Effect of Arginase Inhibition on Ischemia-Reperfusion Injury in Patients with Coronary Artery Disease with and without Diabetes Mellitus
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BACKGROUND: Arginase competes with nitric oxide synthase for their common substrate L-arginine. Up-regulation of arginase in coronary artery disease (CAD) and diabetes mellitus may reduce nitric oxide bioavailability contributing to endothelial dysfunction and ischemia-reperfusion injury. Arginase inhibition reduces infarct size in animal models. Therefore the aim of the current study was to investigate if arginase inhibition protects from endothelial dysfunction induced by ischemia-reperfusion in patients with CAD with or without type 2 diabetes ( CLINICAL TRIAL REGISTRATION NUMBER: NCT02009527). METHODS: Male patients with CAD (n = 12) or CAD + type 2 diabetes (n = 12), were included in this cross-over study with blinded evaluation. Endothelium-dependent vasodilatation was assessed by flow-mediated dilatation (FMD) of the radial artery before and after 20 min ischemia-reperfusion during intra-arterial infusion of the arginase inhibitor (Nω-hydroxy-nor-L-arginine, 0.1 mg/min) or saline. RESULTS: The forearm ischemia-reperfusion was well tolerated. Endothelium-independent vasodilatation was assessed by sublingual nitroglycerin. Ischemia-reperfusion decreased FMD in patients with CAD from 12.7±5.2% to 7.9±4.0% during saline administration (P<0.05). Nω-hydroxy-nor-L-arginine administration prevented the decrease in FMD in the CAD group (10.3±4.3% at baseline vs. 11.5±3.6% at reperfusion). Ischemia-reperfusion did not significantly reduce FMD in patients with CAD + type 2 diabetes. However, FMD at reperfusion was higher following nor-NOHA than following saline administration in both groups (P<0.01). Endothelium-independent vasodilatation did not differ between the occasions. CONCLUSIONS: Inhibition of arginase protects against endothelial dysfunction caused by ischemia-reperfusion in patients with CAD. Arginase inhibition may thereby be a promising therapeutic strategy in the treatment of ischemia-reperfusion injury.
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Arginase inhibition with nor-NG-hydroxy-l-arginine showed protection against ischemia-reperfusion injury and improved endothelial function in patients with coronary artery disease and diabetes and in patients with hypercholesterolemia.
“In these cases, arginase inhibition showed protection against ischemia-reperfusion injury (530) and improved endothelial function in patients with coronary artery disease and diabetes (855) and in patients with hypercholesterolemia (529).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [529]
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Симутис, И. С., Semigolovskii, N. Y., Lobachenko, I. G., Sapegin, A. A., Danilov, M. S., Yusupov, E., Enkina, T. N., Blitsyn, K., Karpov, I. E., & Suvorova, J. V. (2026) · Russian Journal of Cardiology and Cardiovascular Surgery · doi:10.17116/kardio20261902175
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- Authors
- Kövamees, O., Shemyakin, A., & Pernow, J.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Kövamees, Oskar
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-07-29
- Volume
- 9
- Issue
- 7
- Pages
- e103260
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4114552
- OpenAlex
- W2009085606
- Cited by
- 57
- References
- 32
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 6 · 2023: 2 · 2022: 5 · 2021: 3 · 2020: 8 · 2019: 3 · 2018: 10 · 2017: 2 · 2016: 6 · 2015: 7
- FWCI
- 3.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- European Foundation for the Study of Diabetes
- Karolinska Institutet
- Novo Nordisk
- Stockholms Läns Landsting
- Vetenskapsrådet (10857)
- Novo Nordisk Fonden (NNF14OC0010417)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Keywords
- arginase inhibition, ischemia-reperfusion injury, coronary artery disease, type 2 diabetes, endothelial dysfunction, nitric oxide bioavailability, L-arginine, flow-mediated dilation, endothelium-independent vasodilatation, nitroglycerin
- MeSH terms
- Aged, Arginase, Coronary Artery Disease, Diabetes Mellitus, Type 2, Enzyme Inhibitors, Humans, Male, Middle Aged, Vasodilation, Vasodilator Agents, Myocardial Reperfusion Injury, Treatment Outcome, Radial Artery, Cross-Over Studies
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