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

Schlüter KD, Schulz R, Schreckenberg R - Front Physiol (2015)

Bottom Line: 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.In this review we will summarize our current understanding of these processes and give an outlook about possible treatment options for the future.

View Article: PubMed Central - PubMed

Affiliation: Physiologisches Institut, Justus-Liebig-Univiersität Giessen Giessen, Germany.

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 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. 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 remodeling in an unfavorable 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.

No MeSH data available.


Related in: MedlinePlus

Effect of hypoxia (ischemia) on arginine metabolism. Direct effects of low pO2 are the translocation of c-jun in AP-1 dimers, thereby activating AP-1 transcriptional activity, an activation of PKCα and subsequent activation of arginine transporters (CAT2) and inhibition of constitutively expressed NOS isoforms (eNOS and nNOS). Indirect effects of low pO2 are loss of sarcolemmal integrity in some cells (see left), leading to the release of intracellular particles, such as RNA (eRNA), that activates a sheddase (TACE) thereby releasing TNFα. TNFα augments the hypoxia-induced cell damage by activation of AP-1 and increasing arginase (Arg) expression, by activation of arginase activity via nitrosylation and reducing the KM value for the enzymatic reaction, and ROS-dependent inhibition of NOS activity.
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Figure 1: Effect of hypoxia (ischemia) on arginine metabolism. Direct effects of low pO2 are the translocation of c-jun in AP-1 dimers, thereby activating AP-1 transcriptional activity, an activation of PKCα and subsequent activation of arginine transporters (CAT2) and inhibition of constitutively expressed NOS isoforms (eNOS and nNOS). Indirect effects of low pO2 are loss of sarcolemmal integrity in some cells (see left), leading to the release of intracellular particles, such as RNA (eRNA), that activates a sheddase (TACE) thereby releasing TNFα. TNFα augments the hypoxia-induced cell damage by activation of AP-1 and increasing arginase (Arg) expression, by activation of arginase activity via nitrosylation and reducing the KM value for the enzymatic reaction, and ROS-dependent inhibition of NOS activity.

Mentions: Most, but not all investigators that studied the activity of arginase in ischemic and post-ischemic cardiac tissues found a significant increase in total arginase activity, arginase I expression, or both. In principle, expression of arginase II can also be induced by hypoxia as shown for human pulmonary artery smooth muscle cells (Chen et al., 2014; Jin et al., 2014). However, whether induction of arginase II contributes to the increased arginase activity in the heart during ischemia and reperfusion remains to be established. Most remarkable observations of increased arginase activity were made at a very early time-point after the onset of ischemia and reperfusion (Harpster et al., 2006; Grönros et al., 2013). The underlying mechanism by which arginase I expression is induced has been evaluated in detail as described now. Arginase I expression was identified as the strongest and fastest transcriptional adaptation during ischemia and reperfusion in the heart (Harpster et al., 2006). Several mechanisms seemed to be responsible for this effect: At first, hypoxia and reoxygenation damages cardiomyocytes because it leads to excessive calcium load during ischemia and subsequent reoxygenation generates energy that allows a very strong contraction disrupting the sarcolemmal membrane. This cell damage leads to a release of intracellular material into the extracellular compartment (Hearse et al., 1973). This hypercontraction-induced cell damage is the basis for diagnosis of infarct size by quantification of plasma levels of cardiac-specific enzymes, i.e., hs cTnI (= high sensitive cardiac-specific troponin I). Such molecules that are released by hypercontracture may have also a functional relevance in the subsequent activation of arginase expression. 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 may trigger this process via activation of the transcription factor AP-1 (Figure 1). A potential AP-1 binding site has been identified in the promoter region of arginase and TNF-α activates the activity of the transcription factor AP-1 (Zhu et al., 2010). Hypoxia directly recruits c-jun to AP-1 binding sites of the arginase-1 promoter (Singh et al., 2014). c-Jun binds together with activating transcription factor-2 at the AP-1 site, which initiates the transactivation (Zhu et al., 2010). Acute myocardial infarction is sufficient to induce the expression of 15 different genes that are involved in assembly and activation of AP-1 within 15 min (Harpster et al., 2006). All these findings strongly support the assumption that AP-1 activation plays a major role in adaptation of arginine metabolism to hypoxia. Such a scenario would also explain the more general finding that arginase activation under ischemia and reperfusion is not specific for the heart but represents a more general pathway by which tissues respond to hypoxia because cell damage and loss of plasmalemmal integrity is a characteristic feature of anoxic cell damage. As outlined in the next section, hypoxic conditions trigger arginase I expression in nearly all tissues. As mentioned above, arginase II can also be induced by hypoxia. The mechanism has been worked out on pulmonary smooth muscle cells. Hypoxia induced the expression of miR-17-5p that then triggers the up-regulation of arginase II (Jin et al., 2014). Activation of PI3-kinase-Akt signaling pathways can attenuate this activation (Chen et al., 2014). However, it remains to be clarified whether similar concerns hold for arginase II in the heart during acute ischemia and reperfusion.


