Influência do bloqueio do receptor at1 sobre os colágenos I e III miocárdico de ratos obesos por dieta hiperlipídica saturada
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Data
2016-07-08
Autores
Silva-Bertani, Danielle Cristina Tomaz da [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
A obesidade se associa a inúmeros distúrbios modulados pelo sistema renina angiotensina (SRA) e embora exista uma extensa literatura mostrando a relação entre a angiotensina II e o metabolismo do colágeno miocárdico, não encontramos informações relacionando obesidade por dieta hiperlipídica, saturada, colágenos tipos I e III miocárdico e angiotensina-II. Em razão desta constatação e da associação deletéria entre ácidos graxos saturados e sistema cardiovascular, a proposta deste estudo foi testar a hipótese que a obesidade por dieta hiperlipídica saturada, aumenta os colágenos I e III cardíaco via ativação do receptor AT1 do SRA oriundo do excesso de tecido adiposo. Ratos Wistar machos, com 30 dias, foram randomizados em dois grupos: controle(C; n=30) e obeso (Ob; n=30). Os ratos C receberam dieta normolipídica (DN) e os Ob, dieta hiperlipídica (DH), ambas ricas em ácidos graxos saturados por 30 semanas. Após esse período de intervenção dietética, cada grupo foi randomizado em dois subgrupos: DN e DN+Losartan(Los); DH e DH+Los; os subgrupos DN e DH continuaram recebendo as respectivas dietas durante mais 5 semanas e os grupamentos DN+Los e DH+Los, além do suporte nutricional, foram tratados com losartan, um fármaco antagonista de receptores AT1 na dosagem diária de 30 mg/Kg de massa corporal, portanto, o período total do experimento foi de 35 semanas. Foram avaliados os perfis nutricionais e metabólicos. A avaliação cardíaca foi realizada post mortem por análise macroscópica e molecular, esta última através dos níveis proteicos dos colágenos tipos I e III,inibidores teciduais de MMPs (TIMPs) 1 e 2; e receptor AT1,da concentração da angiotensina II, fator de transformação do crescimento beta (TGF-β) e da atividade da metaloproteinase (MMP)-2 e da enzima conversora de angiotensina II (ECA). Também foi analisado a angiotensina II e a atividade da ECA circulante e do tecido adiposo visceral. Os resultados foram analisados por meio de ANOVA e teste de Tukey (p<0,05). A obesidade acarretou aumento no peso corporal final, gordura corporal total e índice de adiposidade. Foram visualizadas algumas comorbidades, como hipertensão arterial sistólica,menor tolerância à glicose, resistência insulínica, hiperinsulinemia e hiperleptinemia,as quais foram minimizadas por meio do bloqueio do losartan. Em relação à avaliação cardíaca, a obesidade aumentou os níveis proteicos do receptor AT1, porém, não alterou a angiotensina II e a atividade da ECA. A administração de losartan nos grupos C e Ob ocasionou diminuição no receptor AT1em relação aos grupos não tratados, entretanto, ocorreu o oposto na angiotensina II e na ECA em ambos os grupos; os animais Ob+Los apresentaram maiores níveis proteicos de receptor AT1 em relação aos C+Los. A obesidade não acarretou efeitos pressóricos significativos na 30ª semana; porém, na 35ª semana, o grupo Ob apresentou aumento da pressão arterial e da expressão proteica dos colágenos tipo I e III, os quais foram amortizados pelo losartan. O TGF-β, os TIMPs 1 e 2 foram maiores no grupo Ob, porém, a atividade da MMP-2 foi menor nesses animais. O fármaco acarretou aumento dos TIMPs e diminuição na MMP-2 nos animais Ob em relação aos C. A obesidade acarretou aumento da concentração da Ang-II e da atividade da ECA plasmática e do tecido adiposo visceral; a administração de losartan no grupo Ob ocasionou redução nessas variáveis plasmática em relação ao grupo Ob não tratado. Com o losartan, a angiotensina II visceral mostrou-se reduzida em ambos os grupos, porém, a atividade da ECA foi reduzida apenas nos animais obesos. Em conclusão, a obesidade por dieta hiperlipídica saturada aumenta os colágenos I e III cardíaco, via receptor AT1, consequente à elevação da angiotensina II circulante, proveniente do excesso de secreção pelo tecido adiposo visceral.
