Author + information
- Received February 5, 2018
- Revision received May 5, 2018
- Accepted May 20, 2018
- Published online August 6, 2018.
- Zhichao Zhou, MD, PhDa,∗∗ ( )(, )@karolinskainst,
- Ali Mahdi, BSca,∗,
- Yahor Tratsiakovich, MD, PhDa,
- Szabolcs Zahorán, MScb,
- Oskar Kövamees, MD, PhDa,
- Filip Nordin, BSca,
- Arturo Eduardo Uribe Gonzalez, MDc,
- Michael Alvarsson, MD, PhDd,
- Claes-Göran Östenson, MD, PhDd,
- Daniel C Andersson, MD, PhDc,e,
- Ulf Hedin, MD, PhDf,
- Edit Hermesz, PhDb,
- Jon O Lundberg, MD, PhDc,
- Jiangning Yang, MD, PhDa and
- John Pernow, MD, PhDa,e
- aDivision of Cardiology, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
- bDepartment of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary
- cDepartment of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- dDivision of Endocrinology and Diabetology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- eHeart and Vascular Theme, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
- fDivision of Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- ↵∗Address for correspondence:
Dr. Zhichao Zhou, CMM L8:03, Division of Cardiology, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm 17176, Sweden.
Background Cardiovascular complications are major clinical problems in type 2 diabetes mellitus (T2DM). The authors previously demonstrated a crucial role of red blood cells (RBCs) in control of cardiac function through arginase-dependent regulation of nitric oxide export from RBCs. There is alteration of RBC function, as well as an increase in arginase activity, in T2DM.
Objectives The authors hypothesized that RBCs from patients with T2DM induce endothelial dysfunction by up-regulation of arginase.
Methods RBCs were isolated from patients with T2DM and age-matched healthy subjects and were incubated with rat aortas or human internal mammary arteries from nondiabetic patients for vascular reactivity and biochemical studies.
Results Arginase activity and arginase I protein expression were elevated in RBCs from patients with T2DM (T2DM RBCs) through an effect induced by reactive oxygen species (ROS). Co-incubation of arterial segments with T2DM RBCs, but not RBCs from age-matched healthy subjects, significantly impaired endothelial function but not smooth muscle cell function in both healthy rat aortas and human internal mammary arteries. Endothelial dysfunction induced by T2DM RBCs was prevented by inhibition of arginase and ROS both at the RBC and vascular levels. T2DM RBCs induced increased vascular arginase I expression and activity through an ROS-dependent mechanism.
Conclusions This study demonstrates a novel mechanism behind endothelial dysfunction in T2DM that is induced by RBC arginase I and ROS. Targeting arginase I in RBCs may serve as a novel therapeutic tool for the treatment of endothelial dysfunction in T2DM.
- endothelial dysfunction
- reactive oxygen species
- red blood cell
- type 2 diabetes
- vascular complication
↵∗ Dr. Zhou and Mr. Mahdi contributed equally to this work.
Dr. Pernow has received grants to support this work from the Swedish Research Council, the Swedish Heart and Lung Foundation, the Stockholm County Council (ALF), the Karolinska Institutet/Stockholm County Council Strategic Cardiovascular Program, the Söderberg Foundation, the Novo Nordisk Foundation, and the Diabetes Research and Wellness Foundation. Dr. Zhou has received grants from the Olausson Fund of Thorax, Karolinska University Hospital and the Karolinska Institutet Fund for Young Scientist. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received February 5, 2018.
- Revision received May 5, 2018.
- Accepted May 20, 2018.
- 2018 American College of Cardiology Foundation
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