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Cardiovascular Research Advance Access first published online on January 15, 2009
This version [Corrected Proof] published online on January 24, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp003
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Cardiac chymase converts rat proAngiotensin-12 (PA12) to angiotensin II: effects of PA12 upon cardiac haemodynamics

Hamish C.G. Prosser1,2,*, Malcolm E. Forster1, A. Mark Richards2 and Chris J. Pemberton2

1 School of Biological Sciences, University of Canterbury, PO Box 4800, Christchurch, New Zealand
2 Christchurch Cardioendocrine Research Group, Department of Medicine, University of Otago, Christchurch, New Zealand

* Corresponding author. Tel: +64 3 3640848; fax: +64 3 3640818. E-mail address: hamishprosser{at}gmail.com

Aims: The aim of this study was to observe the direct physiological and biochemical cardiac effects in response to a newly identified putative component of the renin–angiotensin system, proangiotensin-12 (PA12); and investigate whether PA12 can serve as a substrate for Angiotensin II (AngII) generation.

Methods and results: The direct cardiac actions of PA12 and its role as a substrate for chymase-dependent AngII generation were investigated in Sprague–Dawley rats using an isolated heart model of cardiac ischaemia–reperfusion injury. PA12 potently constricted coronary arteries with no significant effect on left-ventricular contractility. PA12 impaired recovery from global ischaemia, maintaining coronary constriction and markedly increasing release of creatine kinase and troponin I (TnI), indicating greater myocardial injury. Analysis of perfusate collected after transcardiac passage revealed a marked increase in AngII production from hearts infused with PA12. Cardiac AngII production was not blocked by angiotensin-converting enzyme inhibitors, whereas inhibition of chymase with chymostatin significantly reduced AngII production and attenuated PA12-induced vasoconstriction and myocardial damage following ischaemia. Furthermore, Angiotensin II type 1 receptor (AT1R) blockade abolished PA12 activity. In vitro, PA12 was efficiently and precisely converted to AngII as assessed on reverse phase-high performance liquid chromatography coupled to tandem mass spectrometry. This conversion was blocked by chymostatin.

Conclusion: PA12 may act as a circulating substrate for cardiac chymase-mediated AngII production, in contrast to ACE-mediated AngII production from AngI.

KEYWORDS ProAngiotensin-12; Langendorff isolated rat heart; Ischemia-reperfusion injury; Cardiac angiotensin II production; Chymase

Time for primary review: 41 days


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