Mecanismos moleculares envolvidos nas alterações cardiovasculares em modelo experimental de privação de estrogênio associado à hipertensão

Doenças cardiovasculares aumentam significativamente em mulheres na pós menopausa. O estrogênio tem um papel importante na regulação da pressão arterial através de diversos aspectos fisiológicos. O desequilíbrio do sistema renina angiotensina é um fator relevante no desenvolvimento de patologias cardiovasculares. O objetivo desse estudo foi investigar os mecanismos moleculares e alterações cardiovasculares em um modelo experimental de privação de estrogênio endógeno associado com hipertensão. Ratas das linhagens Wistar Kyoto (WKY) e espontaneamente hipertensas (SHR) com 14 semanas de idade foram submetidas a ooforectomia bilateral. Análises de morfologia e número de cardiomiócitos foram realizadas, assim como mensuração de marcadores de lesão cardíaca. Elementos do sistema renina-angiotensina e do sistema calicreína-cininas foram observados e quantificados no coração e na aorta desses animais. Posteriormente, um estudo in vitro foi realizado para verificação do efeito dos resultados encontrados nos animais em células naïve. Com os resultados desse estudo foi verificado que a privação de estrogênio aumenta o eixo ECA/Ang II/AT1R do sistema renina-angiotensina durante a hipertensão. Essa supra regulação foi associada ao aumento de quimase. Esse cenário vasoconstritor levou a uma hipertrofia de cardiomiócitos sem lesão cardíaca. O mesmo comportamento do eixo ECA/Ang II/AT1R foi observado na aorta desses animais. Através de experimento in vitro, observou-se aumento de proliferação e viabilidade celular. Nossos dados indicam que a ooforectomia aumenta o eixo vasoconstritor do sistema renina-angiotensina durante a hipertensão, levando a um quadro patológico semelhante à hipertrofia cardíaca e vascular. O mecanismo de hipertrofia parece não envolver lesão celular direta, mas aumento da proliferação e viabilidade através de uma via dependente da ativação de quimase/AT1R e geração intracelular de ERK1/2.Cardiovascular diseases increase significantly in postmenopausal women. Estrogen plays an important role in regulating blood pressure through several physiological aspects. Deregulation of renin-angiotensin system is a key factor of development of cardiovascular pathologies. The aim of this study was to investigate molecular mechanisms and cardiovascular alterations in an experimental model of endogenous estrogen deprivation associated with hypertension. Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) female rats, at 14 weeks of age underwent bilateral oophorectomy. Analyzes of morphology and number of cardiomyocytes were performed, as well as measurement of cardiac injury markers. Morphology and number of cardiomyocytes were evaluated, as well as cardiac lesion markers. Renin-angiotensin and kinin-kallikrein system elements were analyzed in the heart and aorta of these animals. After, an in vitro study was carried out to verify the effect of the results found in animals on naïve cells. The results of this study showed estrogen deprivation increases the ACE/Ang II/AT1R axis of the renin-angiotensin system during hypertension. This upregulation was associated with increased chymase. This vasoconstrictor scenario led to hypertrophy of cardiomyocytes without cardiac damage. The same behavior of the ACE/Ang II/AT1R axis was observed in the aorta of these animals. Through an in vitro experiment, an increase in experience and cell viability was observed. Our data indicate that oophorectomy increases the vasoconstrictor axis of the renin-angiotensin system during hypertension, leading to a pathological condition similar to cardiac and vascular hypertrophy. The mechanism of hypertrophy seems not to involve direct cell injury, but increased proliferation and viability through a pathway dependent on chymase/AT1R activation and intracellular generation of ERK1/2

Development of different degrees of elastase-induced emphysema in mice: a randomized controlled experimental study

