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Updated: Aug 9, 2025
A Thrombotic Stroke Model Based On Transient Cerebral Hypoxia-ischemia
Published on: August 18, 2015
Unexplored Roles of Erythrocytes in Atherothrombotic Stroke
Charalampos Papadopoulos1, Konstantinos Anagnostopoulos1, Dimitrios Tsiptsios2
1Laboratory of Biochemistry, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
Insights
High blood glucose, homocysteine, and cholesterol levels cause erythrocyte dysfunction, contributing to stroke and atherosclerosis. This dysfunction involves oxidative stress and impaired red blood cell function, increasing stroke risk.
Area of Science:
- Cardiovascular Science
- Hematology
- Pathophysiology
Background:
- Stroke is a leading cause of death and disability globally, imposing significant economic burdens.
- Atherothrombosis, driven by elevated blood glucose, homocysteine, and cholesterol, is a primary mechanism underlying stroke.
- Erythrocyte (red blood cell) dysfunction plays a critical role in the development and progression of atherothrombosis and stroke.
Purpose of the Study:
- To elucidate the multifaceted roles of erythrocytes in atherothrombosis and stroke pathogenesis.
- To investigate how metabolic factors like glucose, homocysteine, and lipids impact erythrocyte function and contribute to vascular disease.
- To explore the mechanisms by which erythrocyte damage promotes inflammation, plaque instability, and ischemic events.
Main Methods:
- Review and synthesis of existing literature on erythrocyte function in the context of metabolic syndrome and stroke.
- Analysis of molecular pathways involved in erythrocyte oxidative stress, phosphatidylserine exposure, and phagocytosis.
- Examination of erythrocyte interactions with endothelial cells, platelets, immune cells, and the coagulation cascade.
Main Results:
- Elevated glucose, homocysteine, and lipids induce oxidative stress in erythrocytes, leading to phosphatidylserine exposure and phagocytosis, thus promoting atherosclerotic plaque expansion.
- Oxidative stress impairs nitric oxide synthesis by upregulating arginase in erythrocytes and endothelial cells, contributing to endothelial dysfunction and activation.
- Dysfunctional erythrocytes release pro-thrombotic factors, activate platelets and immune cells, and their reduced deformability exacerbates hypoxia in ischemic tissues.
Conclusions:
- Erythrocyte dysfunction is a central contributor to atherothrombosis and stroke, driven by metabolic abnormalities.
- Targeting erythrocyte health and function presents a potential therapeutic strategy for preventing and treating stroke.
- Understanding the complex interplay between metabolic factors, erythrocytes, and vascular pathology is crucial for advancing stroke research and clinical management.
Abstract:
Stroke constitutes the second highest cause of morbidity and mortality worldwide while also impacting the world economy, triggering substantial financial burden in national health systems. High levels of blood glucose, homocysteine, and cholesterol are causative factors for atherothrombosis. These molecules induce erythrocyte dysfunction, which can culminate in atherosclerosis, thrombosis, thrombus stabilization, and post-stroke hypoxia. Glucose, toxic lipids, and homocysteine result in erythrocyte oxidative stress. This leads to phosphatidylserine exposure, promoting phagocytosis. Phagocytosis by endothelial cells, intraplaque macrophages, and vascular smooth muscle cells contribute to the expansion of the atherosclerotic plaque. In addition, oxidative stress-induced erythrocytes and endothelial cell arginase upregulation limit the pool for nitric oxide synthesis, leading to endothelial activation. Increased arginase activity may also lead to the formation of polyamines, which limit the deformability of red blood cells, hence facilitating erythrophagocytosis. Erythrocytes can also participate in the activation of platelets through the release of ADP and ATP and the activation of death receptors and pro-thrombin. Damaged erythrocytes can also associate with neutrophil extracellular traps and subsequently activate T lymphocytes. In addition, reduced levels of CD47 protein in the surface of red blood cells can also lead to erythrophagocytosis and a reduced association with fibrinogen. In the ischemic tissue, impaired erythrocyte 2,3 biphosphoglycerate, because of obesity or aging, can also favor hypoxic brain inflammation, while the release of damage molecules can lead to further erythrocyte dysfunction and death.
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