The Hypertension and Vascular Disease Center
Wake Forest University School of Medicine
Winston Salem
NC 27104
USA
E-mail address: cferrari{at}wfubmc.edu
We read with interest the article published by Burrell et al.,1 and the accompanying editorial2 on the role of angiotensin-converting enzyme 2 (ACE2) in the evolution of myocardial infarction (MI) in rats and humans. The demonstration of increased ACE2 gene expression in both the viable myocardium and the penumbra region of the left ventricle of SpragueDawley rats within 28 days after coronary artery ligation (CAL) provides further evidence of an important counter regulatory role for ACE2 in cardiac remodelling. On the other hand, we would like to point out that their studies did not represent the first investigation on the relationship between ACE2 and MI. A study from this laboratory,3 first showed a contribution of ACE2 in cardiac remodelling post-MI in Lewis rats. Although our study showed no change in myocardial ACE2 mRNA in the interventricular septum after CAL, a significant three-fold rise in ACE2 mRNA occurred in rats receiving either of two angiotensin II (Ang II) receptor blockers (losartan or olmesartan) for 28 days after occlusion of a coronary artery.3 The increased cardiac ACE2 mRNA during blockade of Ang II receptors correlated with increases in plasma Ang-(17) and could not be reversed by concomitant pharmacological inhibition of the AT2 receptor with PD123319. As indicated in the editorial4 that accompanied the publication of our paper,3 our study showed for the first time a selective stimulation of the ACE2/Ang-(17) axis in post-MI ventricular remodelling and left ventricular function, while also suggesting that activation of this axis may, in part, explain the beneficial effects of Ang II blockade.
An additional study from our laboratory now showed that the regulatory signal mediating the cardiac ACE2 gene upregulation is negatively regulated by Ang II because 12-day oral administration of lisinopril to normal Lewis rats caused an increase in cardiac ACE2 mRNA5 not different from those found in another group of Lewis rats given losartan or those reported by us previously.3 Collectively, the data obtained from both studies3,5 suggest that inhibition of Ang II synthesis or activity stimulates increase cardiac ACE2 mRNA independent of whether the heart tissue had undergone the associated insult of ischaemic injury. The latter observation is important in the interpretation of increased ACE2 immunoreactivity of explanted human hearts reported by Burrell et al.1 Since the heart tissue analysed from these subjects was from patients receiving heart failure therapy including ACE-inhibitors, it is possible that the increased ACE2 expression in these hearts was a result of the treatment rather than ventricular remodelling. Burrell et al.1 observation of increased ACE2 mRNA after MI in SpragueDawley rats is not confirmed by our studies in Lewis rats,3 although both studies used similar approaches and methods. Whether the difference between the two studies is related to the use of two different rat strain requires further investigation. We appreciate the opportunity to update the readers of European Heart Journal on the progress made in the investigation of the evolving story of ACE2 in the regulation of cardiac function.
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