Mechanism and consequences of the shift in cardiac arginine metabolism following ischaemia and reperfusion in rats

Abstract

SummaryCardiac ischaemia and reperfusion leads to irreversible injury and subsequent tissue remodelling. Initial reperfusion seems to shift arginine metabolism from nitric oxide (NO) to polyamine formation. This may limit functional recovery at reperfusion. The hypothesis was tested whether ischaemia/reperfusion translates such a shift in arginine metabolism in a tumour necrosis factor (TNF)-α-dependent way and renin-angiotensin system (RAS)-dependent way into a sustained effect. Both, the early post-ischaemic recovery and molecular adaptation to ischaemia/reperfusion were analysed in saline perfused rat hearts undergoing global no-flow ischaemia and reperfusion. Local TNF-α activation was blocked by inhibition of TNF-α sheddase ADAM17. To interfere with RAS captopril was administered. Arginase was inhibited by administration of Nor-NOHA. Long-term effects of ischemia/reperfusion on arginine metabolism were analysed in vivo in rats receiving an established ischaemia/reperfusion protocol in the closed chest mode. mRNA expression analysis indicated a shift in the arginine metabolism from NO formation to polyamine metabolism starting within 2 hours (h) of reperfusion and translated into protein expression within 24 h. Inhibition of the TNF-α pathway and captopril attenuated these delayed effects on post-ischaemic recovery. This shift in arginine metabolism was associated with functional impairment of hearts within 24 h. Inhibition of arginase but not that of TNF-α and RAS pathways improved functional recovery immediately. However, no benefit was observed after four months. In conclusion, this study identified TNF-α and RAS to be responsible for depressed cardiac function that occurred a few hours after reperfusion.

Reperfusion injury and reactive oxygen species: The evolution of a concept

“…This “arginine steal” mechanism not only decreases NO production but also increases generation by uncoupling NOS. After reperfusion of ischemic liver [437] or heart [434] , [438] , [439] , arginase activity increases, arginine levels and NO production decrease, and generation increases, providing support for an “arginine steal” mechanism of NOS uncoupling. Pharmacologic inhibition of arginase or arginine supplementation restores the ability of NOS to generate NO and ameliorates various indices of tissue injury.…”

Arginase induction and activation during ischemia and reperfusion and functional consequences for the heart

“…Extracellular RNA (eRNA), which is among intracellular materials released by hypercontracture, triggers the activation of a membrane-bound sheddase that, once activated, releases TNF-α (Cabrera-Fuentes et al, 2014 ; see Figure 1 ). TNF-α has been identified as a pro-inflammatory cytokine that activates arginase I (Schreckenberg et al, 2015b ). This observation is further based on experiments with TNF-α −/− mice in which ischemia and reperfusion does not lead to an induction of arginase I (Gao et al, 2007 ).…”

“…TNF-α knock-out mice had no up-regulation of arginase. Subsequently, inhibition of a sheddase that releases bound TNF-α during hypoxia was sufficient to attenuate arginase induction (Schreckenberg et al, 2015b ). Unlike the direct inhibition of arginase, such an approach does not block arginase activity in M2 macrophages.…”

Arginase induction and activation during ischemia and reperfusion and functional consequences for the heart

“…Extracellular RNA (eRNA), which is among intracellular materials released by hypercontracture, triggers the activation of a membrane-bound sheddase that, once activated, releases TNF-α (Cabrera-Fuentes et al, 2014; see Figure 1). TNF-α has been identified as a proinflammatory cytokine that activates arginase I (Schreckenberg et al, 2015b). This observation is further based on experiments with TNF-α −/− mice in which ischemia and reperfusion does not lead to an induction of arginase I (Gao et al, 2007).…”

“…TNF-α knock-out mice had no up-regulation of arginase. Subsequently, inhibition of a sheddase that releases bound TNF-α during hypoxia was sufficient to attenuate arginase induction (Schreckenberg et al, 2015b). Unlike the direct inhibition of arginase, such an approach does not block arginase activity in M2 macrophages.…”