Signal pathway responsible for hepatocyte preconditioning by nitric oxide

Carini, Rita; Cesaris, Maria Grazia De; Splendore, Roberta; Domenicotti, Cinzia; Nitti, Mariapaola; Pronzato, Maria Adelaide; Albano, Emanuele

doi:10.1016/s0891-5849(03)00039-x

Cited by 37 publications

(36 citation statements)

References 34 publications

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“…Our recent study further proved in vivo the important role of NO in upregulating phosphorylation of ERK1/2 during the induction of brain ischemic tolerance [15]. In addition, Carini et al [35] reported that NO could induce hepatic preconditioning by activating p38 MAPK through a guanylate cyclase/cGK-mediated pathway to improve liver resistance to hypoxia/reperfusion injury. Based on these findings, it is reasonable to believe that LIP-induced enhancement of NO production participates in the induction of brain ischemic tolerance by upregulating such downstream signal molecules as phosphorylated ERKs and p38 MAPK.…”

Section: Discussionsupporting

confidence: 60%

The Role of Nitric Oxide in the Neuroprotection of Limb Ischemic Preconditioning in Rats

et al. 2007

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Brief limb ischemia was reported to protect neurons against injury induced by subsequent cerebral ischemia-reperfusion, and this phenomenon is known as limb ischemic preconditioning (LIP). To explore the role of nitric oxide (NO) in neuroprotection of LIP in rats, we observed changes in the content of nitric oxide (NO) and activity of NO synthase (NOS) in the serum and CA1 hippocampus of rats after transient limb ischemic preconditioning (LIP), and the influence of N(G)-nitro-L-arginine methylester (L-NAME), a NOS inhibitor, on the neuroprotection of LIP against cerebral ischemia-reperfusion injury. Results showed that NO content and NOS activity in serum increased significantly after LIP compared with the sham group. The increase showed a double peak pattern, in which the first one appeared at time 0 (immediate time point) and the second one appeared at 48 h after the LIP (P < 0.01). The NO content and NOS activity in the CA1 hippocampus in LIP group showed similar change pattern with the changes in the serum, except for the first peak of up-regulation of NO content and NOS activity appeared at 6 h after LIP. Pretreatment with L-NAME before LIP blocked the neuroprotection of LIP against subsequent cerebral ischemic insult. The blocking effect of L-NAME was abolished with pretreatment of L-Arg. These findings indicated that NO may be associated with the tolerance of pyramidal cells in the CA1 hippocampus to ischemia induced by LIP in rats.

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Section: Discussionsupporting

confidence: 60%

The Role of Nitric Oxide in the Neuroprotection of Limb Ischemic Preconditioning in Rats

et al. 2007

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“…30 A role of p38MAPK is also evident in the cytoprotective effects exerted by hepatocyte preconditioning with nitric oxide. 31 Phosphatidylinositol 3-kinase is activated following hepatocyte hypoxic preconditioning by the stimulation of adenosine A2A receptors 32 and thus plays a role in the development of hepatic tolerance to hypoxia/reperfusion. Another mechanism that might contribute to I/R-induced liver injury in the isolated rat liver model is the quick degradation of ATP to adenosine during ischemia, causing a decrease in cyclic adenosine monophosphate (cAMP) levels.…”

Section: Discussionmentioning

confidence: 99%

Effect of adenosine A2A receptor agonist (CGS) on ischemia/reperfusion injury in isolated rat liver

et al. 2005

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Ischemia/reperfusion injury during liver transplantation is a major cause of primary nonfunctioning graft for which there is no effective treatment other than retransplantation. Adenosine prevents ischemia-reperfusion-induced hepatic injury via its A2A receptors. The aim of this study was to investigate the role of A2A receptor agonist on apoptotic ischemia/reperfusion-induced hepatic injury in rats. Isolated rat livers within University of Wisconsin solution were randomly divided into four groups: (1) continuous perfusion of Krebs-Henseleit solution through the portal vein for 165 minutes (control); (2) 30-minute perfusion followed by 120 minutes of ischemia and 15 minutes of reperfusion; (3) like group 2, but with the administration of CGS 21680, an A2A receptor agonist, 30 microg/100 ml, for 1 minute before ischemia; (4) like group 3, but with administration of SCH 58261, an A2A receptor antagonist. Serum liver enzyme levels were measured by biochemical analysis, and intrahepatic caspase-3 activity was measured by fluorometric assay; apoptotic cells were identified by morphological criteria, the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) fluorometric assay, and immunohistochemistry for caspase-3. Results showed that at 1 minute of reperfusion, there was a statistically significant reduction in liver enzyme levels in the animals pretreated with CGS (p < 0.05). On fluorometric assay, caspase-3 activity was significantly decreased in group 3 compared to group 2 (p < 0.0002). The reduction in postischemic apoptotic hepatic injury in the CGS-treated group was confirmed morphologically, by the significantly fewer apoptotic hepatocyte cells detected (p < 0.05); immunohistochemically, by the significantly weaker activation of caspase-3 compared to the ischemic group (p < 0.05); and by the TUNEL assay (p < 0.05). In conclusion, the administration of A2A receptor agonist before induction of ischemia can attenuate postischemic apoptotic hepatic injury and thereby minimize liver injury. Apoptotic hepatic injury seems to be mediated through caspase-3 activity.

