ABSTRACT
Background: Treatment of dendritic cells (DC) with aldosterone induces the secretion of IL-6 and TGF-beta. The polarization of naïve T cells to helper 17 T lymphocytes with DCs pre-incubated with aldosterone, has been described in vivo, generating an IL-17 hyper-secreting phenotype, a cytokine associated with cardiac and renal fibrosis. There are mineralocorticoid receptors (MR) in immune cells and their activation may determine the inflammatory (M1) or adaptive (M2) macrophage phenotype. Aldosterone levels could regulate immunogenic gene expression in these cells, modulating the liberation of specific cytokines. Aim: To assess in humans the association of aldosterone levels and IL-17 with inflammatory markers in peripheral blood mononuclear cells (PBMC). Material and Methods: In blood samples of 176 participants aged 18 to 67 years (61 percent women) with a body mass index of 27.1 +/- 4.8 kg/m2, aldosterone, plasma renin activity (ARP), cortisol, C reactive protein, andIL-17 were measured. mRNA was isolated from PBMCs to measure the expression of MR RAC-1, HO-1, TLR-4, CD-14, NGAL and IL-17 by real time polymerase chain reaction. Results: Aldosterone correlated positively with ARP and the expression of CD-14 in PBMCs. Plasma levels of IL-17 were positively associated with the expression of MR, Rac1a and NGAL. Conclusions: Aldosterone and IL-17 levels were associated with inflammatory activation markers in PBMC, which could activate MRand promote a subclinical inflammatory status inducing hypertension.
Subject(s)
Humans , Male , Adolescent , Adult , Female , Young Adult , Middle Aged , Aldosterone/genetics , Hypertension/genetics , Hypertension/blood , /genetics , Aldosterone/blood , Biomarkers , Gene Amplification , /blood , Real-Time Polymerase Chain Reaction , Receptors, MineralocorticoidABSTRACT
The physiological mechanisms involved in isoproterenol (ISO)-induced chronic heart failure (CHF) are not fully understood. In this study, we investigated local changes in cardiac aldosterone and its synthase in rats with ISO-induced CHF, and evaluated the effects of treatment with recombinant human brain natriuretic peptide (rhBNP). Sprague-Dawley rats were divided into 4 different groups. Fifty rats received subcutaneous ISO injections to induce CHF and the control group (n=10) received equal volumes of saline. After establishing the rat model, 9 CHF rats received no further treatment, rats in the low-dose group (n=8) received 22.5 μg/kg rhBNP and those in the high-dose group (n=8) received 45 μg/kg rhBNP daily for 1 month. Cardiac function was assessed by echocardiographic and hemodynamic analysis. Collagen volume fraction (CVF) was determined. Plasma and myocardial aldosterone concentrations were determined using radioimmunoassay. Myocardial aldosterone synthase (CYP11B2) was detected by quantitative real-time PCR. Cardiac function was significantly lower in the CHF group than in the control group (P<0.01), whereas CVF, plasma and myocardial aldosterone, and CYP11B2 transcription were significantly higher than in the control group (P<0.05). Low and high doses of rhBNP significantly improved hemodynamics (P<0.01) and cardiac function (P<0.05) and reduced CVF, plasma and myocardial aldosterone, and CYP11B2 transcription (P<0.05). There were no significant differences between the rhBNP dose groups (P>0.05). Elevated cardiac aldosterone and upregulation of aldosterone synthase expression were detected in rats with ISO-induced CHF. Administration of rhBNP improved hemodynamics and ventricular remodeling and reduced myocardial fibrosis, possibly by downregulating CYP11B2 transcription and reducing myocardial aldosterone synthesis.