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

Schlüter KD, Schulz R, Schreckenberg R - Front Physiol (2015)

Effect of hypoxia (ischemia) on arginine metabolism. Direct effects of low pO2 are the translocation of c-jun in AP-1 dimers, thereby activating AP-1 transcriptional activity, an activation of PKCα and subsequent activation of arginine transporters (CAT2) and inhibition of constitutively expressed NOS isoforms (eNOS and nNOS). Indirect effects of low pO2 are loss of sarcolemmal integrity in some cells (see left), leading to the release of intracellular particles, such as RNA (eRNA), that activates a sheddase (TACE) thereby releasing TNFα. TNFα augments the hypoxia-induced cell damage by activation of AP-1 and increasing arginase (Arg) expression, by activation of arginase activity via nitrosylation and reducing the KM value for the enzymatic reaction, and ROS-dependent inhibition of NOS activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356066&req=5

Figure 1: Effect of hypoxia (ischemia) on arginine metabolism. Direct effects of low pO2 are the translocation of c-jun in AP-1 dimers, thereby activating AP-1 transcriptional activity, an activation of PKCα and subsequent activation of arginine transporters (CAT2) and inhibition of constitutively expressed NOS isoforms (eNOS and nNOS). Indirect effects of low pO2 are loss of sarcolemmal integrity in some cells (see left), leading to the release of intracellular particles, such as RNA (eRNA), that activates a sheddase (TACE) thereby releasing TNFα. TNFα augments the hypoxia-induced cell damage by activation of AP-1 and increasing arginase (Arg) expression, by activation of arginase activity via nitrosylation and reducing the KM value for the enzymatic reaction, and ROS-dependent inhibition of NOS activity.
Mentions: Most, but not all investigators that studied the activity of arginase in ischemic and post-ischemic cardiac tissues found a significant increase in total arginase activity, arginase I expression, or both. In principle, expression of arginase II can also be induced by hypoxia as shown for human pulmonary artery smooth muscle cells (Chen et al., 2014; Jin et al., 2014). However, whether induction of arginase II contributes to the increased arginase activity in the heart during ischemia and reperfusion remains to be established. Most remarkable observations of increased arginase activity were made at a very early time-point after the onset of ischemia and reperfusion (Harpster et al., 2006; Grönros et al., 2013). The underlying mechanism by which arginase I expression is induced has been evaluated in detail as described now. Arginase I expression was identified as the strongest and fastest transcriptional adaptation during ischemia and reperfusion in the heart (Harpster et al., 2006). Several mechanisms seemed to be responsible for this effect: At first, hypoxia and reoxygenation damages cardiomyocytes because it leads to excessive calcium load during ischemia and subsequent reoxygenation generates energy that allows a very strong contraction disrupting the sarcolemmal membrane. This cell damage leads to a release of intracellular material into the extracellular compartment (Hearse et al., 1973). This hypercontraction-induced cell damage is the basis for diagnosis of infarct size by quantification of plasma levels of cardiac-specific enzymes, i.e., hs cTnI (= high sensitive cardiac-specific troponin I). Such molecules that are released by hypercontracture may have also a functional relevance in the subsequent activation of arginase expression. 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 may trigger this process via activation of the transcription factor AP-1 (Figure 1). A potential AP-1 binding site has been identified in the promoter region of arginase and TNF-α activates the activity of the transcription factor AP-1 (Zhu et al., 2010). Hypoxia directly recruits c-jun to AP-1 binding sites of the arginase-1 promoter (Singh et al., 2014). c-Jun binds together with activating transcription factor-2 at the AP-1 site, which initiates the transactivation (Zhu et al., 2010). Acute myocardial infarction is sufficient to induce the expression of 15 different genes that are involved in assembly and activation of AP-1 within 15 min (Harpster et al., 2006). All these findings strongly support the assumption that AP-1 activation plays a major role in adaptation of arginine metabolism to hypoxia. Such a scenario would also explain the more general finding that arginase activation under ischemia and reperfusion is not specific for the heart but represents a more general pathway by which tissues respond to hypoxia because cell damage and loss of plasmalemmal integrity is a characteristic feature of anoxic cell damage. As outlined in the next section, hypoxic conditions trigger arginase I expression in nearly all tissues. As mentioned above, arginase II can also be induced by hypoxia. The mechanism has been worked out on pulmonary smooth muscle cells. Hypoxia induced the expression of miR-17-5p that then triggers the up-regulation of arginase II (Jin et al., 2014). Activation of PI3-kinase-Akt signaling pathways can attenuate this activation (Chen et al., 2014). However, it remains to be clarified whether similar concerns hold for arginase II in the heart during acute ischemia and reperfusion.

Bottom Line: 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.In this review we will summarize our current understanding of these processes and give an outlook about possible treatment options for the future.

View Article: PubMed Central - PubMed

Affiliation: Physiologisches Institut, Justus-Liebig-Univiersität Giessen Giessen, Germany.

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 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. 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 remodeling in an unfavorable 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.

No MeSH data available.


Related in: MedlinePlus