Abstract
Induction and activation of arginase is among the fastest responses of the heart to ischemic events. Induction of arginase expression and enzyme activation under ischemic conditions shifts arginine consumption from nitric oxide formation (NO) to the formation of ornithine and urea. In the heart such a switch in substrate utilisation reduces the impact of the NO/cGMP-pathway on cardiac function that requires intact electromechanical coupling but at the same time it induces ornithine-dependent pathways such as the polyamine metabolism. Both effects significantly reduce the recovery of heart function during reperfusion and thereby limits the success of reperfusion strategies. In this context, changes in arginine consumption trigger cardiac remodelling in an unfavourable way and increases the risk of arrhythmia, specifically in the initial post-ischemic period in which arginase activity is dominating. However, during the entire ischemic period arginase activation might be a meaningful adaptation that is specifically relevant for reperfusion following prolonged ischemic periods. Therefore, a precise understanding about the underlying mechanism that leads to arginase induction as well as of it’s mechanistic impact on post-ischemic hearts is required for optimizing reperfusion strategies. In this review we will summarize our current understanding of these processes and give an outlook about possible treatment options for the future.
Highlights
Induction and activation of arginase is among the fastest responses of the heart to ischemic events
Induction of arginase expression and enzyme activation under ischemic conditions shifts arginine consumption from nitric oxide formation (NO) to the formation of ornithine and urea. In the heart such a switch in substrate utilization reduces the impact of the NO/cGMP-pathway on cardiac function that requires intact electromechanical coupling but at the same time it induces ornithine-dependent pathways such as the polyamine metabolism
Arginase I is located in the cytosol and well-known from hepatic metabolism in which arginase is responsible for the elimination of metabolites from amino acid and nucleotide metabolism
Summary
Arginase is an enzyme that catalyzes the hydrolysis of L-arginine into urea and ornithine. In the ischemic/reperfused heart, arginase I induction is opposed by eNOS down-regulation (Hein et al, 2003) All these molecular responses to hypoxia shift arginine consumption from the NO pathway toward the arginase-dependent pathways and this may be a strategy of cells to withstand hypoxic stress. All these examples suggest that reducing arginine levels will protect hypoxic cells from irreversible damage (Figure 2-I) This advantage of high arginase activity during ischemia may switch into a strong disadvantage as soon as the tissue is reperfused. ROS in the presence of high NOS activity trigger neurological disorders to hypoxia/anoxia in brain and improving arginase activity is again associated with protection (Swamy et al, 2010) These data show different roles for arginase in hypoxic/reoxygenated tissues and indicate that a simple relationship between tissue damage and arginase activity is unlikely to be identified. Activation of arginase in the post-ischemic myocardium has an increased risk of mal-adaption
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