Primary role of angiotensin-converting enzyme-2 in cardiac production of anglotensin-(1-7) in transgenic Ren-2 hypertensive rats

Primary role of angiotensin-converting enzyme 2 in cardiac production of angiotensin-(1-7) in transgenic Ren-2 hypertensive rats. Am J Physiol Heart Circ Physiol 292: H3019-H3024. 2007. First published February 16, 2007: doi: 10.1152/ajplicart.01198.2006. - Angiotensin-converting enzyme-2 (ACE2) converts angiotensin 11 (ANG 11) to angiotensin-(1-7) [ANG-(1-7)], and this enzyme may serve as a key regulatory juncture in various tissues. Although the heart expresses ACE2, the extent that the enzyme participates in the cardiac processing of ANG 11 and ANG-(1-7) is equivocal. Therefore. we utilized the Langendorff preparation to characterize the ACE2 pathway in isolated hearts from male normotensive Sprague-Dawley [Tg((-))] and hypertensive [mRen2]27 [TL(+)] rats. During a 60-min recirculation period with 10 nM ANG II. he presence of ANG-(1-7) was assessed in the cardiac effluent. ANG-(1-7) generation from ANG 11 was similar in both the normal and hypertensive hearts [Tg(-) : 510 +/- 55 pM, n = 20 vs. Tg((+)): 497 +/- 63 pM, n = 14] with peak levels occurring at 30 min after administration of the peptide. ACE2 inhibition (MLN-4760, I LM) sianificantly reduced ANG-(1-7) production by 83% (57 +/- 19 pM,. P < 0.01. n = 7) in the Tg((+)) rats. whereas the inhibitor had no significant effect in the TL, -) rats (285 +/- 53 pM, P > 0.05, n = 10). ACE2 activity was found in the effluent of perfused Tg((-)) and Tg((+)) hearts. and it was highly associated with ACE2 protein expression (r = 0.78). This study is the first demonstration for a direct role of ACE2 in the metabolism of cardiac ANG 11 in the hypertrophic heart of hypertensive rats. We Conclude that predominant expression of cardiac ACE2 activity in the Tg((+)) may be a compensatory response to the extensive cardiac remodeling in this strain.