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Antioxidants
Volume 15
Issue 1
10.3390/antiox15010058
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Targeting Arginase 1 but Not Arginase 2 Protects from Myocardial Ischemia–Reperfusion Injury via Nitric Oxide Signaling by Red Blood Cells in Type 2 Diabetes

by
Jiangning Yang
1,2,*,
Yahor Tratsiakovich
1,2,
Renhai Cao
2,
Ali Mahdi
1,2,3,
Gianluigi Pironti
1,4,
Tong Jiao
1,2,
Rawan Humoud
1,2,
Eftychia Kontidou
1,2,
John Tengbom
1,2,
Aida Collado
1,2,
Zhichao Zhou
1,2,
Yihai Cao
5,
Eleonore Köhler
6,
Adam E. Mullick
7 and
John Pernow
1,2,4
1
Department of Medicine, Unit of Cardiology, Karolinska Institutet, 17177 Stockholm, Sweden
2
Center for Molecular Medicine, Karolinska University Hospital, 17176 Stockholm, Sweden
3
Department of Cardiology, Karolinska University Hospital, 17176 Stockholm, Sweden
4
Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden
5
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
6
Department of Anatomy and Embryology, Maastricht University, 6200 MD Maastricht, The Netherlands
7
Ionis Pharmaceuticals Inc., Carlsbad, CA 92010, USA
*
Author to whom correspondence should be addressed.
Antioxidants 2026, 15(1), 58; https://doi.org/10.3390/antiox15010058 (registering DOI)
Submission received: 21 November 2025 / Revised: 20 December 2025 / Accepted: 28 December 2025 / Published: 1 January 2026
(This article belongs to the Special Issue Blood Cells and Redox Homeostasis in Health and Disease, 2nd Edition)
Versions Notes

Abstract

Background: Arginase influences cardiac tolerance to ischemia–reperfusion by modulating nitric oxide (NO) signaling. In type 2 diabetes (T2D), elevated arginase activity may worsen ischemic injury through red blood cells (RBCs), but the specific roles of arginase isoforms are unclear. Methods: C57BL/6 and db/db mice were pretreated with ARG1 or ARG2 antisense oligonucleotides (ASO) for six weeks. Conditional ARG1 knockout (ARG1fl/fl/Tie2Cretg/−) and wild-type littermates were also studied. Mice underwent coronary artery ligation and reperfusion in vivo for infarct size assessment. In ex vivo experiments, buffer-perfused hearts were subjected to global ischemia–reperfusion with or without RBCs to evaluate recovery of left ventricular developed pressure (LVDP). Results: ARG1 knockdown, but not ARG2, improved post-ischemic recovery of LVDP in isolated hearts. RBCs from ARG1 ASO-treated mice enhanced recovery in wild-type hearts, while ARG1 knockout reduced infarct size compared with controls. Cardioprotection was abolished by NO synthase inhibition. RBCs from male and female ARG1 knockout mice improved LVDP recovery compared with RBCs from wild-type mice. In T2D mice, impaired recovery was restored by ARG1 ASO or RBCs from ARG1 ASO-treated T2D mice. Conclusions: Arginase 1, but not arginase 2, limits cardiac tolerance to ischemia–reperfusion and contributes to increased vulnerability in T2D.
Keywords: arginase; nitric oxide; ischemic tolerance; type 2 diabetes; sex arginase; nitric oxide; ischemic tolerance; type 2 diabetes; sex

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MDPI and ACS Style

Yang, J.; Tratsiakovich, Y.; Cao, R.; Mahdi, A.; Pironti, G.; Jiao, T.; Humoud, R.; Kontidou, E.; Tengbom, J.; Collado, A.; et al. Targeting Arginase 1 but Not Arginase 2 Protects from Myocardial Ischemia–Reperfusion Injury via Nitric Oxide Signaling by Red Blood Cells in Type 2 Diabetes. Antioxidants 2026, 15, 58. https://doi.org/10.3390/antiox15010058

AMA Style

Yang J, Tratsiakovich Y, Cao R, Mahdi A, Pironti G, Jiao T, Humoud R, Kontidou E, Tengbom J, Collado A, et al. Targeting Arginase 1 but Not Arginase 2 Protects from Myocardial Ischemia–Reperfusion Injury via Nitric Oxide Signaling by Red Blood Cells in Type 2 Diabetes. Antioxidants. 2026; 15(1):58. https://doi.org/10.3390/antiox15010058

Chicago/Turabian Style

Yang, Jiangning, Yahor Tratsiakovich, Renhai Cao, Ali Mahdi, Gianluigi Pironti, Tong Jiao, Rawan Humoud, Eftychia Kontidou, John Tengbom, Aida Collado, and et al. 2026. "Targeting Arginase 1 but Not Arginase 2 Protects from Myocardial Ischemia–Reperfusion Injury via Nitric Oxide Signaling by Red Blood Cells in Type 2 Diabetes" Antioxidants 15, no. 1: 58. https://doi.org/10.3390/antiox15010058

APA Style

Yang, J., Tratsiakovich, Y., Cao, R., Mahdi, A., Pironti, G., Jiao, T., Humoud, R., Kontidou, E., Tengbom, J., Collado, A., Zhou, Z., Cao, Y., Köhler, E., Mullick, A. E., & Pernow, J. (2026). Targeting Arginase 1 but Not Arginase 2 Protects from Myocardial Ischemia–Reperfusion Injury via Nitric Oxide Signaling by Red Blood Cells in Type 2 Diabetes. Antioxidants, 15(1), 58. https://doi.org/10.3390/antiox15010058

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