Obesity is associated with numerous disorders modulated by renin angiotensin system (RAS) and although there is an extensive literature showing the relationship between angiotensin II and the metabolism of myocardial collagen, could not find information relating obesity by saturated high-fat diet, myocardial collagen I and III and angiotensin-II. Because of this finding and the deleterious association between saturated fatty acids and cardiovascular system, the purpose of this study was to test the hypothesis that obesity by saturated high-fat diet increase myocardial type I and III collagen by activation of AT1 receptor of the renin-angiotensin system. Thirty-day-old male Wistar rats were randomized into to two groups: control (C; n=30),fed a standard diet and obese (Ob;n=30),fed a high-fat diet rich saturated fatty acids by 30 weeks. After 30 weeks of dietary intervention, each group were randomized into two subgroups: C and C+Losartan(Los); Ob and Ob+Los; the subgroups C and Ob continued to receive their respective diets for over a five week and the C+Los and Ob+Los groups addition of nutritional support, were treated with losartan, an antagonist drug of AT1 receptors in daily dosage of 30mg/kg body weight. After this period of 35 weeks, it was analyzed nutritional and metabolic profiles. It was analyzed systolic blood pressure (SBP) and structural and molecular studies; the hypertrophy was assessed post-death by macroscopic analysis and the molecular, through protein levels of type I and III collagen, inhibitors of MMPs tissue (TIMPs) 1 and 2; and AT1 receptor, the concentration of angiotensin II, beta transforming growth factor (TGF-β) and activity of metalloproteinase (MMP) -2 and angiotensin II converting enzyme (ACE). Angiotensin- II and activity of ACE in the circulation and visceral adipose tissue was also analyzed. Statistical analysis: ANOVA and Tukey's test (p<0,05). The final body weight, total body fat and adiposity index were elevated in both obese groups. In contrast, obesity was associated with disorders of glucose metabolism, insulin and leptin, which were minimized by blocking of AT1 receptor. Taking into account cardiovascular profile, SBP was elevated in Ob group compared to C and reduced in both groups treated with losartan. Obesity increased the protein levels of the AT1 receptor, however, did not alter the angiotensin II and ACE activity. Losartan administration in C and Ob groups caused decrease in AT1 receptor, however, occurred the opposite in angiotensin II and ACE in both groups; Ob+Los animals showed higher AT1 receptor protein levels compared to C+Los. In relation to myocardial type I and III collagen, Ob group exhibited higher expression of these proteins compared to C, and both groups treated with losartan showed lower levels of these collagen in relation to non-medicated counterparts. TGF-β, TIMPs 1 and 2 were higher in Ob group, however, MMP-2 activity was lower in these animals. The drug promoted an increase of TIMP and decrease of MMP-2 in Ob animals. Obesity caused an increase of the Ang-II concentration and ACE activity in circulation and visceral adipose tissue; losartan in Ob group promoted reduction in these plasma variables in relation to Ob untreated group. With losartan, visceral angiotensin II was reduced in both groups, however, ACE activity was lower only in the obese animals. In conclusion, the obesity by saturated high-fat diet increase myocardial type I and III collagen by AT1 receptor, consequent to rise circulating angiotensin II from excess secretion by visceral adipose tissue.
Obesity is associated with numerous disorders modulated by renin angiotensin system (RAS) and although there is an extensive literature showing the relationship between angiotensin II and the metabolism of myocardial collagen, could not find information relating obesity by saturated high-fat diet, myocardial collagen I and III and angiotensin-II. Because of this finding and the deleterious association between saturated fatty acids and cardiovascular system, the purpose of this study was to test the hypothesis that obesity by saturated high-fat diet increase myocardial type I and III collagen by activation of AT1 receptor of the renin-angiotensin system. Thirty-day-old male Wistar rats were randomized into to two groups: control (C; n=30),fed a standard diet and obese (Ob;n=30),fed a high-fat diet rich saturated fatty acids by 30 weeks. After 30 weeks of dietary intervention, each group were randomized into two subgroups: C and C+Losartan(Los); Ob and Ob+Los; the subgroups C and Ob continued to receive their respective diets for over a five week and the C+Los and Ob+Los groups addition of nutritional support, were treated with losartan, an antagonist drug of AT1 receptors in daily dosage of 30mg/kg body weight. After this period of 35 weeks, it was analyzed nutritional and metabolic profiles. It was analyzed systolic blood pressure (SBP) and structural and molecular studies; the hypertrophy was assessed post-death by macroscopic analysis and the molecular, through protein levels of type I and III collagen, inhibitors of MMPs tissue (TIMPs) 1 and 2; and AT1 receptor, the concentration of angiotensin II, beta transforming growth factor (TGF-β) and activity of metalloproteinase (MMP) -2 and angiotensin II converting enzyme (ACE). Angiotensin- II and activity of ACE in the circulation and visceral adipose tissue was also analyzed. Statistical analysis: ANOVA and Tukey's test (p<0,05). The final body weight, total body fat and adiposity index were elevated in both obese groups. In contrast, obesity was associated with disorders of glucose metabolism, insulin and leptin, which were minimized by blocking of AT1 receptor. Taking into account cardiovascular profile, SBP was elevated in Ob group compared to C and reduced in both groups treated with losartan. Obesity increased the protein levels of the AT1 receptor, however, did not alter the angiotensin II and ACE activity. Losartan administration in C and Ob groups caused decrease in AT1 receptor, however, occurred the opposite in angiotensin II and ACE in both groups; Ob+Los animals showed higher AT1 receptor protein levels compared to C+Los. In relation to myocardial type I and III collagen, Ob group exhibited higher expression of these proteins compared to C, and both groups treated with losartan showed lower levels of these collagen in relation to non-medicated counterparts. TGF-β, TIMPs 1 and 2 were higher in Ob group, however, MMP-2 activity was lower in these animals. The drug promoted an increase of TIMP and decrease of MMP-2 in Ob animals. Obesity caused an increase of the Ang-II concentration and ACE activity in circulation and visceral adipose tissue; losartan in Ob group promoted reduction in these plasma variables in relation to Ob untreated group. With losartan, visceral angiotensin II was reduced in both groups, however, ACE activity was lower only in the obese animals. In conclusion, the obesity by saturated high-fat diet increase myocardial type I and III collagen by AT1 receptor, consequent to rise circulating angiotensin II from excess secretion by visceral adipose tissue.
Descrição
Palavras-chave
Obesidade, Dieta hiperlipídica saturada, Colágeno I e III cardíaco, Sistema renina angiotensina, Ratos