Menores niveles tisulares de la enzima convertidora de angiotensina I homologa (ECA-2) y angiotensina-(1-9) están asociados a mayor remodelamiento de la pared aórtica de ratas hipertensas

• María Paz Ocaranza ^[1] ; Jackeline Moya ^[1] ; Melissa Pinto ^[1] ; Nicolás Escudero ^[1] ; Francisco Valenzuela ^[1] ; Manuel Varas ^[1] ; Iván Godoy ^[1] ; Mario Chiong ^[2] ; Sergio Lavandero ^[2] ; Jorge Jalil ^[1]
  1. [1] Pontificia Universidad Católica de Chile

     Pontificia Universidad Católica de Chile

     Santiago, Chile

     
  2. [2] Universidad de Chile

     Universidad de Chile

     Santiago, Chile

     
• Localización: Revista chilena de cardiología, ISSN-e 0718-8560, Vol. 29, Nº. 1, 2010, págs. 69-82
• Idioma: español
• Títulos paralelos:
  • Lower tissue levels of homologous angiotensin I converting enzyme (ACE-2) and angiotensin 1-9 are associated to increased remodeling of the aortic wall of hypertensive rats
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• Resumen
  • español

    Antecedentes: Recientemente hemos propuesto en un modelo experimental de infarto al miocardio una significativa interregulación entre los niveles de la enzima convertidora de angiotensina I (ECA) y su homologa (ECA-2), junto con que angiotensina (Ang)-(1-9) más que Ang-(1-7) actuaría como un contrarregulador de Ang II. Sin embargo tal relación no se ha investigado en el remodelado aórtico hipertensivo. Objetivo: Determinar la expresion de ECA y ECA-2, los niveles de Angs I, II, (1-7) y (1-9) y los parámetros de remodelado de la pared aórtica de ratas hipertensas. Métodos: Ratas normotensas Lewis (n=18) fueron randomizadas a hipertension (HTA) por sobrecarga de presion (modelo Goldblatt, GB, 2 riñones-1 pinzado, n=9). Ratas pseudo-operadas se usaron como controles (S, n=9). A las 6 semanas post cirugía, se determinó la masa cardíaca relativa (MCR) y la presion arterial sistólica (PAS). En la aorta torácica se determinó el grosor de la túnica media (GTM), área de la TM (ATM), niveles de mRNA de ECA y ECA-2, factor de crecimiento transformante tipo ß (TGF-ß), inhibidor del activador de plasminógeno (PAI-1) y de la proteína quimioatractante de monocitos (MCP-1) por RT-PCR. La actividad y niveles proteicos de ECA y ECA-2 por fluorimetría y Western blot y los niveles de Angs I, II, (1-7) y (1-9) por HPLC y radioinmunoensayo. Resultados: La MCR y la PAS aumentaron significativamente (p<0,05) en el grupo GB respecto a su control S. Las ratas hipertensas mostraron un aumento significativo (p<0.05) del GTM (18%), ATM (31%), niveles de mRNA de ECA (164%,), TGF-/3 (105%,), PAI-1(51%>), MCP-1 (53%,) junto con mayor actividad (89%,), niveles proteicos de ECA (130%,) y Ang II (48%,). Esos efectos se asociaron a una significativa disminución del mRNA, los niveles proteicos y actividad de ECA-2 (- 55%, -41%, y 54%, respectivamente) y a menores niveles aórticos (-25%,) de Ang- (1-9), sin diferencias en los niveles de ang-(1-7). Conclusion: Estos resultados fuertemente sugieren que en la hipertension arterial experimental, el remodelado de la pared aórtica está asociado a una interacción entre ECA y ECA-2 y los niveles de Ang II y Ang-(1-9), pero no de Ang-(1-7).

  • English

    Background: In experimental models of myocardial infarction we have recently proposed a significant inter-regulation between levels of Angiotensin I converting enzyme (ACE) and its homologous, ACE-2; in addition, we have proposed that Angiotensin 1-9 (Ang-(1-9)) rather than Ang-(1-7) counter regulates Ang II. These relations have not been investigated in hypertensive aortic wall remodeling. Aim: To measure de expression of ACE and ACE-2, the aortic wall levels of Ang I, Ang II, Ang-(1-7) and Ang-(1-9), along with parameters of aortic wall remodeling in hypertensive rats. Methods: 18 Lewis rats were randomized to Goldblatt (2 kidneys, 1 clamped) induced hypertension (n=9) or sham operation (controls, n=9). Six weeks after surgery, relative cardiac mass (RCM), systolic blood pressure (SBP), medial layer aortic wall thickness (MLT) and ML área (MLA) were measured. The aortic wall levels of ACE and ACE-2, tissue growth factor ß(TGF- ß), plasminogen activator inhibitor (PAI-1) and monocyte chemoattractant protein (MCP-1) were determined by RT-PCR. Activity and protein levels of ACE and ACE-2 were measured by fluorometry and Western Blot and ANG I, Ang II, Ang-(1-7) and Ang-(1-9) levels were determined using HPLC and radioimmunoassay. Results: RCM and SBP increased significantly in hypertensive as opossed to sham operated rats. Hypertensive rats had a significant (p<0.05) increase in MLT (18%), MLA, (31%), mRNA levels of ACE (164%,), TGF-ß (105%,), PAI-1 (51%,) and MCP-1 (53%,). ACE and ACE-2 protein levels increased by 130 and 48%, respectively (p<0.05). All these effects were associated to a significant decrease in mRNA, protein levels and actiity of ACE-2 (-55%, -41%, and -54%, respectively, along with decreased aortic wall levels of Ang-(1-9) (-25%,). Levels of Ang 1-7 were not modified in hypertensive rats. Conclusion: these results strongly suggest that the aortic wall remodeling following experimentally induced hypertension is associated to interaction between ACE and ACE-2 and aortic wall levels of Ang II and Ang-(1-9), but not with those ofAng-(1-7).