A growing body of evidence indicates that
carbon monoxide (CO), once perceived merely as a poisonous gas, exerts antiapoptotic and cytoprotective effects. Using a water-soluble CO-releasing molecule (CORM)
tricarbonylchloro(glycinato)ruthenium(II) (CORM-3), we previously reported that CO induces a delayed protection against
myocardial infarction similar to that observed in the late phase of ischemic preconditioning (PC). In the current study, we investigated the molecular mechanisms underlying this cardioprotective effect. The impact on apoptotic signaling pathways was first examined in the setting of
ischemia/reperfusion injury. Mice were pretreated with CORM-3 or iCORM-3 (which does not release CO) and subjected to
coronary occlusion/reperfusion 24h later. In mice that received CORM-3, there was a significant reduction in markers of apoptosis (cleaved
lamin A, cleaved
caspase-3, and cleaved PARP-1) after
ischemia/reperfusion injury. To elucidate the mechanism of CORM-3-induced cardioprotection we further examined the activation of
transcription factors and induction of cardioprotective and apoptosis modulating
proteins. Infusion of CORM-3 rapidly activated the stress-responsive
transcription factors nuclear factor kappaB (NF-κB), signal transducers and activators of transcription (STAT)1, STAT3, and NF-E2-related factor-2 (Nrf2). This was followed 24h later by upregulation of cardioprotective
proteins (heme oxygenase-1 [HO-1],
cyclooxygenase-2 [COX-2], and extracellular
superoxide dismutase [Ec-SOD]) and antiapoptotic
proteins involving both the mitochondria-mediated (Mcl-1) and the
death receptor-mediated (c-
FLIP(S) and c-
FLIP(L)) apoptosis pathways. We conclude that CO released by CORM-3 triggers a cardioprotective signaling cascade that recruits the
transcription factors NF-κB, STAT1/3, and Nrf2 with a subsequent increase in cardioprotective and antiapoptotic molecules in the myocardium leading to the late PC-mimetic
infarct-sparing effects. This article is part of a Special Issue entitled 'Possible Editorial'.