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1 The Hypertension & Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
2 The Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States; The Hypertension and Vascular Disease Center, Wake Forest University School of Medicine
3 Max Delbrück Center for Molecular Medicine, Humboldt University Berlin, Charité, Berlin-Buch, Germany
4 Hypertension Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
* To whom correspondence should be addressed. E-mail: atrask{at}wfubmc.edu.
Angiotensin-converting enzyme 2 (ACE2) converts angiotensin II (Ang II) 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 II 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 [Tg(+)] rats. During a 60-minute recirculation period with 10 nM Ang II, the presence of Ang-(1-7) was assessed in the cardiac effluent. Ang-(1-7) generation from Ang II was similar in both the normal and hypertensive hearts (Tg(-): 510 ± 55 pM, n=20 versus Tg(+): 497 ± 63 pM, n=14) with peak levels occurring at 30 minutes after administration of the peptide. ACE2 inhibition (MLN-4760, 1µM) significantly 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 Tg(-) 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 II 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.
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