Extracellular Hemoglobin: Modulation of Cellular Functions and Pathophysiological Effects

Abstract

Hemoglobin is essential for maintaining cellular bioenergetic homeostasis through its ability to bind and transport oxygen to the tissues. Besides its ability to transport oxygen, hemoglobin within erythrocytes plays an important role in cellular signaling and modulation of the inflammatory response either directly by binding gas molecules (NO, CO, and CO2) or indirectly by acting as their source. Once hemoglobin reaches the extracellular environment, it acquires several secondary functions affecting surrounding cells and tissues. By modulating the cell functions, this macromolecule becomes involved in the etiology and pathophysiology of various diseases. The up-to-date results disclose the impact of extracellular hemoglobin on (i) redox status, (ii) inflammatory state of cells, (iii) proliferation and chemotaxis, (iv) mitochondrial dynamic, (v) chemoresistance and (vi) differentiation. This review pays special attention to applied biomedical research and the use of non-vertebrate and vertebrate extracellular hemoglobin as a promising candidate for hemoglobin-based oxygen carriers, as well as cell culture medium additive. Although recent experimental settings have some limitations, they provide additional insight into the modulatory activity of extracellular hemoglobin in various cellular microenvironments, such as stem or tumor cells niches.

Changes in Hemoglobin Properties in Complex with Glutathione and after Glutathionylation

“…The obtained data are important for understanding the functioning of hemoglobin in erythrocytes, since the level of glutathionylated hemoglobin is significantly increased in various pathologies associated with the development of oxidative stress [4,6], and the noncovalent complex is important for the adaptation of erythrocytes to hypoxic conditions [3]. In addition, the influence of glutathione on the properties of extracellular hemoglobin, which is above normal levels in plasma in pathologies associated with hemoglobinemia [40], cannot be excluded. However, extracellular hemoglobin is rapidly oxidized to met-hemoglobin [40].…”

“…In addition, the influence of glutathione on the properties of extracellular hemoglobin, which is above normal levels in plasma in pathologies associated with hemoglobinemia [40], cannot be excluded. However, extracellular hemoglobin is rapidly oxidized to met-hemoglobin [40]. Because glutathione can reduce metal ions [41,42], it is possible to reduce methemoglobin with GSH.…”

Revealing Natural Intracellular Peptides in Gills of Seahorse Hippocampus reidi

“…Hemoglobin is an essential protein for maintaining cellular homeostasis due to its ability to bind and transport oxygen to the tissues. This protein has also been associated with immune response modulation, signal transduction and antimicrobial activity [ 50 ]. Hemoglobin has been known as a source of endogenous bioactive peptides that present several different functions [ 51 , 52 , 53 ].…”

Comparison of Evolutionary Relationships between Branchiostoma floridae, Ciona intestinalis, and Homo sapiens Globins Provide Evidence of Gene Co-Option and Convergent Evolution

“…In contrast, Gb-4 has an N-terminal signal peptide sequence with a cleavage site (Supplementary Table S1), suggesting that it may be a secreted protein. Although the physiological functions of extracellular hemoglobin released by the hemolysis of red blood cells have been discussed [32], no secretion of globin protein, which has a signal peptide sequence, has been reported in vertebrates. On the other hand, in the vascular fluid, hemolymph, or coelomic fluid of some invertebrate phyla, including Annelida, Nematoda, Arthropoda, and Mollusca [33,34], extracellular hemoproteins of various forms and sizes such as monomeric hemoglobin and giant (ca.…”