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Previous issue date: 2014-02-12 / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / Activation of the Angiotensin Converting Enzyme 2 (ACE2)-Angiotensin-(1-7) [Ang(1-7)]-Mas Receptor axis results in protective effects in the cardiovascular system. ACE 2 is an important component of Renin-Angiotensin System, because it is able to convert Angiotensin II in Ang-(1-7). Recents studies have shown that diminazene aceturate (DIZE) act as an activator of ACE 2. The objective of this study was to evaluate the cardiovascular effects of chronic treatment with DIZE in pressureoverloaded rats and the possible mechanisms involved in these effects. Male Wistar rats (200-350 g) were divided in four groups: (1) Sham; (2) Coarcted (abdominal aortic banding, CAA); (3) CAA + DIZE (1 mg/kg, gavage); e (4) CAA + DIZE (1 mg/kg, gavage) + A-779 (120 µg/day, osmotic mini-pumps). Twenty one days after surgery procedure, the blood pressure was recorded, the hearts were isolated and perfused according to Langendorff method. Vascular reactivity was measured by isolated aortic ring preparation. In order to evaluate the cardiac hypertrophy, the left ventricular mass index (VMI) was calculated through the ratio of the left ventricular wet weight to tibia length. The cross-sectional area of cardiomyocytes (CSA) was also evaluated. The mRNA levels for ANP, BNP e TGF-β were also evaluated by qRT-PCR. The expression of ACE-2 and ERK1/2, AKT, mTOR, GATA-4, catalase and SOD proteins involved in hypertrophic pathways was analyzed by Western Blot technique. The results are presented as means ± SEM. One-way ANOVA followed by the Newman-Keuls post-test was used to analyze the blood pressure, cardiac morphometric parameters, isolated heart, qRT-PCR and Western Blot experiments. Two-way ANOVA followed by the Bonferroni post-test was used for aortic rings preparation protocols. All statistical analyses were considered significant at P<0.05. Isolated hearts from coarcted rats presented a significant decrease in the left ventricular end systolic pressure (128.1 ± 9.0 vs. 79.1 ± 12.8 mmHg in CAA, P<0.05), left ventricular developed pressure (118.1 ± 8.9 vs. 69.0 ± 12.7 mmHg in CAA, P<0.05), +dP/dt (2295.0 ± 161.8 vs. 1406.0 ± 246.5 mmHg/s in CAA, P<0.05) and dP/dt (1787.0 ± 166.0 vs. 1066.0 ± 181.9 mmHg/s in CAA, P<0.05). The DIZE treatment attenuated all of these effects induced by CAA. Moreover, DIZE treatment increased the coronary flow in hypertrophic hearts (CAA: 11.6 ± 0.8 vs. CAA+DIZE: 15.8 ± 0.6 mL/min, P<0.05). This effect was blocked by A-779. Pressure–overloaded hearts showed a significant increase in VMI (0.17 ± 0.01 vs. 0.21 ± 0.01 g/cm in CAA, P<0.05) and CSA (8.98 ± 0.54 vs. 10.72 ± 0.27 µm in CAA, P<0.05). The chronic treatment with DIZE prevented the heart hypertrophy (10.72 ± 0.27 in CAA vs. 9.25 ± 0.23 µm in CAA+DIZE, P<0.05). Indeed, treatment with A-779 attenuated the antihypertrophic effect induced by DIZE treatment. The coarcted rats presented a increase in mRNA expression of ANP, BNP and TGF-β and the DIZE treatment reverted this effect. The pressure overload decreased the acetylcholine-induced relaxation in aortic rings from coarcted rats and treatment with DIZE was not able to improve this effect. The coarctation decreased the phosphorylation of the AKT, which was not changed by DIZE treatment. The expression of ACE 2, total and phosphorylated ERK1/2, total AKT, mTOR, SOD and catalase was not changed by coarctation or by ACE 2 activation. These results show that the chronic treatment with DIZE was efficient in preventing the left ventricular hypertrophy and cardiac dysfunction induced by pressure overload. These effects were independent of changes in the expression of ACE 2, ERK1/2, AKT, mTOR, SOD and catalase. Thus, DIZE has important therapeutic potential for cardiovascular diseases. / A ativação do eixo Enzima Conversora de Angiotensina 2 (ECA2)-Angiotensina-(1-7) [Ang-(1-7)]-Receptor Mas resulta em importantes efeitos protetores no sistema cardiovascular..A ECA 2 é um importante componente do Sistema ReninaAngiotensina, pois hidrolisa a Angiotensina II em Ang-(1-7). Recentes estudos tem demonstrado que o aceturato de diminazeno (DIZE) apresenta capacidade de aumentar a atividade da ECA 2. Sendo assim, o objetivo deste estudo foi avaliar os efeitos cardiovasculares do DIZE nas mudanças induzidas por sobrecarga pressórica e possíveis mecanismos intracelulares envolvidos nestes efeitos. Foram utilizados ratos Wistar (200-350 g), divididos em quatro grupos: (1) Sham; (2) Coarctados (coarctação da aorta abdominal, CAA), (3) CAA + DIZE (1 mg/kg, gavagem); e (4) CAA + DIZE (1 mg/kg, gavagem) + A-779 (120 µg/dia, mini-bombas osmóticas). Decorridos 21 dias da coarctação, a pressão arterial dos animais foi registrada, os corações foram isolados e perfundidos pelo método de Langendorff com pressão constante. A reatividade vascular foi avaliada por preparação de anéis de aorta isolada. Para avaliar a hipertrofia cardíaca, o peso dos ventrículos esquerdos foi normalizado pelo comprimento das tíbias e expresso como índice de massa ventricular (IMV), além da área de secção transversa dos cardiomiócitos (AST) ser também medida. Os níveis de mRNA para ANP, BNP e TGF-β também foram avaliados por qRT-PCR. A expressão de ECA 2 e das proteínas ERK1/2, AKT, mTOR, GATA-4, SOD e catalase, envolvidas em vias pró-hipertróficas, foi analisada através da técnica de Western Blot. Os resultados foram apresentados como média ± erro padrão da média. Para as análises de pressão arterial média, coração isolado e parâmetros morfométricos, qRT-PCR e Western Blot, foi utilizado o teste ANOVA One Way seguido pelo pós-teste de Newman-Keuls. Para a reparação de anéis de aorta isolada, foi usado ANOVA Two Way seguido pelo teste de Bonferroni. As diferenças foram consideradas significativas com P<0,05. Os corações isolados dos ratos coarctados apresentaram diminuição significativa da pressão ventricular esquerda ao final da sístole (128,1 ± 9,0 vs. 79,1 ± 12,8 mmHg em CAA, P<0,05), pressão desenvolvida pelo ventrículo esquerdo (118,1 ± 8,9 vs. 69,0 ± 12,7 mmHgem CAA, P<0,05), +dP/dt (2295,0 ± 161,8 vs. 1406,0 ± 246,5 mmHg/s em CAA, P<0,05) e -dP/dt (1787,0 ± 166,0 vs. 1066,0 ± 181,9 mmHg/s em CAA, P<0,05). A ativação da ECA 2 atenuou a disfunção ventricular esquerda induzida pela coarctação. O tratamento com DIZE aumentou o fluxo coronariano dos corações hipertrofiados (CAA: 11,6 ± 0,8 vs. CAA+DIZE: 15,8 ± 0,6 mL/min, P<0,05). Este efeito foi loqueado pelo A-779. Os corações submetidos a sobrecarga pressórica mostraram um umento significativo do IMV (0,17 ± 0,01 vs. 0,21 ± 0,01 g/cm em CAA, P<0,05) e AST (9,37 ± 0,55 vs. 10,72 ± 0,27 µm em CAA, P<0,05). A ativação da ECA 2 preveniu a hipertrofia cardíaca (AST: 10,72 ± 0,27 vs. 9,25 ± 0,23 µm em CAA + DIZE, P<0,05). O tratamento com A-779 atenuou o efeito anti-hipertrófico produzido pelo DIZE nos corações coarctados. A coarctação também promoveu aumento da expressão de mRNA de ANP, BNP e TGF-β e o tratamento com DIZE reverteu esse efeito. A sobrecarga pressórica diminuiu o relaxamento induzido por acetilcolina em anéis de aorta isolada e o tratamento com o ativador da ECA 2 não foi capaz de alterar esse efeito. A coarctação diminuiu a fosforilação da AKT e o tratamento com DIZE não foi capaz de alterá-la. Não foram encontradas alterações na expressão das proteínas ECA 2, ERK1/2 total e fosforilada, AKT total, mTOR, GATA-4, SOD e catalase. Tais resultados mostram que o tratamento crônico com DIZE apresenta efeitos cardioprotetores contra a disfunção cardíaca induzida pela sobrecarga pressórica através da diminuição da hipertrofia ventricular esquerda, sem mudanças na expressão de ECA 2, ERK1/2, AKT, mTOR, GATA-4, SOD e catalase. Portanto, o DIZE possui importante potencial terapêutico frente a doenças cardiovasculares.
| Identifer | oai:union.ndltd.org:IBICT/oai:repositorio.bc.ufg.br:tde/3035 |
| Date | 12 February 2014 |
| Creators | Macedo, Larissa Matuda |
| Contributors | Castro, Carlos Henrique de, Colugnati, Diego Basile |
| Publisher | Universidade Federal de Goiás, Programa de Pós-graduação em Biologia (ICB), UFG, Brasil, Instituto de Ciências Biológicas - ICB (RG) |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da UFG, instname:Universidade Federal de Goiás, instacron:UFG |
| Rights | info:eu-repo/semantics/openAccess |
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