Role of Nitric Oxide and Protein S-Nitrosylation in Ischemia-Reperfusion Injury

Abstract

Ischemia-reperfusion injury (IRI) is a process in which damage is induced in hypoxic tissue when oxygen supply is resumed after ischemia. During IRI, restoration of reduced nitric oxide (NO) levels may alleviate reperfusion injury in ischemic organs. The protective mechanism of NO is due to anti-inflammatory effects, antioxidant effects, and the regulation of cell signaling pathways. On the other hand, it is generally known that S-nitrosylation (SNO) mediates the detrimental or protective effect of NO depending on the action of the nitrosylated target protein, and this is also applied in the IRI process. In this review, the effect of each change of NO and SNO during the IRI process was investigated.

Fyn Signaling in Ischemia-Reperfusion Injury: Potential and Therapeutic Implications

“…The increase of cyclic guanosine monophosphate (cGMP) and the activation of downstream signaling pathways further aggravate CIRI. [ 55 ].…”

Role and Posttranslational Regulation of Cx46 Hemichannels and Gap Junction Channels in the Eye Lens

“…Nitric oxide (NO) is a gaseous transmitter that signals through the activation of the guanylyl cyclase and the formation of S-nitrosothiols, resulting in S-nitrosylated proteins ( Hess et al, 2005 ; Nakamura and Lipton, 2016 ; Lee et al, 2021 ). NO is a short-lived and highly reactive gas produced during conversion of arginine to citrulline and NO by NO synthases ( Snyder, 1992 ; Iwanaga et al, 1999 ), and NO production is stimulated by Ca 2+ or regulated at the transcriptional level, depending on the synthases involved ( Bredt and Snyder, 1994 ; Nelson et al, 2003 ; Nakamura and Lipton, 2016 ).…”

“…NO is a short-lived and highly reactive gas produced during conversion of arginine to citrulline and NO by NO synthases ( Snyder, 1992 ; Iwanaga et al, 1999 ), and NO production is stimulated by Ca 2+ or regulated at the transcriptional level, depending on the synthases involved ( Bredt and Snyder, 1994 ; Nelson et al, 2003 ; Nakamura and Lipton, 2016 ). The formation of S-nitrosylated proteins results from reaction between a redox-sensitive thiol group (actually a thiolate anion) and a nitrosonium cation (NO + ) in the presence of transition metals that accept an electron from NO ( Hess et al, 2005 ; Martinez-Ruiz et al, 2011 ; Nakamura and Lipton, 2016 ; Lee et al, 2021 ), although other mechanisms are possible ( Hess et al, 2005 ; Martinez-Ruiz et al, 2011 ; Smith and Marletta, 2012 ; Nakamura and Lipton, 2016 ), including protein-to-protein transnitrosylation. In the latter, NO is transferred from a donor protein to a specific acceptor protein ( Nakamura and Lipton, 2013 ; Jia et al, 2014 ).…”

“…Although details on the S-nitrosylation selectivity are not completely understood, S-nitrosylation is promoted by proximity to the NO source and local hydrophobicity that serves to concentrate NO ( e.g. , thiols close to the membrane), the presence of charged amino acids in close proximity, and location in flexible regions ( Liu et al, 1998 ; Hess et al, 2005 ; Doulias et al, 2010 ; Smith and Marletta, 2012 ; Nakamura and Lipton, 2016 ; Lee et al, 2021 ). S-nitrosylation is often a relatively labile modification and reducing agents and enzymes such as thioredoxin and S-nitrosoglutathione (GSNO) reductases can remove the NO from the modified cysteines ( Benhar et al, 2008 ; Benhar et al, 2009 ; Nakamura and Lipton, 2016 ).…”

Recovery of reduced thiol groups by superoxide-mediated denitrosation of nitrosothiols

“…in aldehyde dehydrogenase-2 (ALDH-2) [ 27 , 28 ]. Nitrosation conditions, succeeded by excessive O 2 •− fluxes, are hallmarks of ischemia reperfusion [ 29 ]. In this context, nitrosation and inactivation of mitochondrial Complex I has been identified as a protective mechanism by its inhibitory influence on the formation of large fluxes of reactive oxygen species by the respiratory chain in the initial stages of reperfusion [ [30] , [31] , [32] , [33] ].…”