Dimorfismo Sexual na Hipertrofia Ventricular Esquerda e Função cardíaca de Ratos Espontaneamente Hipertensos: O Papel da Atividade da Enzima Conversora de Angiotensina (ECA) e ECA2 no Ventrículo Esquerdo e no Rim
Nome: POLYANA LIMA MEIRELES DALPIAZ
Tipo: Tese de doutorado
Data de publicação: 01/09/2015
Orientador:
Nome |
Papel |
|---|---|
| NAZARE SOUZA BISSOLI | Orientador |
Banca:
| Nome |
Papel |
|---|---|
| TADEU UGGERE DE ANDRADE | Examinador Externo |
| SONIA ALVES GOUVEA | Examinador Interno |
| NAZARE SOUZA BISSOLI | Orientador |
| MARCELO PERIM BALDO | Examinador Interno |
| HENRIQUE DE AZEVEDO FUTURO NETO | Examinador Externo |
Resumo: Os hormônios sexuais podem ser um fator-chave para as diferenças entre os sexos observadas nos índices e na gravidade das doenças renais e cardiovasculares. Este é o primeiro estudo a relacionar função cardíaca, efeitos tróficos e status hormonal com a atividade tecidual de 2 importantes e antagônicos componentes do SRA, ECA e ECA2, no rim e ventrículo esquerdo (VE), de ratos SHRs. Ratos SHR machos (M) e fêmeas (F), 12 semanas de idade, fêmea (F) e macho (M) foram divididos em dois grupos experimentais (n = 7 em cada grupo): Sham (S) e Gonadectomizado (G). Cinquenta dias após gonadectomia, avaliamos: hipertrofia ventricular esquerda, dP/dt + e dP/dt -, atividade da ECA (aECA) e atividade da ECA2 (aECA2) no rim e no VE e Western Blot do receptor AT1, SERCA2a, fosfolambam (PLB) e razão da PLB/SERCA2a. Os machos SHR exibiram maior da aECA e aECA2, maior hipertrofia ventricular comparado as fêmeas. A orquiectomia reduziu aECA e a hipertrofia ventricular, enquanto a ovariectomia aumentou essas variáveis. A função cardíaca nos machos do grupo sham, apresentaram menor dP/dt+ (SM: 5140 ± 259 mmHg vs. SF: 6485 ± 178 mmHg) e menor dP/dt- do que as fêmeas (MS: -3.717 ± 129 mmHg vs. FS: -5.250 ± 115 mmHg). A gonadectomia, inverteu os resultados, as fêmeas tiveram redução da dP/dt+ (GM = 6.728 ± 177 mmHg vs GF: 5453 ± 229 mmHg) e dP/dt- (SM: -4.851 ± 290 mmHg vs GF = -3.913 ± 136 mmHg). Não foi observada diferença na SERCA2a, nem entre grupo sham, nem entre o grupo gonadectomizado, enquanto que o PLB e do PLB/ SERCA2a, somente a ovariectomia promoveu aumento nestas duas variáveis. Na expressão do receptor AT1, os machos exibiram maior expressão que as fêmeas, e gonadectomia reduziu nos machos e eliminou a diferença. A ovariectomia conduziu a aumento da hipertrofia cardíaca, maior aECA2, expressão PLB e da razão PLB/SERCA2a, e agravamento de variáveis hemodinâmicas, enquanto que nos machos, a remoção de testosterona teve efeito oposto. No rim, as fêmeas SHR apresentaram maior aECA e aECA2. A gonadectomia não mudou a ECA. Neste modelo, no rim. A ECA2 parece ter maior participação na modulação local que a ECA. A avaliação de dimorfismo sexual dos componentes do SRA pode contribuir para o desenvolvimento continuado de intervenções terapêuticas eficazes para as doenças cardiovasculares.
Abstract
There is growing interest in sex differences and RAS components; however, whether gender influences cardiac angiotensin I-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activity is still unknown. In the present work we determined the relationship between ACE and ACE2 activity on kidney and heart, left ventricular function and gender in spontaneously hypertensive rats (SHRs). Twelve-week-old female (F) and male (M) SHRs were divided into 2 experimental groups (n = 7 in each group): sham (S) and gonadectomized (G). Fifty days after gonadectomy, we measured positive and negative first derivatives (dP/dt+ and dP/dt-), hypertrophy (morphometric analysis) and ACE and ACE2 catalytic activity in kidney and LV (left ventricle). Expression of calcium handling proteins and AT1 receptor was measured by western blot analysis. Male rats exhibited higher cardiac ACE and ACE2 activity as well as hypertrophy compared to female rats. Orchiectomy reduced ACE activity and hypertrophy, while ovariectomy increased these variables. In relation to cardiac function, the sham group, male to compared female rats, had a lower +dP/dt (MS: 5140 ± 259 mmHg vs. FS: 6485 ± 178 mmHg) and lower -dP/dt (MS: -3.717 ± 129 mmHg vs. FS: -5.250 ± 115 mmHg) than the female sham group. After gonadectomy, the results inverted such that they were increased in males and reduced in female rats in dP/dt+ (GM = 6.728 ± 177 mmHg vs FG: 5453 ± 229 mmHg) and dP/dt- (SM: -4.851 ± 290 mmHg vs GF = -3.913 ± 136 mmHg). No difference among the groups in the SERCA2a protein expression was observed. The gonadectomy increased protein expression of PLB and the PLB to SERCA2a ratio in female rats, but did not alter in male rats. In conclusion, the ovariectomy leads to increased cardiac hypertrophy, ACE2 activity, PLB expression and PLB to SERCA2a ratio, and worsening of hemodynamic variables, wher-eas in males the removal of testosterone has the opposite effect in RAS components.
Our data suggest that sex steroids are of great importance for both female and male SHRs in influencing cardiac function and in regulating the RAS in kidney and LV. In our study, in LV the withdrawal of estrogen in females led to increased cardiac hypertrophy, increased ACE2 activity, PLB expression and PLB to SERCA2a ratio, what could be related to worsening of hemodynamic variables. In males, however, the removal of testosterone had the opposite effect in RAS components. The increase in ACE2 activity after ovariectomy and the reduction after orchiectomy seems to be occurring to counterbalance the observed changes. In the kidney, in females the activity of ACE and ACE2 was higher, favoring the balance between these two important components of the RAS. In the male, conversely, lower levels of ACE and ACE2 favoring the imbalance. ACE, although important, has not changed with the hormonal status, so that in this model, the ACE2 have greater involvement in local modulation of these components. Certainly, the assessment of sexual dimorphism of the components of the RAS can help the continued development of effective therapeutic interventions for cardiovascular diseases.
