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Cardiovascular Research Advance Access first published online on September 2, 2009
This version [Corrected Proof] published online on September 18, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp303
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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.

Arginase inhibition mediates cardioprotection during ischaemia–reperfusion

Christian Jung1,*, Adrian T. Gonon1, Per-Ove Sjöquist1, Jon O. Lundberg2 and John Pernow1

1 Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden
2 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

* Corresponding author. Tel: +46 8 51773560, Fax: +46 8 313147, Email: christian.jung{at}karolinska.se or jung_christian{at}gmx.de

Aims: Nitric oxide (NO) is vital for the integrity of the cardiovascular system and protection against ischaemic heart disease. Arginase is up-regulated during ischaemia–reperfusion (IR) and this enzyme might compete with NO synthase (NOS) for arginine. The present study investigated whether arginase blockade protects from myocardial IR injury and whether such an effect is coupled to increased NO bioavailability.

Methods and results: Sprague–Dawley rats were subjected to 30 min of coronary artery ligation, followed by 2 h of reperfusion. The animals were given either saline, or the arginase inhibitor N-omega-hydroxy-nor-L-arginine (nor-NOHA) with or without the NO scavenger carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (cPTIO) or the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) iv 15 min before ischaemia. The infarct size was 79 ± 4% of the area at risk in the control group. Nor-NOHA treatment reduced the infarct size to 39 ± 7% (P < 0.001). Administration of cPTIO or L-NMMA completely abolished the protective effect of nor-NOHA. Expression of arginase I was significantly (P < 0.05) increased in ischaemic myocardium. Nor-NOHA treatment resulted in higher plasma levels of nitrite (P < 0.05) and a 10-fold increase in the citrulline/ornithine ratio (P < 0.001), indicating a shift in arginine utilization towards NOS.

Conclusion: Inhibition of arginase protects from myocardial infarction by a mechanism that is dependent on NOS activity and bioavailability of NO by shifting arginine utilization from arginase towards NOS. These findings suggest that targeting of arginase is a promising future therapeutic strategy for protection against myocardial IR injury.

KEYWORDS Arginase; Nor-NOHA; Nitric oxide; Ischaemia–reperfusion; Cardioprotection

Time for primary review: 16 days


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