second part of our review, we outline recent data from our laboratory (mainly) on the molecular effects of the ARB drugs on aldosterone production and on circulating aldosterone levels, which may underlie (at least in part) the apparent clinical superiority of candesartan (and valsartan) over most other ARBs currently in clinical use.


Assuntos
Aldosterona/sangue , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Benzimidazóis/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Tetrazóis/uso terapêutico , Valsartana/uso terapêutico , Animais , Biomarcadores/sangue , Regulação para Baixo , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Recuperação de Função Fisiológica , Resultado do Tratamento
4.
Rev Med Chil ; 147(4): 490-498, 2019 Apr.
Artigo em Espanhol | MEDLINE | ID: mdl-31344212

RESUMO

The renin-angiotensin-aldosterone system modulates volume, sodium and potassium homeostasis. In the setting of a high sodium diet, up to 30% of patients with hypertension have a low or suppressed renin and increased volume. This phenotype of low renin hypertension (LRH) is multifactorial and includes infrequent inherited genetic syndromes, milder phenotypes of classic diseases and environmental exposures. All these conditions have in common a higher cardiovascular risk mediated by the over activation of the mineralocorticoid receptor (MR), present not only in the kidney, but also in vasculature, myocardium and adipocytes. Consequently, the aim of LRH treatment goes beyond the control of blood pressure and requires antagonizing MR with specific pharmacologic agents, pursuing normalization of renin as a clinical objective. Due to the unusual evaluation of renin status by non-endocrinologists and lack of disease awareness, only a minority of hypertensive patients receive this pathophysiologically-driven treatment that should reduce cardiovascular outcomes.


Assuntos
Hipertensão/metabolismo , Hipertensão/terapia , Sistema Renina-Angiotensina/fisiologia , Aldosterona/metabolismo , Gerenciamento Clínico , Humanos , Hipertensão/fisiopatologia , Receptores de Mineralocorticoides/metabolismo , Renina/metabolismo
6.
Toxicol Lett ; 313: 30-41, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31181250

RESUMO

The hedgehog (HH) signaling pathway plays an important role in lung development, but its significance in silicosis is unclear. We showed that in human coal pneumoconiosis autopsy specimens, Sonic Hedgehog (SHH) and the Glioma-associated oncogene homolog transcription factors family (GLI) 1 proteins were up-regulated, whereas Patch-1 (PTC) was down-regulated. The protein levels of SHH, smoothened (SMO), GLI1, GLI2, α-smooth muscle actin (α-SMA) and collagen type Ⅰ (Col Ⅰ) were also elevated gradually in the bronchoalveolar lavage fluid (BALF) of different stages of coal pneumoconiosis patients, dynamic silica-inhalation rat lung tissue and MRC-5 cells induced by Ang II at different time points, whereas the PTC and GLI3 levels were diminished gradually. Ac-SDKP, an active peptide of renin-angiotensin system (RAS), is an anti-fibrotic tetrapeptide. Targeting RAS axis also has anti-silicotic fibrosis effects. However, their roles on the HH pathway are still unknown. Here, we reported that Ac-SDKP + Captopril, Ac-SDKP, Captopril, or Ang (1-7) could alleviate silicotic fibrosis and collagen deposition, as well as improve the lung functions of silicotic rat. These treatments decreased the expression of SHH, SMO, GLI1, GLI2, α-SMA, and Col Ⅰ and increased the expression of PTC and GLI3 on both the silicotic rat lung tissue and MRC-5 cells induced by Ang II. We also reported that Ang II may promote myofibroblast differentiation via the GLI1 transcription factor and independently of the SMO receptor.


Assuntos
Angiotensina II/farmacologia , Angiotensina I/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/farmacologia , Diferenciação Celular/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/farmacologia , Fibrose Pulmonar/prevenção & controle , Sistema Renina-Angiotensina/efeitos dos fármacos , Silicose/prevenção & controle , Adulto , Idoso , Animais , Antracose/metabolismo , Antracose/patologia , Linhagem Celular , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Proteínas Hedgehog/metabolismo , Humanos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Silicose/metabolismo , Silicose/patologia
7.
Biochemistry (Mosc) ; 84(2): 181-186, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31216977

