Red Blood Cells in Type 2 Diabetes Impair Cardiac Post-Ischemic Recovery Through an Arginase-Dependent Modulation of Nitric Oxide Synthase and Reactive Oxygen Species

Yang, Jiangning; Zheng, Xiaowei; Mahdi, Ali; Zhou, Zhichao; Tratsiakovich, Yahor; Jiao, Tong; Kiss, Attila; Kövamees, Oskar; Alvarsson, Michael; Catrina, Sergiu‐Bogdan; Lundberg, Jon O.; Brismar, Kerstin; Pernow, John

doi:10.1016/j.jacbts.2018.03.006

Cited by 49 publications

(74 citation statements)

References 37 publications

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“…Conversely, arginine metabolism by arginase 1, which is also present and functional in mature RBCs (D'Alessandro et al, 2019a), generates ornithine without the net production of vasoactive NO. Increased arginase-1 activity in the RBCs of patients with Type 2 diabetes is associated with superoxide production and accelerated endothelial dysfunction (Yang et al, 2018;Mahdi et al, 2019;Pernow et al, 2019), suggesting a link between increased RBC arginase-1 activity and CVD. We previously showed that macaque RBCs had significantly higher levels of arginine and its catabolites, compared to human RBCs.…”

Section: Discussionmentioning

confidence: 99%

“…We highlight this pathway, given the importance of nitric oxide (NO) as an RBC-transported signaling molecule that modulates vascular responsiveness to hypoxia (Doctor and Stamler, 2011); in addition, NO depletion may be a relevant component of the storage lesion that affects transfusion efficacy (Bennett-Guerrero et al, 2007;Kanias et al, 2013;Reynolds et al, 2018). Further, in the context of cardiovascular disease (CVD), RBC imbalances in arginase and NO synthase suggest that increased RBC arginase-1 activity decreases NO bioavailability, superoxide production, endothelial dysfunction, and enhances post-ischemic cardiac failure (Yang et al, 2018;Mahdi et al, 2019;Pernow et al, 2019). Nonetheless, to our knowledge no studies have examined RBC metabolomes of multiple, closely related, primate species, particularly regarding arginine metabolism.…”

Section: Introductionmentioning

confidence: 99%

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ZOOMICS: Comparative Metabolomics of Red Blood Cells From Old World Monkeys and Humans

et al. 2020

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As part of the ZOOMICS project, we set out to investigate common and diverging metabolic traits in the blood metabolome across various species by taking advantage of recent developments in high-throughput metabolomics. Here we provide the first comparative metabolomics analysis of fresh and stored human (n = 21, 10 males, 11 females), olive baboon (n = 20), and rhesus macaque (n = 20) red blood cells at baseline and upon 42 days of storage under blood bank conditions. The results indicated similarities and differences across species, which ultimately resulted in a differential propensity to undergo morphological alterations and lyse as a function of the duration of refrigerated storage. Focusing on purine oxidation, carboxylic acid, fatty acid, and arginine metabolism further highlighted species-specific metabolic wiring. For example, through a combination of steady state measurements and 13 C 6 15 N 4-arginine tracing experiments, we report an increase in arginine catabolism into ornithine in humans, suggestive of species-specific arginase 1 activity and nitric oxide synthesis-an observation that may impact the translatability of cardiovascular disease studies carried out in non-human primates (NHPs). Finally, we correlated metabolic measurements to storage-induced morphological alterations via scanning electron microscopy and hemolysis, which were significantly lower in human red cells compared to both NHPs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ZOOMICS: Comparative Metabolomics of Red Blood Cells From Old World Monkeys and Humans

et al. 2020

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“…44 Interestingly, arginase is up-regulated in erythrocytes in type 2 diabetes-an important comorbidity in patients with STEMI. 45,46 Accordingly, it was recently demonstrated that erythrocytes from both mice and patients with type 2 diabetes markedly impair recovery of cardiac systolic function, increase left ventricular end-diastolic pressure and increase infarct size following IR in comparison with erythrocytes from control mice or healthy humans. 46 The underlying mechanism behind this effect was increased arginase activity in erythrocytes which led to a decrease in NO production.…”

Section: Erythrocytesmentioning

confidence: 99%

“…45,46 Accordingly, it was recently demonstrated that erythrocytes from both mice and patients with type 2 diabetes markedly impair recovery of cardiac systolic function, increase left ventricular end-diastolic pressure and increase infarct size following IR in comparison with erythrocytes from control mice or healthy humans. 46 The underlying mechanism behind this effect was increased arginase activity in erythrocytes which led to a decrease in NO production. It further resulted in increased reactive oxygen species (ROS) production due to uncoupling of NOS3 and increased expression of NADPH oxidase (NOX2) in erythrocytes.…”

