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Arginase inhibition mediates cardioprotection during ischaemia–reperfusion
Abstract
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 N(G)-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.
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Metadata
- Authors
- Jung, C., Gonon, A. T., Sjoquist, P.-O., Lundberg, J. O., & Pernow, J.
- Affiliations
- Karolinska University Hospital (SE)
- Karolinska Institutet (SE)
- Corresponding author
- Jung, C.
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-09-02
- Volume
- 85
- Issue
- 1
- Pages
- 147-154
- ISSN
- 0008-6363 (ISSN-L)
- OpenAlex
- W2019788114
- Cited by
- 139
- References
- 35
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 11 · 2023: 1 · 2022: 7 · 2021: 6 · 2020: 16 · 2019: 3 · 2018: 8 · 2017: 6 · 2016: 6 · 2015: 10 · 2014: 17 · 2013: 16 · 2012: 8
- FWCI
- 6.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cardiovascular Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Novo Nordisk
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Keywords
- arginase inhibition, myocardial ischemia-reperfusion injury, nitric oxide bioavailability, nitric oxide synthase, arginine utilization, nor-NOHA, cardioprotection, myocardial infarct size, nitrite, L-NMMA, cPTIO
- MeSH terms
- Amino Acids, Animals, Arginase, Arginine, Blood Pressure, Enzyme Inhibitors, Heart Rate, Male, Myocardial Infarction, Myocardium, Nitric Oxide, Nitrites, Myocardial Reperfusion Injury, Rats, Sprague-Dawley, Nitric Oxide Synthase, Rats
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