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Aldosterone and its Antagonists Modulate Elastin Deposition in the HeartBunda, Severa 20 January 2009 (has links)
Myocardial infarction activates the renin-angiotensin system, consequently upregulating aldosterone production that may stimulate pathological cardiac fibrosis via mineralocorticoid receptor (MR) activation.
Results presented in this thesis were derived from an in vitro experimental model using cultures of human cardiac fibroblasts to study the effect of aldosterone on elastin production. They first confirmed that treatment with 1-50 nM of aldosterone leads to a significant increase in collagen type I production via MR activation. Most importantly, we discovered that treatment with 1-50 nM of aldosterone also increases elastin mRNA levels, tropoelastin synthesis, and elastic fiber deposition. Strikingly, pretreatment with MR antagonist spironolactone did not eliminate aldosterone-induced increases in elastin production.
Interestingly, while cultures treated with elevated aldosterone concentrations (100 nM and 1 µM) showed a further increase (~3.5-fold) in collagen and (~3-fold) in elastin mRNA levels, they demonstrated subsequent increases only in the net deposition of collagen but not elastin. In fact, cultures treated with elevated aldosterone concentrations displayed a striking decrease in the net deposition of insoluble elastin, which could be reversed with spironolactone or with MMP inhibitors doxycycline or GM6001.
Most importantly, we discovered that the pro-elastogenic effect of aldosterone involves a rapid increase in tyrosine phosphorylation of the insulin-like growth factor-I receptor (IGF-IR) and that the IGF-IR kinase inhibitor AG1024 or an anti-IGF-IR neutralizing antibody inhibits both IGF-I- and aldosterone-induced elastogenesis (Bunda et al., Am J Pathol. 171:809-819, 2007). Furthermore, we showed that the PI3 kinase signaling pathway propagates the elastogenic signal following IGF-IR activation and that activation of c-Src is an important prerequisite for aldosterone-dependent facilitation of the IGF-IR/PI3 kinase signaling.
Results of explorative microarray analysis of 1 hour aldosterone-treated cultures revealed that aldosterone treatment upregulated expression of a heterotrimeric G protein, Gα13, that activates the PI3 kinase signaling pathway. We additionally demonstrated that aldosterone treatment transiently increases the interaction between Gα13 and c-Src and that siRNA-dependent elimination of Gα13 inhibited the pro-elastogenic effect of aldosterone.
In summary, aldosterone, which stimulates collagen production in cardiac fibroblasts through the MR-dependent pathway, also increases elastogenesis via a parallel MR-independent pathway involving the activation of Gα13, c-Src, and IGF-IR/PI3 kinase signaling.
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Aldosterone and its Antagonists Modulate Elastin Deposition in the HeartBunda, Severa 20 January 2009 (has links)
Myocardial infarction activates the renin-angiotensin system, consequently upregulating aldosterone production that may stimulate pathological cardiac fibrosis via mineralocorticoid receptor (MR) activation.
Results presented in this thesis were derived from an in vitro experimental model using cultures of human cardiac fibroblasts to study the effect of aldosterone on elastin production. They first confirmed that treatment with 1-50 nM of aldosterone leads to a significant increase in collagen type I production via MR activation. Most importantly, we discovered that treatment with 1-50 nM of aldosterone also increases elastin mRNA levels, tropoelastin synthesis, and elastic fiber deposition. Strikingly, pretreatment with MR antagonist spironolactone did not eliminate aldosterone-induced increases in elastin production.
Interestingly, while cultures treated with elevated aldosterone concentrations (100 nM and 1 µM) showed a further increase (~3.5-fold) in collagen and (~3-fold) in elastin mRNA levels, they demonstrated subsequent increases only in the net deposition of collagen but not elastin. In fact, cultures treated with elevated aldosterone concentrations displayed a striking decrease in the net deposition of insoluble elastin, which could be reversed with spironolactone or with MMP inhibitors doxycycline or GM6001.
Most importantly, we discovered that the pro-elastogenic effect of aldosterone involves a rapid increase in tyrosine phosphorylation of the insulin-like growth factor-I receptor (IGF-IR) and that the IGF-IR kinase inhibitor AG1024 or an anti-IGF-IR neutralizing antibody inhibits both IGF-I- and aldosterone-induced elastogenesis (Bunda et al., Am J Pathol. 171:809-819, 2007). Furthermore, we showed that the PI3 kinase signaling pathway propagates the elastogenic signal following IGF-IR activation and that activation of c-Src is an important prerequisite for aldosterone-dependent facilitation of the IGF-IR/PI3 kinase signaling.
