Redox signaling and cardioprotection - translatability and mechanism.

The morbidity and mortality from coronary artery disease (CAD) remain significant worldwide. The treatment for acute myocardial infarction has improved over the past decades, including early reperfusion of culprit coronary arteries. Although it is mandatory to reperfond the ischemic territory as soon as possible, paradoxically this leads to additional myocardial injury, namely ischemia/reperfusion injury, in which a pivotal role is played by redox stress and for which no effective therapy is currently available. In this review, we report evidence that redox environment plays pivotal roles not only in ischemia/reperfusion injury, but also in cardioprotection. In fact cardioprotective strategies, such as pre- and post-conditioning, result in a robust reduction of infarct size in animals and redox signaling plays a role of paramount importance in these conditioning strategies. Nitrosative signaling and cysteine redox modifications, such as S-nitrosation/-nitrosylation, are also emerging as very important mechanisms in conditioning cardioprotection. The reasons of the switch from protective oxidative/nitrosative signaling to deleterious oxidative/nitrosative/nitrative stress are not fully understood. The complex regulation of this switch is, at least in part, responsible of the diminished or absent cardioprotection by conditioning protocols observed in aging animals and with comorbidities as well as in humans. Therefore, it is important to understand at a mechanistic level the reasons for these differences before proposing a safe and useful transition of ischemic or pharmacological conditioning. Indeed, more mechanistic novel therapeutic strategies are required to protect the heart from ischemia/reperfusion injury and to improve clinical outcomes in patients with CAD.