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.
Highlights
Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) are lipid-soluble, endogenously-produced gaseous messenger molecules [1]
An extensive amount of work has been conducted over the last several decades and has led to the discovery that each gasotransmitter possess a number of physiological actions
In 2001 a comprehensive review investigating the role of NO in modulating myocardial injury spanning from 1991-2001 found that 73% of the studies reported that NO was cardioprotective, whereas 12% reported that NO was detrimental [17]
Summary
Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) are lipid-soluble, endogenously-produced gaseous messenger molecules [1]. The role of endogenous CO in cardioprotection has been demonstrated using carbon monoxidereleasing molecules (CO-RMs) to elicit pharmacological activities in myocardial cells against I/R injury [48] Taken together, these studies suggest the use HO-1 induced CO production and direct administration of CO provide potential therapeutic alternatives for the pharmacological regulation of myocardial I/R injury [9,49,50]. Extensive research performed in recent years has clearly demonstrated that the efficacy of gasotransmitter therapy in ameliorating in vitro or in vivo I/ R injury Most importantly, these studies have provided important information regarding the doses of each gas that provide cytoprotection and suggest that the use of these gases at or near the levels considered to be produced under physiological conditions in vivo is optimal to protect a number of organs including the heart, liver, kidney, and brain. In much the same manner to that described for NO, H2S increases the expression of HO-1 in a Nrf-2 dependent manner [43]
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