European Heart Journal Advance Access originally published online on April 15, 2005
European Heart Journal 2005 26(11):1141-1142; doi:10.1093/eurheartj/ehi257
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Myocardial infarction increases ACE2 expression in rat and humans: reply
One University Place
DB224 Rensselaer
NY 12144
USA
Tel: +1 518 573 8315
Fax: +1 518 375 7029
E-mail address: lzisman{at}myomatrix.com
Dr Ferrario correctly points out that the findings from Dr Burrell's laboratory differ from those reported by his group. No change in ACE2 gene expression was found in his group's study after myocardial infarction (MI) without drug treatment, whereas Dr Burrell's group1 found that ACE2 gene expression and activity were increased in viable myocardium after MI in the rat. Dr Ferrario suggests that this difference may be attributable to the strain of rat used. It is of interest to note that in both the Sprague–Dawley rat and the Wistar rat cardiac ACE activity was increased post-MI.2,3 Dr Ferrario's finding that ACE mRNA was not increased in the Lewis rat post-MI seems to support the argument that there may be inter-strain differences in the cardiac renin-angiotensin-aldosterone system (RAAS) response to stress. Unfortunately, neither ACE activity nor ACE2 activity was reported in Dr Ferrario's Lewis rat MI study.
Differences in methodology could also explain the different findings reported by Dr Burrell's group and Dr Ferrario's group. Dr Burrell's lab used real-time quantitative polymerase chain reaction (PCR) (the cycle threshold method) to assess gene expression, whereas Dr Ferrario's group relied on densitometric analysis of PCR fragments after 30 or more amplification cycles. In addition, the control genes used were different: Dr Burrell's lab used 18S and Dr Ferrario's group used EF1
.
With regard to studies in human tissues, it has now been demonstrated in relatively large series that ACE protein concentration, activity, and gene expression are increased in failing human heart ventricles.4,5 These studies controlled for treatment with ACE-inhibitors. There was no significant difference in cardiac ACE gene or protein expression in subjects treated with ACE-inhibitors compared with those not so treated. It has also been shown that ACE2 activity was increased in failing human heart ventricles from patients with either idiopathic dilated cardiomyopathy or primary pulmonary hypertension.6 Of note, none of the patients with primary pulmonary hypertension received treatment with either an ACE-inhibitor or an angiotensin type I receptor antagonist. In my opinion, the key incremental finding reported by Dr Burrell's group with regard to studies of human heart tissue is that ACE2 was present in cardiac myocytes from failing human heart, a finding that had not been previously reported.
A common theme in human heart failure of diverse aetiology, whether idiopathic, ischaemic, or caused by pressure overload, is an increase in wall stress. It is my suggestion that investigators in this field direct their attention to mechanisms whereby increased wall stress can lead to increased ACE2 expression and/or activity in the failing heart. Furthermore, the functional consequences of such increased expression need to be explored. The data reported by Dr Burrell's group show that the Sprague–Dawley rat MI model is appropriate to use for such investigations because it closely reflects what occurs in failing human heart.
All of the above being said, I would like to acknowledge here, as I have done elsewhere,6 Dr Ferrario's and his colleagues' groundbreaking work which has demonstrated the potential importance of angiotensin-(1–7) as a counter-regulatory hormone in heart failure.
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] - Hirsch AT, Talsness CE, Schunkert H, Paul M, Dzau VJ. Tissue-specific activation of cardiac angiotensin converting enzyme in experimental heart failure. Circ Res 1991;69:475–482.
[Abstract/Free Full Text] - Pinto YM, de Smet BG, van Gilst WH, Scholtens E, Monnink S, de Graeff PA, Wesseling H. Selective and time related activation of the cardiac renin-angiotensin system after experimental heart failure: relation to ventricular function and morphology. Cardiovasc Res 1993;27:1933–1938.
[Abstract/Free Full Text] - Zisman LS, Asano K, Dutcher D, Ferdensi T, Jenkin M, Bush E, Bohlmeyer T, Robertson AD, Bristow MR, Perryman MB. Differential regulation of cardiac angiotensin converting enzyme (ACE) binding sites and AT1 receptor density in the failing human heart. Circulation 1998;98:1735–1741.
[Abstract/Free Full Text] - Studer R, Reinecke H, Muller B, Holtz J, Just H and Drexler H. Increased angiotensin-I converting enzyme gene expression in the failing human heart. J Clin Invest 1994;94:301–310.[ISI][Medline]
- Zisman LS, Keller RS, Weaver B, Lin Q, Speth R, Bristow MR, Canver CC. Increased angiotensin-(1-7) forming activity in failing human heart ventricles: evidence for upregulation of the angiotensin-converting enzyme homologue, ACE2. Circulation 2003;108:1707–1712.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||