Emergent role of gasotransmitters in ischemia-reperfusion injury

Abstract

Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) are lipid-soluble, endogenously produced gaseous messenger molecules collectively known as gasotransmitters. Over the last several decades, gasotransmitters have emerged as potent cytoprotective mediators in various models of tissue and cellular injury. Specifically, when used at physiological levels, the exogenous and endogenous manipulation of these three gases has been shown to modulate ischemia/reperfusion injury by inducing a number of cytoprotective mechanisms including: induction of vasodilatation, inhibition of apoptosis, modulation of mitochondrial respiration, induction of antioxidants, and inhibition of inflammation. However, while the actions are similar, there are some differences in the mechanisms by which these gasotransmitters induce these effects and the regulatory actions of the enzyme systems can vary depending upon the gas being investigated. Furthermore, there does appear to be some crosstalk between the gases, which can provide synergistic effects and additional regulatory effects. This review article will discuss several models and mechanisms of gas-mediated cytoprotection, as well as provide a brief discussion on the complex interactions between the gasotransmitter systems.

Figure 1

Enzymatic Synthesis of Nitric Oxide. Nitric oxide (NO) is produced from amino acid L-arginine by the enzymatic action of nitric oxide synthase (NOS). There are there forms of NOS: endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS). NO activates guanylate cyclase (GC), which leads to increased production of 3',5'-monophosphate (cGMP).

Figure 2

Enzymatic Synthesis of Carbon Monoxide. Heme is catabolised by heme oxygenases (HO), to form biliverdin, carbon monoxide, and iron. Carbon monoxide can activate soluble guanylyl cyclase, which causes an increase in cyclic guanosine monophosphate levels (cGMP). Biliverdin is subsequently converted to bilirubin by biliverdin reductase.

Figure 3

Enzymatic Synthesis of Hydrogen Sulfide. There are three enzymatic pathways involved in the synthesis of hydrogen sulfide (H₂S) in mammalian systems. Cystathionine β-synthase (CBS) produces H₂S through a reaction involving the generation of cystathionine from homocysteine and L-cysteine from cystathione. Cystathionine γ-lyase (CGL or CSE) produces H₂S through a reaction involving the generation of L-cysteine from cystathionine. 3-mercaptopyruvate sulfur transferase (3MST) produces H₂S through a reaction involving the generation of 3-mercaptopyruvate (3MP) from α-ketoglutarate (α-KG) by cysteine aminotransferase (CAT).

Figure 4

Summary of Mechanisms by which Gasotransmitters can Induce Cytoprotection. The gasotransmitters share unique and similar pathways by which they protect against tissue and cellular injury. Both CO and NO have been shown to regulate smooth muscle relaxation through the sGC/cGMP pathway. NO and H₂S have been shown to regulate cell proliferation and vascular smooth muscle relaxation balance through mitogen-activated protein kinases (MAPK), and ATP-sensitive potassium channels (K_ATP ). In addition, H₂S and CO regulate oxidant/antioxidant balance through the transcription factor NF-E2-related factor (Nrf2).