Results of explorative microarray analysis of 1 hour aldosterone-treated cultures revealed that aldosterone treatment upregulated expression of a heterotrimeric G protein, Gα13, that activates the PI3 kinase signaling pathway. We additionally demonstrated that aldosterone treatment transiently increases the interaction between Gα13 and c-Src and that siRNA-dependent elimination of Gα13 inhibited the pro-elastogenic effect of aldosterone.
In summary, aldosterone, which stimulates collagen production in cardiac fibroblasts through the MR-dependent pathway, also increases elastogenesis via a parallel MR-independent pathway involving the activation of Gα13, c-Src, and IGF-IR/PI3 kinase signaling.
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Bloqueio do receptor mineralocorticoide em hipertensos com síndrome metabólica: estudo da vasodilatação fluxo-mediadaLovisi, Julio Cesar Moraes 09 September 2013 (has links)
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Previous issue date: 2013-09-09 / INTRODUÇÃO: A epidemia de obesidade e de síndrome metabólica (SM) observada nos últimos anos se associa a uma série de agravos clínicos como neoplasias, diabetes mellitus e doenças cardiovasculares, notadamente a hipertensão arterial (HA). Diversos mecanismos etiopatogênicos têm sido descritos na HA associada à SM entre os quais citam-se a participação da aldosterona (ALDO) e da disfunção endotelial. OBJETIVOS: avaliar os efeitos do bloqueio do receptor mineralocorticoide (RMC) na função endotelial, na pressão arterial (PA) e em parâmetros inflamatórios e renais de indivíduos com SM. PACIENTES E MÉTODOS: Foram selecionados 42 pacientes elegíveis para o protocolo. Todos os voluntários foram submetidos a exame clínico, avaliação laboratorial com dosagens de mediadores inflamatórios e de excreção urinária de albumina, além de avaliação cardiológica, com monitorização ambulatorial da pressão arterial (MAPA), ecocardiograma e estudo da vasodilatação fluxo-mediada (VDFM), antes e após o tratamento. Destes, 28 indivíduos foram tratados com espironolactona (ESPIRO) na dose de 25-50 mg/dia e 14 com amlodipina (AMLO) na dose 5-10 mg/dia por 16 semanas (Resultados 1). Após essa avaliação, com objetivo de homogeneizar os grupos para melhor comparação dos parâmetros de VDFM, inflamatórios e renais, foram selecionados 27 indivíduos alocados em dois grupos por meio da aplicação da técnica do Propensity Score (PS). Deste modo foram constituídos dois grupos homogêneos, a saber: 16 pacientes em um grupo tratado com ESPIRO e 11 no grupo controle, tratados com AMLO, por um período de 16 semanas (Resultados 2).
Resultados 1: Os dados iniciais mostraram que o tratamento da HA com ESPIRO e com AMLO resultou em redução significante da PA em ambos os grupos. No grupo ESPIRO foi observado aumento da VDFM, enquanto no grupo AMLO houve redução significativa desse parâmetro. Observamos ainda redução significativa da microalbuminúria e de mediadores inflamatórios no grupo ESPIRO, o que não ocorreu no grupo AMLO. Finalmente, observou- se aumento significativo do colesterol HDL no grupo ESPIRO o que não foi observado no grupo AMLO.
Resultados 2: com a aplicação do PS e consequente maior homogeneidade entre os grupos houve a confirmação desses achados nos 2 grupos (ESPIRO e AMLO) e, adicionalmente, permitiu a subdivisão destes em inflamados (PCR>3,0 mg/dL) e não inflamados (PCR < 3,0
mg/dL). Quando se avaliaram a VDFM, o comportamento pressórico e de parâmetros metabólicos e renais observou-se aumento da VDFM, maior redução da PA, aumento do colesterol HDL e redução da albuminúria que foram significativas no grupo ESPIRO, notadamente no subgrupo não inflamado em comparação ao grupo inflamado.
