Red blood cells from endothelial nitric oxide synthase-deficient mice induce vascular dysfunction involving oxidative stress and endothelial arginase I

Zhuge, Zhengbing; Haworth, SarahMcCann; Nihlén, Carina; Carvalho, Lucas Rannier Ribeiro Antonino; Heuser, Sophia K.; Nasiell, Josefine; Cortese‐Krott, Miriam M.; Weitzberg, Eddie; Lundberg, Jon O.; Carlström, Mattias

doi:10.1016/j.redox.2023.102612

Cited by 16 publications

(12 citation statements)

References 51 publications

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“…An intriguing further question arises as to whether NOferroheme species formed in RBC can slowly partition back to the vascular wall. This may be relevant to the recent demonstration of the endothelium damaging effect of RBC obtained from eNOS knockout mice 40 as well as for the export of vasodilatory [19][20][21][22] and cardioprotective 41 NO bioactivity by RBCs.…”

Section: Discussionmentioning

confidence: 93%

NO-ferroheme is a signaling entity in the vasculature

Zhuge

Schiffer

Guimarães

et al. 2023

Preprint

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Despite wide appreciation of the biological role of nitric oxide (NO) synthase (NOS) signaling, questions remain about the chemical nature of NOS-derived bioactivity. Here we show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species which can exchange proteins, partition to the hydrophobic phase, and directly activate the sGC-cGMP-PKG pathway without the intermediacy of free NO. The NO-ferroheme entity efficiently relaxes isolated blood vessels and induces hypotension in rodents, which is greatly potentiated after blockade of NOS activity. While free NO-induced relaxations are abolished by an NO scavenger and in the presence of red blood cells or blood plasma, NO-ferroheme preserves its vasoactivity, suggesting physiological relevance of these yet underappreciated species. We conclude that NO-ferroheme behaves as a signaling entity in the vasculature.

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Section: Discussionmentioning

confidence: 93%

NO-ferroheme is a signaling entity in the vasculature

Zhuge

Schiffer

Guimarães

et al. 2023

Preprint

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“…The erythrocyte is considered to control the local blood flow via three possible nitric oxide‐mediated mechanisms: (i) release ATP to stimulate the production of nitric oxide by the endothelial cells, (ii) release nitric oxide derived from nitrosohaemoglobin, and (iii) release nitric oxide derived from the nitric oxide synthases and the nitrate–nitrite–nitric oxide reduction pathway in the erythrocyte 104,176,454,508–518 . Products of normal nitrogen metabolism, such as nitrosothiols 100 and peroxynitrite, can also induce vasodilation 519–522 .…”

Section: The Dynamics Of Erythrocyte Metabolismmentioning

confidence: 99%

“…The major sources of superoxide (i.e., the parent reactive oxygen species) and hydrogen peroxide production in the erythrocyte are NADPH oxidases, superoxide dismutase, haemoglobin auto-oxidation, and free iron, that is, nonheme-conjugated iron. 73,94,172,173 Some studies report the presence of NADPH oxidases in erythrocytes, [174][175][176] yet, further experimental evidence is required. NADPH oxidases utilize NADPH and oxygen to produce NADP + and superoxide.…”

Section: Redox Metabolismmentioning

confidence: 99%

“…273,485,504-507 3.5.2 | Erythrocytes "pave their own path" in the microcirculation The erythrocyte is considered to control the local blood flow via three possible nitric oxide-mediated mechanisms: (i) release ATP to stimulate the production of nitric oxide by the endothelial cells, (ii) release nitric oxide derived from nitrosohaemoglobin, and (iii) release nitric oxide derived from the nitric oxide synthases and the nitrate-nitrite-nitric oxide reduction pathway in the erythrocyte. 104,176,454,[508][509][510][511][512][513][514][515][516][517][518] Products of normal nitrogen metabolism, such as nitrosothiols 100 and peroxynitrite, can also induce vasodilation. [519][520][521][522] During low oxygen tension, the erythrocyte deformation increases ATP release via the activation of mechanosensitive Piezo1 channels.…”

Section: The Erythrocyte Transports Carbon Dioxide and Buffers Ph In ...mentioning

confidence: 99%

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Erythrocyte metabolism

Chatzinikolaou,

Margaritelis,

Paschalis

et al. 2024

Acta Physiologica

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Our aim is to present an updated overview of the erythrocyte metabolism highlighting its richness and complexity. We have manually collected and connected the available biochemical pathways and integrated them into a functional metabolic map. The focus of this map is on the main biochemical pathways consisting of glycolysis, the pentose phosphate pathway, redox metabolism, oxygen metabolism, purine/nucleoside metabolism, and membrane transport. Other recently emerging pathways are also curated, like the methionine salvage pathway, the glyoxalase system, carnitine metabolism, and the lands cycle, as well as remnants of the carboxylic acid metabolism. An additional goal of this review is to present the dynamics of erythrocyte metabolism, providing key numbers used to perform basic quantitative analyses. By synthesizing experimental and computational data, we conclude that glycolysis, pentose phosphate pathway, and redox metabolism are the foundations of erythrocyte metabolism. Additionally, the erythrocyte can sense oxygen levels and oxidative stress adjusting its mechanics, metabolism, and function. In conclusion, fine‐tuning of erythrocyte metabolism controls one of the most important biological processes, that is, oxygen loading, transport, and delivery.

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“…RBCs influence NO bioavailability and endothelial cell integrity, impacting vascular tone and endothelial health. [68] Altered RBC properties, including impaired deformability, contribute to decreased oxygen delivery to tissues. Tissue hypoxia is a key factor in the development of diabetic complications, including retinopathy, nephropathy, and neuropathy.…”

Section: Rbcs As Mediators Of Diabetic Complicationsmentioning

confidence: 99%

Red blood cells as biomarkers and mediators in complications of diabetes mellitus: A review

Obeagu

2024

Medicine

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Red blood cells (RBCs), traditionally recognized for their oxygen transport role, have garnered increasing attention for their significance as crucial contributors to the pathophysiology of diabetes mellitus. In this comprehensive review, we elucidate the multifaceted roles of RBCs as both biomarkers and mediators in diabetes mellitus. Amidst the intricate interplay of altered metabolic pathways and the diabetic milieu, RBCs manifest distinct alterations in their structure, function, and lifespan. The chronic exposure to hyperglycemia induces oxidative stress, leading to modifications in RBC physiology and membrane integrity. These modifications, including glycation of hemoglobin (HbA1c), establish RBCs as invaluable biomarkers for assessing glycemic control over extended periods. Moreover, RBCs serve as mediators in the progression of diabetic complications. Their involvement in vascular dysfunction, hemorheological changes, and inflammatory pathways contributes significantly to diabetic microangiopathy and associated complications. Exploring the therapeutic implications, this review addresses potential interventions targeting RBC abnormalities to ameliorate diabetic complications. In conclusion, comprehending the nuanced roles of RBCs as biomarkers and mediators in diabetes mellitus offers promising avenues for enhanced diagnostic precision, therapeutic interventions, and improved patient outcomes. This review consolidates the current understanding and emphasizes the imperative need for further research to harness the full potential of RBC-related insights in the realm of diabetes mellitus.

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Red blood cells from endothelial nitric oxide synthase-deficient mice induce vascular dysfunction involving oxidative stress and endothelial arginase I

Cited by 16 publications

References 51 publications

NO-ferroheme is a signaling entity in the vasculature

NO-ferroheme is a signaling entity in the vasculature

Erythrocyte metabolism

Red blood cells as biomarkers and mediators in complications of diabetes mellitus: A review

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