Therapeutic Potential of Carbon Monoxide (CO) and Hydrogen Sulfide (H2S) in Hemolytic and Hemorrhagic Vascular Disorders—Interaction between the Heme Oxygenase and H2S-Producing Systems

Abstract

Over the past decades, substantial work has established that hemoglobin oxidation and heme release play a pivotal role in hemolytic/hemorrhagic disorders. Recent reports have shown that oxidized hemoglobins, globin-derived peptides, and heme trigger diverse biological responses, such as toll-like receptor 4 activation with inflammatory response, reprogramming of cellular metabolism, differentiation, stress, and even death. Here, we discuss these cellular responses with particular focus on their mechanisms that are linked to the pathological consequences of hemorrhage and hemolysis. In recent years, endogenous gasotransmitters, such as carbon monoxide (CO) and hydrogen sulfide (H2S), have gained a lot of interest in connection with various human pathologies. Thus, many CO and H2S-releasing molecules have been developed and applied in various human disorders, including hemolytic and hemorrhagic diseases. Here, we discuss our current understanding of oxidized hemoglobin and heme-induced cell and tissue damage with particular focus on inflammation, cellular metabolism and differentiation, and endoplasmic reticulum stress in hemolytic/hemorrhagic human diseases, and the potential beneficial role of CO and H2S in these pathologies. More detailed mechanistic insights into the complex pathology of hemolytic/hemorrhagic diseases through heme oxygenase-1/CO as well as H2S pathways would reveal new therapeutic approaches that can be exploited for clinical benefit.

Carbon Monoxide-Releasing Molecule-3 Suppresses the Malignant Biological Behavior of Tongue Squamous Cell Carcinoma via Regulating Keap1/Nrf2/HO-1 Signaling Pathway

“…CO has long been considered a freely diffusible and toxic gas molecule because its binding affinity is 400 times that of oxygen, which can lead to CO poisoning and eventually respiratory failure. However, recent research shows that CO can act as an intracellular messenger molecule with multiple biological functions, including anti-inflammatory, antioxidant, and anticancer [22,23]. CORMs are effective in regulating CO release in vivo and in vitro at appropriate circumstances [24].…”

Recent advances in the application of gasotransmitters in spinal cord injury

“…It inhibits platelet aggregation, reduces leukocyte adhesion and cell apoptosis, and lowers the production of pro-inflammatory cytokines [ 48 ]. CO, as a product of heme degradation, has been shown to have various biological functions such as anti-inflammatory, anti-apoptotic and antioxidant at low concentrations [ 48 , 49 ]. The safe dose of CO promotes neuro-regeneration by triggering the sGC/cGMP/MAPK signaling pathway and a cascade between the HO-CO, HIF-1α/VEGF, and NOS pathways [ 50 , 51 ].…”

Interactions of reactive sulfur species with metalloproteins

“…Growing evidence support that ligation and redox interactions between heme proteins and reactive sulfur species play a signaling and/or regulatory role in the human body [ [85] , [86] , [87] , [88] , [89] , [90] , [91] ]. In the current review, we present reported interactions of RSS with heme proteins concerning their primary function, such as oxygen transport and storage, mitochondrial electron transport, and antioxidant capacity.…”