CONCLUSÃO: O bloqueio dos RMC em hipertensos com SM melhorou a função endotelial e reduziu a pressão arterial, com impacto favorável sobre marcadores metabólicos, inflamatórios e na excreção urinária de albumina. Estes achados apontam para efeitos benéficos adicionais à redução pressórica em pacientes portadores de SM tratados com bloqueadores dos RMC. / INTRODUCTION: The epidemic of obesity and metabolic syndrome (MS) described in recent years is associated with a series of clinical conditions such as malignancy, diabetes mellitus, and cardiovascular diseases, chiefly systemic arterial hypertension (AH). There are several mechanisms proposed to explain the development of MS-associated AH, among which the role of aldosterone and endothelial dysfunction are noteworthy. OBJECTIVES: assess the effects of mineralocorticoid receptor blockade (MRB) on endothelial function, blood pressure (BP) and inflammatory and renal parameters of individuals with the MS. PATIENTS AND METHODS: Forty-two eligible patients were selected. All volunteers underwent clinical examination, laboratory determination of inflammatory mediators and urinary albumin excretion, and cardiologic examination with 24-hour ambulatory blood pressure (24-h ABPM), echocardiography and assessment of the flow-mediated vasodilation (FMD) at baseline and after treatment. Twenty-eight individuals received spironolactone (SPIRO), 25-50mg/day, and 14 individuals received amlodipine (AMLO), 5-10mg/day, for 16 weeks (Results 1). In order to homogenize the groups and better compare the FMD and the inflammatory and renal parameters, 27 individuals were selected and allocated to two groups according to the propensity score (PS) technique: 16 individuals treated with SPIRO and 11 controls, treated with AMLO, for 16 weeks (Results 2).
Results 1: Both SPIRO-treated and AMLO-treated groups had significant BP reductions. While the SPIRO-treated group had increased FMD, the AMLO-treated group had a significant reduction of this parameter. There was also a significant reduction of microalbuminuria and inflammatory mediators in the SPIRO-treated group, but not in the AMLO one. There was a significant increase of HDL-cholesterol in the SPIRO group, but not in the AMLO one.
Results 2: With the PS technique, and consequent better homogenization of the groups, we confirmed these findings in the two groups (SPIRO and AMLO) and further subdivided them into those with inflammation (CRP>3.0mg/dl) and those without inflammation (CRP<3.0mg/dl). There were significantly increased FMV, greater BP reduction, increased HDL-cholesterol, and significant reduction of albuminuria in the SPIRO group, notably in the subgroup without inflammation, as compared with that with inflammation.
CONCLUSION: MRB in hypertensive subjects with the MS improved endothelial function and reduced blood pressure, with a favorable impact on metabolic and inflammatory markers and on the urinary albumin excretion. These findings point to MRB as a new option for treatment of AH in individuals with the MS.
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L’impact de l’inhibition de l’aldostérone sur l’homéostasie du glucose et le risque de diabète chez les patients atteints d’insuffisance cardiaqueKorol, Sandra 12 1900 (has links)
Le système rénine-angiotensine-aldostérone est impliqué dans la physiopathologie de
l’insuffisance cardiaque (IC). L’inhibition de l’aldostérone par les antagonistes du récepteur
aux minéralocorticoïdes (ARM), la spironolactone et l’éplérénone, est associée à une
réduction de morbidité et mortalité. Or, la spironolactone est un antagoniste non sélectif, avec
des effets hors-cibles sur d’autres récepteurs stéroïdiens. Des données suggèrent qu’elle
pourrait avoir un effet défavorable sur l’homéostasie du glucose, avec une augmentation en
hémoglobine glyquée (HbA1c), un marqueur de contrôle du glucose à long terme. Au contraire,
l’éplérénone semble exercer un effet neutre. Les objectifs de cette thèse de doctorat sont les
suivants : 1) Assembler toutes les connaissances dans la littérature au sujet de l’effet
glycémique des ARM; 2) Évaluer le risque de développement de diabète avec la
spironolactone chez les patients IC; 3) Analyser si la spironolactone peut moduler l’effet
glycémique d’autres médicaments utilisés en IC; 4) Comparer la spironolactone à l’éplérénone
sur des marqueurs de glucose chez les patients IC avec dérèglements glycémiques. Quatre
projets ont été effectués afin de répondre à ces questions. Premièrement, une revue
systématique a permis d’identifier toutes les études publiées contenant de l’information sur
l’effet glycémique des ARM. Les résultats étaient hétérogènes, mais ont suggéré que l’effet est
dépendant de la pathologie et serait potentiellement néfaste dans les maladies à haut risque
d’évènements cardiovasculaires. Une méta-analyse d’études en diabète indique que l’effet à
long terme serait non significatif. Le deuxième projet utilise une cohorte de patients IC de