Section: Erythrocytesmentioning

confidence: 99%

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Circulating blood cells and extracellular vesicles in acute cardioprotection

Davidson

Andreadou

Barile

et al. 2018

Cardiovascular Research

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115

111

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During an ST-elevation myocardial infarction (STEMI), the myocardium undergoes a prolonged period of ischaemia. Reperfusion therapy is essential to minimize cardiac injury but can paradoxically cause further damage. Experimental procedures to limit ischaemia and reperfusion (IR) injury have tended to focus on the cardiomyocytes since they are crucial for cardiac function. However, there is increasing evidence that non-cardiomyocyte resident cells in the heart (as discussed in a separate review in this Spotlight series) as well as circulating cells and factors play important roles in this pathology. For example, erythrocytes, in addition to their main oxygen-ferrying role, can protect the heart from IR injury via the export of nitric oxide bioactivity. Platelets are well-known to be involved in haemostasis and thrombosis, but beyond these roles, they secrete numerous factors including sphingosine-1 phosphate (S1P), platelet activating factor, and cytokines that can all strongly influence the development of IR injury. This is particularly relevant given that most STEMI patients receive at least one type of platelet inhibitor. Moreover, there are large numbers of circulating vesicles in the blood, including microvesicles and exosomes, which can exert both beneficial and detrimental effects on IR injury. Some of these effects are mediated by the transfer of microRNA (miRNA) to the heart. Synthetic miRNA molecules may offer an alternative approach to limiting the response to IR injury. We discuss these and other circulating factors, focussing on potential therapeutic targets relevant to IR injury. Given the prevalence of comorbidities such as diabetes in the target patient population, their influence will also be discussed. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.

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Anaemia is associated with severe RBC dysfunction and a reduced circulating NO pool: vascular and cardiac eNOS are crucial for the adaptation to anaemia

et al. 2020

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Anaemia is frequently present in patients with acute myocardial infarction (AMI) and contributes to an adverse prognosis. We hypothesised that, besides reduced oxygen carrying capacity, anaemia is associated with (1) red blood cell (RBC) dysfunction and a reduced circulating nitric oxide (NO) pool, (2) compensatory enhancement of vascular and cardiac endothelial nitric oxide synthase (eNOS) activity, and (3) contribution of both, RBC dysfunction and reduced circulatory NO pool to left ventricular (LV) dysfunction and fatal outcome in AMI. In mouse models of subacute and chronic anaemia from repeated mild blood loss the circulating NO pool, RBC, cardiac and vascular function were analysed at baseline and in reperfused AMI. In anaemia, RBC function resulted in profound changes in membrane properties, enhanced turnover, haemolysis, dysregulation of intra-erythrocytotic redox state, and RBC-eNOS. RBC from anaemic mice and from anaemic patients with acute coronary syndrome impaired the recovery of contractile function of isolated mouse hearts following ischaemia/reperfusion. In anaemia, the circulating NO pool was reduced. The cardiac and vascular adaptation to anaemia was characterised by increased arterial eNOS expression and activity and an eNOS-dependent increase of end-diastolic left ventricular volume. Endothelial dysfunction induced through genetic or pharmacologic reduction of eNOS-activity abrogated the anaemia-induced cardio-circulatory compensation. Superimposed AMI was associated with decreased survival. In summary, moderate blood loss anaemia is associated with severe RBC dysfunction and reduced circulating NO pool. Vascular and cardiac eNOS are crucial for the cardio-circulatory adaptation to anaemia. RBC dysfunction together with eNOS dysfunction may contribute to adverse outcomes in AMI.

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Red Blood Cells in Type 2 Diabetes Impair Cardiac Post-Ischemic Recovery Through an Arginase-Dependent Modulation of Nitric Oxide Synthase and Reactive Oxygen Species

Abstract: Visual Abstract

Cited by 49 publications

References 37 publications

ZOOMICS: Comparative Metabolomics of Red Blood Cells From Old World Monkeys and Humans

ZOOMICS: Comparative Metabolomics of Red Blood Cells From Old World Monkeys and Humans

Circulating blood cells and extracellular vesicles in acute cardioprotection

Anaemia is associated with severe RBC dysfunction and a reduced circulating NO pool: vascular and cardiac eNOS are crucial for the adaptation to anaemia

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