Cardioprotective Pathways During Reperfusion: Focus on Redox Signaling and Other Modalities of Cell Signaling

Abstract

Post-ischemic reperfusion may result in reactive oxygen species (ROS) generation, reduced availability of nitric oxide (NO ), Ca 2+ overload, prolonged opening of mitochondrial permeability transition pore, and other processes contributing to cell death, myocardial infarction, stunning, and arrhythmias. With the discovery of the preconditioning and postconditioning phenomena, reperfusion injury has been appreciated as a reality from which protection is feasible, especially with postconditioning, which is under the control of physicians. Potentially cooperative protective signaling cascades are recruited by both pre-and postconditioning. In these pathways, phosphorylative= dephosphorylative processes are widely represented. However, cardioprotective modalities of signal transduction also include redox signaling by ROS, S-nitrosylation by NO and derivative, S-sulfhydration by hydrogen sulfide, and O-linked glycosylation with beta-N-acetylglucosamine. All these modalities can interact and regulate an entire pathway, thus influencing each other. For instance, enzymes can be phosphorylated and=or nitrosylated in specific and=or different site(s) with consequent increase or decrease of their specific activity. The cardioprotective signaling pathways are thought to converge on mitochondria, and various mitochondrial proteins have been identified as targets of these post-transitional modifications in both pre-and postconditioning. Antioxid. Redox Signal. 14, 833-850.

Post-ischemic early acidosis in cardiac postconditioning modifies the activity of antioxidant enzymes, reduces nitration, and favors protein S-nitrosylation

“…A pivotal cardioprotective role for NO • from enzymatic and non-enzymatic origin has been shown for both pre and postconditioning [13,15,25,26,[46][47][48][49][50]60,66,69]. In fact, NO • is a cardiovascular protective molecule via multiple effects, both in normoxia and particularly during reperfusion [15,50,66].…”

“…Therefore a vicious cycle is likely to be established in the so-called ROS-induced ROS release (RIRR) [26,27,34]; thus inducing ROS stress and reperfusion injury [for reviews see 46,50]. Survival mechanisms in the heart can be triggered by short, non-lethal periods of ischemia and reperfusion, applied either before (preconditioning) or immediately after (postconditioning, PostC) the index ischemia [3,10,20,25,33,[44][45][46]62]. Both in vivo and in vitro ischemic-and pharmacologicalpreconditioning triggering require protective ROS signaling.…”

“…Also PostC-protection requires ROS signaling and delayed recovery of intracellular pH during initial reperfusion. The mechanisms by which PostC alters the pathophysiology of reperfusion injury involves molecular and physiological mechanisms, such as delaying realkalinization of tissue pH [8,9,17,29,30,55], triggering release of ROS and autacoids [13,46,[50][51][52]54,61], and activation of kinases that impact cellular and subcellular targets or effectors, such as mPTP [e.g., 20, 46,50,52]. Importantly acidic buffer (AB) given for the first few minutes of reperfusion is as protective as a PostC protocol [8,9,13,17,29,30,34,55].…”

“…PostC protection is also influenced by the interplay between endothelial and cardiac function, with a flow of nitric-oxide (NO • ) from endothelium to myocardium [20,46,50,67]. Indeed, persistence of acidosis is important for non-enzymatic NO • production [59,69].…”

“…Indeed, persistence of acidosis is important for non-enzymatic NO • production [59,69]. So that ROS in concert with NO • and reactive nitrogen species (RNS) may put the heart into a protected state [26,38,46,[49][50][51][52]63].…”