The Mystery of Red Blood Cells Extracellular Vesicles in Sleep Apnea with Metabolic Dysfunction

Abstract

Sleep is very important for overall health and quality of life, while sleep disorder has been associated with several human diseases, namely cardiovascular, metabolic, cognitive, and cancer-related alterations. Obstructive sleep apnea (OSA) is the most common respiratory sleep-disordered breathing, which is caused by the recurrent collapse of the upper airway during sleep. OSA has emerged as a major public health problem and increasing evidence suggests that untreated OSA can lead to the development of various diseases including neurodegenerative diseases. In addition, OSA may lead to decreased blood oxygenation and fragmentation of the sleep cycle. The formation of free radicals or reactive oxygen species (ROS) can emerge and react with nitric oxide (NO) to produce peroxynitrite, thereby diminishing the bioavailability of NO. Hypoxia, the hallmark of OSA, refers to a decline of tissue oxygen saturation and affects several types of cells, playing cell-to-cell communication a vital role in the outcome of this interplay. Red blood cells (RBCs) are considered transporters of oxygen and nutrients to the tissues, and these RBCs are important interorgan communication systems with additional functions, including participation in the control of systemic NO metabolism, redox regulation, blood rheology, and viscosity. RBCs have been shown to induce endothelial dysfunction and increase cardiac injury. The mechanistic links between changes of RBC functional properties and cardiovascular are largely unknown. Extracellular vesicles (EVs) are secreted by most cell types and released in biological fluids both under physiological and pathological conditions. EVs are involved in intercellular communication by transferring complex cargoes including proteins, lipids, and nucleic acids from donor cells to recipient cells. Advancing our knowledge about mechanisms of RBC-EVs formation and their pathophysiological relevance may help to shed light on circulating EVs and to translate their application to clinical practice. We will focus on the potential use of RBC-EVs as valuable diagnostic and prognostic biomarkers and state-specific cargoes, and possibilities as therapeutic vehicles for drug and gene delivery. The use of RBC-EVs as a precision medicine for the diagnosis and treatment of the patient with sleep disorder will improve the prognosis and the quality of life in patients with cardiovascular disease (CVD).

Epidemiological studies of sleep disorder in educational community of Pakistani population, its major risk factors and associated diseases

“…High WBCs were recorded in sleep disorder patients in the present study similar finding to the results of other studies conducted earlier [ 60 , 61 ]. RBCs were in the normal range however other studies showed a higher levels of RBCs in patients with sleep disorders [ 62 ]. Haemoglobin level (7.1–17 g/dl) was different from the lower reference range however from the upper reference rage was normal.…”

Extracellular Vesicles as New Players in Drug Delivery: A Focus on Red Blood Cells-Derived EVs

“…Extracellular vesicles are highly enriched with proteins with different functions, such as tetraspanins (CD9, CD63, CD81, and CD82), which are involved in cell penetration, invasion, and fusion events; heat shock proteins (HSP70, HSP90), which are involved in antigen anchoring and presentation; and MVB formation proteins (Alix, TSG101), which are involved in exosomal release [ 158 ]. Additionally, cytoskeletal proteins (e.g., actin), denatured hemoglobin, proteins 4.1, 4.2, enzymes such as carbonic anhydrase, anion transport proteins (Band 3), glycoproteins (e.g., CD235a), membrane-associated proteins such as stomatin and flotillin, and CD47, which inhibits phagocytosis by interacting with macrophage signal regulatory protein alpha [ 159 ].…”

“…As discussed, RBCEVs possess several features that make them particularly suitable for therapeutic applications: (i) blood is easily accessible from blood banks, thus RBCs can be produced from blood at large scale and at low cost; (ii) autologous transfusion, from their own donor (or patient), or allogenic transfusion, from a universal 0-donor, of RBCEVs, are possible; (iii) RBCEVs are safer compared with other cell-derived EVs because they lack DNA, minimizing the risk of horizontal gene transfer; (iv) RBCEVs are completely nontoxic and have higher biocompatibility than synthetic EVs; (v) RBCEVs can be frozen and thawed many times without affecting their integrity and efficacy [ 158 ]. In this regard, a publication recently investigated different buffers and conditions to allow a longer stability of frozen EVs [ 195 ].…”

“…Furthermore, RBCEVs are non-toxic and non-immunogenic when transferred to the right blood group, unlike common vectors such as adenoviruses, lentiviruses, nanoparticles, and other synthetic EVs. Finally, blood banks are easily accessible for their production, and the obtained RBCEVs can be frozen and thawed for many cycles without losing their efficacy and integrity [ 158 ], thus allowing injectable formulations to be prepared.…”

Blood Cell-Derived Microvesicles in Hematological Diseases and beyond

“…Additionally, intermittent hypoxia in patients with OSA provokes RMV release through ROS and iCa 2+ stresses [ 78 ]. It has been reported by in vitro studies that the detrimental effect of RMVs on eNOS activity is a causal factor for the observed endothelial dysfunction and hypertension in OSA patients [ 78 , 79 ]. In cellular microenvironments enriched in cytokines (as in the case of several inflammatory conditions), the RMVs are supposed to offer a substrate for the production of bioactive lipids (such as arachidonic acid and lysophosphatidic acid) through phosphatidylserine exposure, that have a negative impact on endothelial function and vascular integrity [ 181 ].…”