bases de données administratives entre 1995 et 2009 (suivi jusqu’en 2010). Nous n’avons pas
détecté d’association significative entre l’utilisation de la spironolactone et le risque de
diabète. Par contre, l’étude a démontré qu’un âge plus jeune, la digoxine, et les
corticostéroïdes augmentent le risque de diabète. Le troisième projet est une sous-étude d’une
étude clinique CANDIID-II (Effect of ACE inhibitor alone versus ACE inhibitor plus high
dose candesartan on BNP, immune markers, inflammatory status, and urinary kinins in
patients with symptomatic left ventricular systolic dysfunction) chez des patients IC traités
avec un inhibiteur de l’enzyme de conversion à l’angiotensine et le candésartan, antagoniste
du récepteur à l’angiotensine II. Ces classes pharmacologiques ont des effets bénéfiques sur la
glycémie. En comparant les patients traités aussi avec la spironolactone versus les patients
sans ARM, nous n’avons pas trouvé que la spironolactone module l’effet bénéfique du
candésartan sur le métabolisme du glucose. Le dernier projet consiste d’une étude prospective,
multicentrique, randomisée, contrôlée à double-insu : SNOW (A comparison of the effects of
selective and non selective mineralocorticoid antagonism on glucose homeostasis and lipid
profile of heart failure patients with glucose intolerance or type 2 diabetes). Elle compare,
pendant 16 semaines, la spironolactone à l’éplérénone sur des marqueurs glycémiques,
notamment, l’HbA1c, chez 62 patients IC avec diabète de type II ou intolérance au glucose.
Aucune différence significative n’a été observée entre les groupes. En résumé, les résultats de
cette thèse indiquent que les ARM ne présentent pas de risque de détérioration du contrôle du
glucose sur une durée modérée à longue en IC. / The renin-angiotensin-aldosterone system is involved in the pathophysiology of heart failure
(HF). The inhibition of aldosterone by mineralocorticoid receptor antagonists (MRAs),
spironolactone and eplerenone, is associated with a reduction in morbidity and mortality.
However, spironolactone is a non selective antagonist, with off-target effects on other steroid
receptors. There is some evidence suggesting that it may have an unfavorable effect on
glucose homeostasis, with an increase in glycated hemoglobin (HbA1c), a marker of long-term
glucose control. On the contrary, eplerenone seems to exert a neutral effect. The objectives of
this doctoral thesis were the following: 1) Compile all current knowledge in the literature on
the subject of MRAs’ glycemic effects; 2) Evaluate the risk of developing diabetes with
spironolactone in HF patients; 3) Analyze if spironolactone may modulate the glycemic effects
of other medications used in HF; 4) Compare spironolactone to eplerenone on markers of
glucose control in HF patients with glycemic disorders. Four projects were conducted in order
to meet these objectives. Firstly, a systematic review allowed us to identify all published
studies containing information on MRAs’ glycemic effects. The literature search yielded
heterogenous results; however, it suggested that the effect was disease-specific and would be
potentially harmful in diseases with a high risk of cardiovascular events. A meta-analysis of
studies in diabetes insinuated that the effect is non significant on a long-term basis. The
second project uses a cohort of HF patients from administrative databases between 1995 and
2009 (follow-up till 2010). We did not detect a significant association between the use of
spironolactone and the risk of diabetes. On the other hand, the study demonstrated that
younger age, digoxin, and corticosteroids increase the risk of diabetes. The third project is a
substudy of a clinical trial CANDIID-II (Effect of ACE inhibitor alone versus ACE inhibitor
plus high dose candesartan on BNP, immune markers, inflammatory status, and urinary kinins
in patients with symptomatic left ventricular systolic dysfunction) among HF patients treated
with an angiotensin converting enzyme inhibitor and candesartan, an angiotensin II receptor
blocker. These pharmacological classes have beneficial effects on glycemia. By comparing
patients also treated with spironolactone versus patients without an MRA, we did not find that
spironolactone alters the effect of candesartan on glucose metabolism. The last project
consisted of a prospective, multicenter, randomized, controlled, double-blind trial: SNOW (A
comparison of the effects of selective and non selective mineralocorticoid antagonism on
glucose homeostasis and lipid profile of heart failure patients with glucose intolerance or type
2 diabetes). It compares, for 16 weeks, spironolactone to eplerenone on glycemic markers,
notably, HbA1c, among 62 HF patients with type II diabetes or glucose intolerance. There was
no significant difference between groups. In summary, the research results from this thesis
reveal that, in HF, MRAs do not present additional risks of deterioration in glucose control
over a moderate to long period.
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