Introduction: Mouse models of emphysema are important tools for testing different therapeutic strategies. The aim of this study was to develop a mouse model of emphysema induced by different doses of elastase in order to produce different degrees of severity.Methods: Thirty female mice (C57BL/6) were used in this study. Different doses of porcine pancreatic elastase were administered intratracheally once a week for four weeks, as follows: 0.1 U (n=8), 0.15 U (n=7), and 0.2 U (n=7). Control mice (n=8) received 50 microL of sterile saline solution intratracheally. Lung mechanics were analyzed by plethysmography. Mean linear intercept and volume fraction occupied by collagen and elastic fibers were determined.Results: An increase in lung resistance was observed with 0.2 U of elastase [median (P-25-P75): 2.02 (1.67; 2.34) cmH2O.s/mL], as well as a decrease in tidal volume and minute ventilation. Peak expiratory flow increased significantly in the groups treated with 0.15 U and 0.2 U of elastase. Mean linear intercept was higher with 0.15 U and 0.2 U of elastase, with destruction of alveolar walls [median (P-25-P75): 30.31 (26.65-43.13) microm and 49.49 (31.67-57.71) microm respectively]. The volume fraction occupied by collagen and elastic fibers was lower in the group receiving 0.2 U of elastase.Conclusion: Four intratracheal instillations of 0.2 U of elastase once a week induced changes in lung function and histology, producing an experimental model of severe pulmonary emphysema, whereas 0.15 U resulted in only histological changes.Introduction: Mouse models of emphysema are important tools for testing different therapeutic strategies. The aim of this study was to develop a mouse model of emphysema induced by different doses of elastase in order to produce different degrees of severity. Methods: Thirty female mice (C57BL/6) were used in this study. Different doses of porcine pancreatic elastase were administered intratracheally once a week for four weeks, as follows: 0.1 U (n=8), 0.15 U (n=7), and 0.2 U (n=7). Control mice (n=8) received 50 microL of sterile saline solution intratracheally. Lung mechanics were analyzed by plethysmography. Mean linear intercept and volume fraction occupied by collagen and elastic fibers were determined. Results: An increase in lung resistance was observed with 0.2 U of elastase [median (P-25-P75): 2.02 (1.67; 2.34) cmH2O.s/mL], as well as a decrease in tidal volume and minute ventilation. Peak expiratory flow increased significantly in the groups treated with 0.15 U and 0.2 U of elastase. Mean linear intercept was higher with 0.15 U and 0.2 U of elastase, with destruction of alveolar walls [median (P-25-P75): 30.31 (26.65-43.13) microm and 49.49 (31.67-57.71) microm respectively]. The volume fraction occupied by collagen and elastic fibers was lower in the group receiving 0.2 U of elastase. Conclusion: Four intratracheal instillations of 0.2 U of elastase once a week induced changes in lung function and histology, producing an experimental model of severe pulmonary emphysema, whereas 0.15 U resulted in only histological changes

Development of different degrees of elastaseinduced emphysema in mice : a randomized controlled experimental study

Introduction: Mouse models of emphysema are important tools for testing different therapeutic strategies. The aim of this study was to develop a mouse model of emphysema induced by different doses of elastase in order to produce different degrees of severity. Methods: Thirty female mice (C57BL/6) were used in this study. Different doses of porcine pancreatic elastase were administered intratracheally once a week for four weeks, as follows: 0.1 U (n=8), 0.15 U (n=7), and 0.2 U (n=7). Control mice (n=8) received 50 microL of sterile saline solution intratracheally. Lung mechanics were analyzed by plethysmography. Mean linear intercept and volume fraction occupied by collagen and elastic fibers were determined. Results: An increase in lung resistance was observed with 0.2 U of elastase [median (P-25-P75): 2.02 (1.67; 2.34) cmH2O.s/mL], as well as a decrease in tidal volume and minute ventilation. Peak expiratory flow increased significantly in the groups treated with 0.15 U and 0.2 U of elastase. Mean linear intercept was higher with 0.15 U and 0.2 U of elastase, with destruction of alveolar walls [median (P-25-P75): 30.31 (26.65-43.13) microm and 49.49 (31.67-57.71) microm respectively]. The volume fraction occupied by collagen and elastic fibers was lower in the group receiving 0.2 U of elastase. Conclusion: Four intratracheal instillations of 0.2 U of elastase once a week induced changes in lung function and histology, producing an experimental model of severe pulmonary emphysema, whereas 0.15 U resulted in only histological changes