RESUMO

Preeclampsia (PE) is a severe complication that develops in 10% pregnant women. It is the leading cause of maternal and perinatal morbidity and mortality worldwide. The goal of this study was to reveal the frequency of polymorphisms in the angiotensin-converting enzyme gene (ACE I/D) and type 1 angiotensin II receptor gene (AGTR1 A1166C) in pregnant women with severe early- and late-onset PE. A retrospective case-control study of 55 pregnant women with PE (main group) and 30 patients with uncomplicated pregnancy (control group) was conducted. In the main group, we considered two subgroups - early-onset PE (20 patients) and late-onset PE (36 patients). The I/D polymorphism of the ACE gene is associated with the risk of developing PE. The presence of the D allele increases the risk of severe PE. In case of DD genotype, the probability of early-onset PE is 5 times higher than that of the late-onset PE. The analyzed data confirm the involvement of renin-angiotensin system in the PE development. We conclude that the ACE gene polymorphism is a genetic predictor of the early-onset severe PE. Studying the polymorphic loci of the ACE gene makes it possible to use them for the individualized prognosis of the development and course of PE in patients.


Assuntos
Polimorfismo de Nucleotídeo Único/genética , Pré-Eclâmpsia/genética , Sistema Renina-Angiotensina/genética , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Gravidez , Estudos Retrospectivos
10.
Clin J Am Soc Nephrol ; 14(6): 798-809, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31110051

RESUMO

BACKGROUND AND OBJECTIVES: Oral sodium zirconium cyclosilicate (formerly ZS-9) binds and removes potassium via the gastrointestinal tract. Sodium zirconium cyclosilicate-associated restoration and maintenance of normokalemia and adverse events were evaluated in a two-part, open label, phase 3 trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the correction phase, adult outpatients with plasma potassium ≥5.1 mmol/L (i-STAT Point-of-Care) received sodium zirconium cyclosilicate 10 g three times daily for 24-72 hours until normokalemic (potassium =3.5-5.0 mmol/L). Qualifying participants entered the ≤12-month maintenance phase and received sodium zirconium cyclosilicate 5 g once daily titrated to maintain normokalemia without dietary or medication restrictions. Prespecified primary end points were restoration of normal serum potassium values (3.5-5.0 mmol/L) during the correction phase and maintenance of serum potassium ≤5.1 mmol/L during the maintenance phase. Adverse events were assessed throughout. RESULTS: Of 751 participants, 746 (99%) achieved normokalemia during the correction phase (mean serum potassium =4.8 mmol/L; 95% confidence interval, 4.7 to 4.8) and entered the maintenance phase; 466 (63%) participants completed the 12-month trial. Participants were predominantly white, men, and age ≥65 years old; 74% had an eGFR<60 ml/min per 1.73 m2, and 65% used renin-angiotensin-aldosterone system inhibitors. Mean time on sodium zirconium cyclosilicate was 286 days. Mean daily sodium zirconium cyclosilicate dose was 7.2 g (SD=2.6). Over months 3-12, mean serum potassium was 4.7 mmol/L (95% confidence interval, 4.6 to 4.7); mean serum potassium values ≤5.1 and ≤5.5 mmol/L were achieved by 88% and 99% of participants, respectively. Of 483 renin-angiotensin-aldosterone system inhibitor users at baseline, 87% continued or had their dose increased; 11% discontinued. Among 263 renin-angiotensin-aldosterone system inhibitor-naïve participants, 14% initiated renin-angiotensin-aldosterone system inhibitor therapy. Overall, 489 (66%) participants experienced adverse events during the maintenance phase, and 22% experienced a serious adverse event. Of eight (1%) deaths, none were considered related to sodium zirconium cyclosilicate. Nine (1%) and 34 (5%) participants experienced serum potassium <3.0 and 3.0-3.4 mmol/L, respectively. CONCLUSIONS: After achieving normokalemia, individualized once daily sodium zirconium cyclosilicate was associated with maintenance of normokalemia without substantial renin-angiotensin-aldosterone system inhibitor changes for ≤12 months.


Assuntos
Hiperpotassemia/sangue , Adulto , Idoso , Humanos , Masculino , Potássio/sangue , Sistema Renina-Angiotensina/efeitos dos fármacos , Silicatos
12.
Eur J Endocrinol ; 181(1): 39-44, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31075757

