Deletion of Angiotensin-Converting Enzyme 2 Accelerates Pressure Overload-Induced Cardiac Dysfunction by Increasing Local Angiotensin II

Abstract

Abstract-Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that cleaves angiotensin II to angiotensin 1-7.Recently, it was reported that mice lacking ACE2 (ACE2 Ϫ/y mice) exhibited reduced cardiac contractility. Because mechanical pressure overload activates the cardiac renin-angiotensin system, we used ACE2Ϫ/y mice to analyze the role of ACE2 in the response to pressure overload. Twelve-week-old ACE2 Ϫ/y mice and wild-type (WT) mice received transverse aortic constriction (TAC) or sham operation. Sham-operated ACE2 Ϫ/y mice exhibited normal cardiac function and had morphologically normal hearts. In response to TAC, ACE2 Ϫ/y mice developed cardiac hypertrophy and dilatation. Furthermore, their hearts displayed decreased cardiac contractility and increased fetal cardiac gene induction, compared with WT mice. In response to chronic pressure overload, ACE2 Ϫ/y mice developed pulmonary congestion and increased incidence of cardiac death compared with WT mice. On a biochemical level, cardiac angiotensin II concentration and activity of mitogen-activated protein (MAP) kinases were markedly increased in ACE2 Ϫ/y mice in response to TAC. Administration of candesartan, an AT 1 subtype angiotensin receptor blocker, attenuated the hypertrophic response and suppressed the activation of MAP kinases in ACE2 Ϫ/y mice. Activation of MAP kinases in response to angiotensin II was greater in cardiomyocytes isolated from ACE2 Ϫ/y mice than in those isolated from WT mice. ACE2 plays an important role in dampening the hypertrophic response to pressure overload mediated by angiotensin II. Disruption of this regulatory function may accelerate cardiac hypertrophy and shorten the transition period from compensated hypertrophy to cardiac failure.

Decreased Expression of Angiotensin-Converting Enzyme 2 in Pancreatic Ductal Adenocarcinoma Is Associated with Tumor Progression

“…Most groups agree, however, that deletion of ACE2 causes significant potentiation of the effects of ANGII (Yamamoto et al 2006;Epelman et al 2008;Moon et al 2008;Soler et al 2008). Yamamoto and his colleagues recently reported that deletion of ACE2 accelerates pressure overload-induced cardiac dysfunction in mice.…”

“…Yamamoto and his colleagues recently reported that deletion of ACE2 accelerates pressure overload-induced cardiac dysfunction in mice. They hypothesized that ACE2 plays an important role in dampening the hypertrophic response that is mediated by ANG II because the concentration of cardiac ANG II and the activation of mitogen-activated protein kinase by ANG II are markedly increased in ACE2-deficient mice (Yamamoto et al 2006). Thus, we presume the anti-proliferative effect of ACE2 in PDAC is partially mediated by opposing the function of ANG II.…”

La sobreexpresión del gen de enzima convertidora de angiotensina homóloga (ECA2) revierte la hipertensión arterial y el remodelado cardíaco experimental

“…Mientras que las ratas WKY en iguales condiciones experimentales no mostraron diferencias. Recientemente, Raizada y colaboradores usaron un lentivirus ECA2 para prevenir la fibrosis y la hipertrofia miocárdica en ratas SHR y el RM post infarto al miocardio 11 y Yamamoto et al 9 encontraron que la deleción del gen de la ECA2 aumentó la disfunción cardíaca inducida por sobrecarga de presión y el RM asociado con el aumento de los niveles de Ang II y activación del receptor tipo 1 de Ang II. Nuestros resultados muestran que la sobreexpresión adenoviral de la ECA2 disminuyó la hipertrofia al disminuir tanto el peso cardíaco como el área y perímetro de los cardiomiocitos.…”

“…Esta capacidad de regular los niveles de Ang I 1-7 , como también el clearence de ang II 7 , hacen a la ECA2 blanco terapéutico para la regulación de la PA y de sus complicaciones 8 . Varios estudios se han realizado en relación a rol de la ECA2 en la fisiología cardíaca 1,5,8,9,10,11,12 . La deficiencia de la ECA2 se ha asociado a daño cardíaco severo y aumento en los niveles plasmáticos y cardía-cos de ang II 8,9 , situación que ha sido revertida en ratas knockout para ECA y ECA2 8 .…”

“…Varios estudios se han realizado en relación a rol de la ECA2 en la fisiología cardíaca 1,5,8,9,10,11,12 . La deficiencia de la ECA2 se ha asociado a daño cardíaco severo y aumento en los niveles plasmáticos y cardía-cos de ang II 8,9 , situación que ha sido revertida en ratas knockout para ECA y ECA2 8 . Estudios recientes han mostrado evidencia de que la sobreexpresión de la ECA2 a nivel del miocardio se asocia a prevención de la hipertrofia y fibrosis hipertensiva inducida por ang II, disminución en la producción de colágeno (col) I y III inducido por hipoxia en cultivo primario de fibroblastos 10 y protección de la función cardíaca y endotelial en isquemia coronaria permanente 11 .…”