European Heart Journal Advance Access originally published online on April 15, 2005
European Heart Journal 2005 26(11):1142-1143; doi:10.1093/eurheartj/ehi275
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Myocardial infarction increases ACE2 expression in rat and humans: reply
Department of Medicine
The University of Melbourne
Heidelberg Repatriation Hospital
Waterdale Road
Heidelberg Heights
Melbourne VIC 3081
Australia
Tel: +61 3 94962159
Fax: +61 3 94974554
E-mail address: l.burrell{at}unimelb.edu.a
Baker Heart Research Institute
Melbourne
Australia
Baker Heart Research Institute
Melbourne
Australia
Thank you for the opportunity to respond to the comments from Ferrario and co-workers.2 We reported that myocardial infarction (MI) leads to significant upregulation of cardiac ACE2 mRNA in the Sprague–Dawley rat,1 and that treatment with an angiotensin-converting enzyme inhibitor (ACE-inhibitor) after MI does not alter ACE2 gene expression. Our results were strengthened by the observation that cardiac ACE2 activity increased in parallel to ACE2 gene expression. Indeed, we observed the increase in cardiac ACE2 after MI in three distinct studies within the same paper; at day 7 after MI, at day 28 after MI, as well as in a third group of MI rats treated for 28 days with vehicle or ramipril.
In contrast, Ferrario and co-workers2 found that cardiac ACE2 mRNA was unchanged after MI in the Lewis rat, but increased in MI rats after 28 days treatment with an angiotensin receptor blocker. Whether the changes at the gene level were translated to increased ACE2 activity was not investigated. Although the results suggest selective stimulation of the ACE2/Ang-(1–7) axis post-MI, it is possible that similar results would be obtained following angiotensin receptor blocker treatment in normal hearts from Lewis rats; this is certainly a concept that requires further exploration.
We believe that the rat strain used may play a major role in the opposite effect of MI on cardiac ACE2 noted in the two studies.1,2 For example, at day 28 post-MI, there was activation of the circulating renin–angiotensin system (RAS) in the Lewis rat, which had increased plasma Ang 1, Ang II, and Ang-(1–7).2 On the other hand, using highly sensitive and specific HPLC based radioimmunoassays,3 we reported that plasma levels of Ang 1, Ang II, and Ang-(1–7) were similar in day 28 post-MI and sham-operated rats.3 In addition, Ferrario and co-workers2 found no increase in cardiac ACE in day 28 post-MI Lewis rats, although this is a consistent finding after MI in Sprague–Dawley and Wistar rats4 as well as in the failing human heart.5 Indeed, activation of tissue ACE is recognized as a key factor in the progression of cardiovascular disease6 and underpins the clinical use of ACE inhibitors after MI.
In our most recent report, the increases in ACE2 observed in rat MI heart were also seen in ischaemic human hearts.1 These data confirm the utility of the Sprague–Dawley rat as a model in improving our understanding of ACE2 and its role in the counter-regulatory response to MI in the rat and in humans.
References
- Burrell LM, Risvanis J, Kubota E, Dean RG, MacDonald PS, Lu S, Tikellis C, Grant SL, Lew RA, Smith AI, Cooper ME, Johnston CI. Myocardial infarction increases ACE2 expression in rat and humans. Eur Heart J 2005;26:369–375.
[Abstract/Free Full Text] - Ishiyama Y, Gallagher PE, Averill DB, Tallant EA, Brosnihan KB, Ferrario CM. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension 2004;43:970–976.
[Abstract/Free Full Text] - Duncan AM, Burrell LM, Campbell DC. Angiotensin and bradykinin peptides in rats with myocardial infarction. J Card Fail 1997;3:41–52.[CrossRef][Medline]
- Passier RCJ, Smits JFM, Verluyten JA, Studer R, Drexler H, Daemen MJAP. Activation of angiotensin-converting enzyme expression in infarct zone following myocardial infarction. Am J Physiol 1995;269:H1268–H1276.
- Paul M, Pinto YM, Schunkert H, Ganten D, Bohm M. Activation of the renin-angiotensin system in heart failure and hypertrophy–studies in human hearts and transgenic rats. Eur Heart J 1994;15(Suppl. D):63–67.
- Johnston CI. Tissue angiotensin converting enzyme in cardiac and vascular hypertrophy, repair, and remodeling. Hypertension 1994;23:258–268.
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