RESUMO

Background: In patients suffering from primary adrenal insufficiency (AI) mortality is increased despite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, mainly due to an increased cardiovascular risk. Since activation of the renin-angiotensin-aldosterone system (RAAS) plays an important role in the modulation of cardiovascular risk factors, we performed in-depth characterization of the RAAS activity. Methods: Eight patients with primary AI (female = 5; age: 56 ± 21 years; BMI: 22.8 ± 2 kg/m2; mean blood pressure: 140/83 mmHg; hydrocortisone dose: 21.9 ± 5 mg/day; fludrocortisone dose: 0.061 ± 0.03 mg/day) and eight matched healthy volunteers (female = 5; age: 52 ± 21 years; BMI: 25.2 ± 4 kg/m2; mean blood pressure:135/84 mmHg) were included in a cross-sectional case-control study. Angiotensin metabolite profiles (RAS-fingerprints) were performed by liquid chromatography mass spectrometry. Results: In patients suffering from primary AI, RAAS activity was highly increased with elevated concentrations of renin concentration (P = 0.027), angiotensin (Ang) I (P = 0.022), Ang II (P = 0.032), Ang 1-7 and Ang 1-5. As expected, aldosterone was not detectable in the majority of AI patients, resulting in a profoundly suppressed aldosterone-to-AngII ratio (AA2 ratio, P = 0.003) compared to controls. PRA-S, the angiotensin-based marker for plasma renin activity, correlated with plasma renin activity (r = 0.983; P < 0.01) and plasma renin concentration (r = 0.985; P < 0.001) and was significantly increased in AI patients. Conclusions: AI is associated with a unique RAAS profile characterized by the absence of aldosterone despite strongly elevated levels of angiotensin metabolites, including the potent vasoconstrictor AngII. Despite state-of-the-art hormone replacement therapy, the RAAS remains hyperactivated. The contribution of Ang II in cardiovascular diseases in AI patients as well as a potential role for providing useful complementary information at diagnosis and follow up of AI should be investigated in future trials.


Assuntos
Doença de Addison/fisiopatologia , Aldosterona/fisiologia , Sistema Renina-Angiotensina/fisiologia , Doença de Addison/complicações , Hormônio Adrenocorticotrópico/sangue , Adulto , Idoso , Aldosterona/sangue , Angiotensina II/sangue , Angiotensinas/sangue , Pressão Sanguínea , Índice de Massa Corporal , Doenças Cardiovasculares/etiologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Renina/sangue , Fatores de Risco
13.
Rev Med Chil ; 147(2): 173-180, 2019 Feb.
Artigo em Espanhol | MEDLINE | ID: mdl-31095165

RESUMO

BACKGROUND: To reduce the progression of chronic kidney disease (CKD) and cardiovascular risk, the guidelines recommend the blockade of the renin-angiotensin-aldosterone system (RAAS) in patients with proteinuria. AIM: To assess the frequency of enalapril or losartan use in diabetics or hypertensive patients with stage 3 CKD. MATERIAL AND METHODS: Review of clinical records of patients with CKD in an urban primary care clinic. RESULTS: We identified 408 subjects aged 40 to 98 years (66% women) with stage 3 CKD. Sixty six percent had only hypertension and 34% were diabetic with or without hypertension. Seventy four percent received RAAS blockers (52% used enalapril, 45% losartan and 2% both medications). RAAS blockers were used in 70% of hypertensive and 78% of diabetic patients. The prescription in hypertensive diabetics with microalbuminuria was lower than in those without microalbuminuria (72% vs 87%, p < 0.05), but the opposite occurred in pure hypertensive patients with and without microalbuminuria (88% vs 69%, p < 0.05). There were no significant differences in blood pressure levels, microalbuminuria or serum potassium levels between RAAS blocker users and non-users. No differences were observed either between enalapril and losartan users. CONCLUSIONS: The adherence to clinical guidelines is insufficient and users of the recommended drugs did not achieve the expected goals.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Enalapril/uso terapêutico , Losartan/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminúria/urina , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/normas , Creatinina/sangue , Diabetes Mellitus/tratamento farmacológico , Progressão da Doença , Quimioterapia Combinada , Enalapril/administração & dosagem , Enalapril/normas , Feminino , Humanos , Hipertensão/tratamento farmacológico , Losartan/administração & dosagem , Losartan/normas , Masculino , Pessoa de Meia-Idade , Proteinúria/urina , Sistema Renina-Angiotensina , Cooperação e Adesão ao Tratamento/psicologia
14.
Ther Adv Cardiovasc Dis ; 13: 1753944719851950, 2019 Jan-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31144599