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“…These include studies from isolated hepatocytes that suggest a preconditioning effect limiting increases in [Na ϩ ] i during hypoxia is mediated by NO through cGK and p38 MAPK (11) and furthermore that atrial natriuretic peptide diminishes hypoxia-induced increases in [Na ϩ ] i by a similar pathway that inhibits NHE1 (10). These results are also consistent with studies that suggest activation of p38 MAPK inhibits the response of NHE1 to angiotensin II in vascular smooth muscle cells by phosphorylating the NHE1 at serine/threonine residues located between amino acids 671 and 714 (27).…”

Section: Discussionmentioning

confidence: 99%

Acute effects of 17β-estradiol on myocardial pH, Na⁺, and Ca²⁺ and ischemia-reperfusion injury

Anderson¹,

Kirkland²,

Beyschau³

et al. 2005

American Journal of Physiology-Cell Physiology

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Evidence suggests that 1) ischemia-reperfusion injury is due largely to cytosolic Ca 2ϩ accumulation resulting from functional coupling of Na ϩ /Ca 2ϩ exchange (NCE) with stimulated Na ϩ /H ϩ exchange (NHE1) and 2) 17␤-estradiol (E2) stimulates release of NO, which inhibits NHE1. Thus we tested the hypothesis that acute E2 limits myocardial Na ϩ and therefore Ca 2ϩ accumulation, thereby limiting ischemia-reperfusion injury. NMR was used to measure cytosolic pH (pHi), Na ϩ (Na i ϩ ), and calcium concentration ([Ca 2ϩ ]i) in Krebs-Henseleit (KH)-perfused hearts from ovariectomized rats (OVX). Left ventricular developed pressure (LVDP) and lactate dehydrogenase (LDH) release were also measured. Control ischemia-reperfusion was 20 min of baseline perfusion, 40 min of global ischemia, and 40 min of reperfusion. The E2 protocol was identical, except that 1 nM E2 was included in the perfusate before ischemia and during reperfusion. E2 significantly limited the changes in pH i, Na i ϩ , and [Ca 2ϩ ]i during ischemia (P Ͻ 0.05). In control OVX vs. OVXϩE2, pH i fell from 6.93 Ϯ 0.03 to 5.98 Ϯ 0.04 vs. 6.96 Ϯ 0.04 to 6.68 Ϯ 0.07; Na i ϩ rose from 25 Ϯ 6 to 109 Ϯ 14 meq/kg dry wt vs. 25 Ϯ 1 to 76 Ϯ 3; [Ca 2ϩ ]i changed from 365 Ϯ 69 to 1,248 Ϯ 180 nM vs. 293 Ϯ 66 to 202 Ϯ 64 nM. E2 also improved recovery of LVDP and diminished release of LDH during reperfusion. Effects of E2 were diminished by 1 M N -nitro-L-arginine methyl ester. Thus the data are consistent with the hypothesis. However, E2 limitation of increases in [Ca 2ϩ ]i is greater than can be accounted for by the thermodynamic effect of reduced Na i ϩ accumulation on NCE. myocardial ischemia; Na ϩ /H ϩ exchange; Na ϩ /Ca 2ϩ exchange; nuclear magnetic resonance; ischemic biology; ion channels/membrane transport; transplantation IT IS CLEAR THAT OUR UNDERSTANDING of the effects of endogenous and exogenous estrogen on the cardiovascular system, and in particular on its role in modifying susceptibility to ischemic injury, is deficient. It is more important than ever that fundamental research be conducted to understand the basis for the effects of estrogen (50). Because results of various studies are inconsistent and/or difficult to interpret, we have taken a reductionist approach to testing the acute effects of exogenous 17␤-estradiol (E2) on ischemic myocardium within the context of the well-accepted paradigm that ischemic injury is largely the result of the following chain of events. Anaerobic metabolism decreases cytosolic pH (pH i ), which stimulates pHregulatory Na ϩ /H ϩ exchange (NHE1) to increase Na ϩ uptake and thereby increase intracellular Na ϩ (Na i ϩ ). Increases in (3,7,31,37,46,49). In the heart, there are questions about whether the bulk of Na ϩ and Ca 2ϩ entry occurs during ischemia or reperfusion, but there is a growing consensus that much of the Ca 2ϩ entry is Na ϩ dependent (36). Numerous studies have shown that E2 stimulates NOS activity and/or the release of nitric oxide (NO) in the heart (20,39,40) and that female hormonelinked changes in Na ϩ...

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Signal pathway responsible for hepatocyte preconditioning by nitric oxide

Cited by 37 publications

References 34 publications

The Role of Nitric Oxide in the Neuroprotection of Limb Ischemic Preconditioning in Rats

The Role of Nitric Oxide in the Neuroprotection of Limb Ischemic Preconditioning in Rats

Effect of adenosine A2A receptor agonist (CGS) on ischemia/reperfusion injury in isolated rat liver

Acute effects of 17β-estradiol on myocardial pH, Na⁺, and Ca²⁺ and ischemia-reperfusion injury

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Signal pathway responsible for hepatocyte preconditioning by nitric oxide

Cited by 37 publications

References 34 publications

The Role of Nitric Oxide in the Neuroprotection of Limb Ischemic Preconditioning in Rats

The Role of Nitric Oxide in the Neuroprotection of Limb Ischemic Preconditioning in Rats

Effect of adenosine A2A receptor agonist (CGS) on ischemia/reperfusion injury in isolated rat liver

Acute effects of 17β-estradiol on myocardial pH, Na+, and Ca2+ and ischemia-reperfusion injury

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Acute effects of 17β-estradiol on myocardial pH, Na⁺, and Ca²⁺ and ischemia-reperfusion injury