Subject(s)
Animals , Humans , Male , Aldosterone/blood , /metabolism , Heart Failure/drug therapy , Myocardium/metabolism , Natriuretic Agents/therapeutic use , Natriuretic Peptide, Brain/therapeutic use , Aldosterone/genetics , Cardiotonic Agents , Chronic Disease , Collagen/analysis , Disease Models, Animal , Echocardiography , Fibrosis/etiology , Heart Failure/chemically induced , Heart Failure/metabolism , Hemodynamics/drug effects , Isoproterenol , Long-Term Care , Myocardium/pathology , Natriuretic Agents/administration & dosage , Natriuretic Peptide, Brain/administration & dosage , Rats, Sprague-Dawley , Real-Time Polymerase Chain Reaction , Recombinant Proteins/therapeutic use , Transcription, Genetic/drug effects , Ventricular Remodeling/drug effectsABSTRACT
Essential hypertension is a disease multifactorially triggered by genetic and environmental factors. The contribution of genetic polymorphisms of the renin-angiotensin-aldosterone system and clinical risk factors to the development of resistant hypertension was evaluated in 90 hypertensive patients and in 115 normotensive controls living in Southwestern Brazil. Genotyping for insertion/deletion of angiotensin-converting enzyme, angiotensinogen M235T, angiotensin II type 1 receptor A1166C, aldosterone synthase C344T, and mineralocorticoid receptor A4582C polymorphisms was performed by PCR, with further restriction analysis when required. The influence of genetic polymorphisms on blood pressure variation was assessed by analysis of the odds ratio, while clinical risk factors were evaluated by logistic regression. Our analysis indicated that individuals who carry alleles 235-T, 1166-A, 344-T, or 4582-C had a significant risk of developing resistant hypertension (P < 0.05). Surprisingly, when we tested individuals who carried the presumed risk genotypes A1166C, C344T, and A4582C we found that these genotypes were not associated with resistant hypertension. However, a gradual increase in the risk to develop resistant hypertension was detected when the 235-MT and TT genotypes were combined with one, two or three of the supposedly more vulnerable genotypes - A1166C (AC/AA), C344T (TC/TT) and A4582C (AC/CC). Analysis of clinical parameters indicated that age, body mass index and gender contribute to blood pressure increase (P < 0.05). These results suggest that unfavorable genetic renin-angiotensin-aldosterone system patterns and clinical risk variables may contribute to increasing the risk for the development of resistant hypertension in a sample of the Brazilian population.
Subject(s)
Humans , Male , Female , Middle Aged , Aldosterone/genetics , Hypertension/genetics , Polymorphism, Genetic , Renin-Angiotensin System/genetics , Brazil , Case-Control Studies , Gene Frequency , Genetic Predisposition to Disease , Genotype , Hypertension/blood , Logistic Models , Risk Factors , Sex FactorsABSTRACT
El último paso para la producción de aldosterona (11-desoxicorticosterona a aldosterona) en mitocondrias de zona glomerulosa de adrenal de rata es catalizado por la enzima CYP11B2. CYP11B1, en zona fasciculata, transforma 11-desoxicorticosterona en corticosterona o 18-hidroxi-11-desoxicorticosterona. CYO11B1 y CYP11B2 tienen alta homología y sus genes se hallan en tándem en el cromosoma 8q22. Mutaciones en el gen de CYP11B2 y recombinaciones genéticas entre éste y el gen de CYP11B1 serían las responsables de las alteraciones en la enzimología de la producción de aldosterona, dando una nueva denominación y explicación a las deficiencias anteriormente conocidas como de CMOI y CMOII
Subject(s)
Humans , Animals , Rats , Aldosterone/biosynthesis , Hyperaldosteronism/physiopathology , Aldosterone/genetics , Cytochrome P-450 CYP11B2/genetics , Cytochrome P-450 CYP11B2/physiology , Glucocorticoids/therapeutic use , Hypertension/complications , Hyperaldosteronism/classification , Hyperaldosteronism/etiology , Steroid 11-beta-Hydroxylase/genetics , Steroid 11-beta-Hydroxylase/physiologyABSTRACT
La última etapa de la biosíntesis de aldosterona (ALDO) involucra la oxidación mitocondrial de 11-desoxicorticosterona (DOC), a través de varios caminos, que comienzan en sus metabolicos corticosterona (B) y 18-hidroxi-11-desoxicorticosterona (18OHDOC). Todas las reacciones de estos caminos son catalizadas por enzimas de la familia de los citocromos P450. El número y la identidad de cada una de ellas han sido objeto de investigaciones en los últimos treinta años. El modelo, actualmente en vigencia, postula que en la adrenal de la vaca todas las reacciones que llevan desde DOC a ALDO son catalizadas por un único citocromo P450-11ß/18 hidroxilasa/aldosintetasa, presente en toda la corteza adrenal. En cambio, en la adrenal de rata, ratón y humano, la catálisis total es llevada a cabo por el citocromo P450 CYP11B2 sólo presente en la zona glomerulosa, mientras que en la zona fasciculata existe el citocromo P450 CYP11B1, que sólo cataliza la transformación de DOC en B o en 18 OH-DOC. Este modelo, avalado por experimentos de bioquímica celular y molecular, no explica, sin embargo, algunos hechos experimentales