RESUMO

Women are at increased risk for developing depression and cardiovascular disease (CVD) across the lifespan and their comorbidity is associated with adverse outcomes that contribute significantly to rates of morbidity and mortality in women worldwide. Immune-system activity has been implicated in the etiology of both depression and CVD, but it is unclear how inflammation contributes to sex differences in this comorbidity. This narrative review provides an updated synthesis of research examining the association of inflammation with depression and CVD, and their comorbidity in women. Recent research provides evidence of pro-inflammatory states and sex differences associated with alterations in the hypothalamic-pituitary-adrenal axis, the renin-angiotensin-aldosterone system and the serotonin/kynurenine pathway, that likely contribute to the development of depression and CVD. Changes to inflammatory cytokines in relation to reproductive periods of hormonal fluctuation (i.e. the menstrual cycle, perinatal period and menopause) are highlighted and provide a greater understanding of the unique vulnerability women experience in developing both depressed mood and adverse cardiovascular events. Inflammatory biomarkers hold substantial promise when combined with a patient's reproductive and mental health history to aid in the prediction, identification and treatment of the women most at risk for CVD and depression. However, more research is needed to improve our understanding of the mechanisms underlying inflammation in relation to their comorbidity, and how these findings can be translated to improve women's health.


Assuntos
Doenças Cardiovasculares/imunologia , Depressão/imunologia , Sistema Imunitário/imunologia , Inflamação/imunologia , Reprodução/imunologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Depressão/metabolismo , Depressão/fisiopatologia , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Imunitário/metabolismo , Sistema Imunitário/fisiopatologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Cinurenina/imunologia , Cinurenina/metabolismo , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Sistema Renina-Angiotensina/imunologia , Serotonina/imunologia , Serotonina/metabolismo , Transdução de Sinais
15.
Oxid Med Cell Longev ; 2019: 4546975, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049135

RESUMO

Alcoholic cardiomyopathy (ACM) caused by alcohol consumption manifests mainly as by maladaptive myocardial function, which eventually leads to heart failure and causes serious public health problems. The (pro)renin receptor (PRR) is an important member of the local tissue renin-angiotensin system and plays a vital role in many cardiovascular diseases. However, the mechanism responsible for the effects of PRR on ACM remains unclear. The purpose of this study was to determine the role of PRR in myocardial fibrosis and the deterioration of cardiac function in alcoholic cardiomyopathy. Wistar rats were fed a liquid diet containing 9% v/v alcohol to establish an alcoholic cardiomyopathy model. Eight weeks later, rats were injected with 1 × 109v.g./100 µl of recombinant adenovirus containing EGFP (scramble-shRNA), PRR, and PRR-shRNA via the tail vein. Cardiac function was assessed by echocardiography. Cardiac histopathology was measured by Masson's trichrome staining, immunohistochemical staining, and dihydroethidium staining. In addition, cardiac fibroblasts (CFs) were cultured to evaluate the effects of alcohol stimulation on the production of the extracellular matrix and their underlying mechanisms. Our results indicated that overexpression of PRR in rats with alcoholic cardiomyopathy exacerbates myocardial oxidative stress and myocardial fibrosis. Silencing of PRR expression with short hairpin RNA (shRNA) technology reversed the myocardial damage mediated by PRR. Additionally, PRR activated phosphorylation of ERK1/2 and increased NOX4-derived reactive oxygen species and collagen expression in CFs with alcohol stimulation. Administration of the ERK kinase inhibitor (PD98059) significantly reduced NOX4 protein expression and collagen production, which indicated that PRR increases collagen production primarily through the PRR-ERK1/2-NOX4 pathway in CFs. In conclusion, our study demonstrated that PRR induces myocardial fibrosis and deteriorates cardiac function through ROS from the PRR-ERK1/2-NOX4 pathway during ACM development.


Assuntos
Cardiomiopatia Alcoólica/metabolismo , Sistema de Sinalização das MAP Quinases , Miocárdio/metabolismo , NADPH Oxidase 4/metabolismo , Receptores de Superfície Celular/metabolismo , Sistema Renina-Angiotensina , Remodelação Ventricular , Animais , Cardiomiopatia Alcoólica/patologia , Modelos Animais de Doenças , Fibrose , Masculino , Miocárdio/patologia , Ratos , Ratos Wistar
16.
Mol Med Rep ; 19(6): 4553-4560, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059021

RESUMO

Cardiac fibrosis secondary to long­term hypertension is known to promote cardiac dysfunction; however, few therapeutic agents are available for the treatment of this condition in clinical practice. The heptapeptide alamandine (Ala) has recently been identified as a component of the renin­angiotensin system (RAS), which exerts a protective effect against cardiac hypertrophy; however, it is unknown whether Ala may also be useful for the treatment of cardiac fibrosis. In the present study, the potential therapeutic effects of Ala on long­term hypertension­induced cardiac fibrosis were investigated in an aged, spontaneous hypertensive rat model. Weekly blood pressure (BP) measurements revealed that daily Ala treatment significantly decreased the systolic, diastolic and mean arterial BP compared with the control. Of note, the observed reduction in BP in Ala­treated animals markedly differed to that observed in rats treated with hydralazine (Hyd). Echocardiography further demonstrated that Ala treatment decreased the ratio of left ventricle mass to body weight, and alleviated structural and functional parameters associated with cardiac fibrosis, including left ventricular volume, ejection fraction and fractional shortening compared with the control and Hyd­treated groups. Furthermore, Ala deceased the density of cardiac fibrosis, as assessed by Masson and Sirius red staining; reduced expression of fibrotic proteins, including connective tissue growth factor, collagen I (COL1A1) and matrix metalloproteinase 9, was also observed. In addition, Ala treatment further decreased the expression of angiotensin II­induced fibrotic markers at the mRNA and protein levels in cultured cardiac fibroblasts; Ala­mediated inhibition of COL1A1 expression and Akt phosphorylation was inhibited via the Mas­related G protein receptor antagonist, PD123319. Collectively, the findings of the present study suggest that Ala is an effective anti­hypertensive peptide that can attenuate cardiac dysfunction and fibrosis induced by chronic hypertension, independent of BP.


Assuntos
Cardiomegalia/tratamento farmacológico , Fibrose/tratamento farmacológico , Hipertensão/tratamento farmacológico , Oligopeptídeos/farmacologia , Angiotensina II/genética , Angiotensina II/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea , Cardiomegalia/etiologia , Colágeno Tipo I/antagonistas & inibidores , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Fibrose/etiologia , Ventrículos do Coração/metabolismo , Hipertensão/complicações , Imidazóis/farmacologia , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Sistema Renina-Angiotensina
17.
Minerva Med ; 110(5): 439-449, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31142099

RESUMO

Immunoglobulin A nephropathy (IgAN) is the world's commonest primary glomerular disease with variable clinical presentation and progression rates that are dependent on clinical-pathologic phenotype and duration of follow-up. Overall 4-40% of patients progress to end-stage kidney disease (ESKD) by 10 years. Treatment decisions remain a challenge due to these variations. The ultimate goal of management is to prevent progression to ESKD and of vital importance is the potential reversible early detection of active glomerular inflammation prior to scarring. IgAN is globally, is the most common biopsy proven glomerulonephritis and a leading cause of ESKD. The Oxford pathological classification was devised by a collaborative pathology and nephrology network to provide an evidence-based scoring system with reproducible independent pathology features of predictive value. Clinical variables that alter prognosis include male sex, increasing age, increased body weight, smoking, Pacific Asian ethnicity, hypertension, proteinuria, and complement deficiency. Excellent conservative therapy is the cornerstone of therapy with tight blood control, renin-angiotensin system inhibition, and statin therapy. The role of immunosuppressive therapy including corticosteroids in IgAN remains open with ongoing clinical trials of low dose oral corticosteroids and enteric coated budesonide. Complement activation contributes to the pathogenic process of IgAN with evidence from genetic, serological, histological and in-vitro studies. This knowledge has translated to clinical trials of investigational agents directly targeting the alternative pathway.


Assuntos
Glomerulonefrite por IGA , Anti-Inflamatórios/uso terapêutico , Via Alternativa do Complemento , Tratamento Conservador , Gerenciamento Clínico , Progressão da Doença , Feminino , Previsões , Predisposição Genética para Doença , Glomerulonefrite por IGA/epidemiologia , Glomerulonefrite por IGA/etiologia , Glomerulonefrite por IGA/terapia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertensão Renal/tratamento farmacológico , Hipertensão Renal/etiologia , Imunossupressores/uso terapêutico , Rim/patologia , Rim/fisiopatologia , Falência Renal Crônica/etiologia , Falência Renal Crônica/prevenção & controle , Masculino , Prognóstico , Sistema Renina-Angiotensina/efeitos dos fármacos , Fatores de Risco
18.
Int J Mol Sci ; 20(9)2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31035359

RESUMO

Cardiovascular diseases (CVDs) still represent the greatest burden on healthcare systems worldwide. Despite the enormous efforts over the last twenty years to limit the spread of cardiovascular risk factors, their prevalence is growing and control is still suboptimal. Therefore, the availability of new therapeutic tools that may interfere with different pathophysiological pathways to slow the establishment of clinical CVDs is important. Previously, the inhibition of neurohormonal systems, namely the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, has proven to be useful in the treatment of many CVDs. Attempts have recently been made to target an additional hormonal system, that of the natriuretic peptides (NPs), which, when dysregulated, can also play a role in the development CVDs. Indeed, a new class of drug, the angiotensin receptor-neprilysin inhibitors (ARNi), has the ability to counteract the effects of angiotensin II as well as to increase the activity of NPs. ARNi have already been proven to be effective in the treatment of heart failure with reduced ejection fraction. New evidence has suggested that, in the next years, the field of ARNi application will widen to include other CVDs, such as heart failure, with preserved ejection fraction and hypertension.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Hipertensão/tratamento farmacológico , Neprilisina/antagonistas & inibidores
19.
Cardiovasc Diabetol ; 18(1): 46, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953516

RESUMO

BACKGROUND: SGLT2-inhibitors are potent antihyperglycemic drugs for patients with type 2 diabetes and have been shown to reduce body weight. However, it is unclear which body compartments are reduced and to what extent. METHODS: In this longitudinal observational study, we analyzed the body composition of 27 outpatients with type 2 diabetes mellitus during the first week and up to 6 months after initiation of treatment with SGLT2-inhibitors (n = 18 empagliflozin, n = 9 dapagliflozin) using bioimpedance spectroscopy (BCM, Fresenius). Fluid status of hypertensive patients taking medication with hydrochlorothiazide (n = 14) and healthy persons (n = 16) were analyzed for comparison. RESULTS: At 6 months, HbA1c decreased by 0.8% (IQR 2.3; 0.4), body weight and BMI by 2.6 kg (1.5; 9.3) and 0.9 kg/m2 (0.4; 3.3), respectively. Bioimpedance spectroscopy revealed significant decrease in adipose tissue mass and fat tissue index while lean tissue parameters remained stable. Overhydration (OH) and extracellular water (ECW) decreased by - 0.5 L/1.73 m2 (- 0.1; - 0.9) and - 0.4 L/1.73 m2 (- 0.1; - 0.8) at day 3, respectively, and returned to the initial value after 3 and 6 months. Plasma renin activity increased by 2.1-fold (0.5; 3.6) at 1 month and returned to the initial level at month 3 and 6. Fluid status of patients with SGLT2 inhibitors after 6 months showed no difference from that of hypertensive patients taking hydrochlorothiazide or healthy persons. CONCLUSIONS: Body weight reduction under the treatment with SGLT2-inhibitors is caused by reduction of adipose tissue mass and transient loss of extracellular fluid, which is accompanied by upregulation of renin-angiotensin-aldosterone system (RAAS). Permanent loss of extracellular water does not occur under SGLT2 inhibition.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Composição Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Idoso , Compostos Benzidrílicos/efeitos adversos , Índice de Massa Corporal , Água Corporal/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Impedância Elétrica , Feminino , Glucosídeos/efeitos adversos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Perda de Peso/efeitos dos fármacos
20.
Transl Res ; 209: 121-137, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30930180

RESUMO

Cardiovascular disease is a leading cause of mortality in the world and is exacerbated by the presence of cardiac fibrosis, defined by the accumulation of noncontractile extracellular matrix proteins. Cardiac fibrosis is directly linked to cardiac dysfunction and increased risk of arrhythmia. Despite its prevalence, there is a lack of efficacious therapies for inhibiting or reversing cardiac fibrosis, largely due to the complexity of the cell types and signaling pathways involved. Ongoing research has aimed to understand the mechanisms of cardiac fibrosis and develop new therapies for treating scar formation. Major approaches include preventing the formation of scar tissue and replacing fibrous tissue with functional cardiomyocytes. While targeting the renin-angiotensin-aldosterone system is currently used as the standard line of therapy for heart failure, there has been increased interest in inhibiting the transforming growth factor-ß signaling pathway due its established role in cardiac fibrosis. Significant advances in cell transplantation therapy and biomaterials engineering have also demonstrated potential in regenerating the myocardium. Novel techniques, such as cellular direct reprogramming, and molecular targets, such as noncoding RNAs and epigenetic modifiers, are uncovering novel therapeutic options targeting fibrosis. This review provides an overview of current approaches and discuss future directions for treating cardiac fibrosis.


Assuntos
Terapia de Alvo Molecular , Miocárdio/patologia , Animais , Materiais Biocompatíveis/farmacologia , Fibrose , Humanos , Sistema Renina-Angiotensina , Transdução de Sinais
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