Mechanisms of hepatocyte protection against hypoxic injury by atrial natriuretic peptide

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

doi:10.1053/jhep.2003.50033

Cited by 39 publications

(29 citation statements)

References 36 publications

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“…Here, we show that changes in pHi exhibited in response to physiological concentrations of ANP can be responsible for ROS production through the activation of p38 MAPK and PLD. Since experimental evidences [46] describe the ability of ANP to inhibit cell growth, our data support the possibility that ROS production may be involved in the mechanism by which ANP inhibits HepG2 cell growth, by necrosis [47] Finally, our findings appear partially in disagreement with previous reports showing the ANP ability to reduce liver ischemia/reperfusion injury and improving hepatocytes resistance to oxidative stress [48]. It should not be surprising that ANP elicits different effects.…”

Section: Discussioncontrasting

confidence: 55%

Atrial Natriuretic Peptide Effects on Intracellular pH Changes and ROS Production in HEPG2 Cells: Role of p38 MAPK and Phospholipase D

Baldini¹,

Vito²,

Vismara³

et al. 2005

Cell Physiol Biochem

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Aims: The present study was performed to evaluate Atrial Natriuretic Peptide (ANP) effects on intracellular pH, phospholipase D and ROS production and the possible relationship among them in HepG2 cells. Cancer extracellular microenvironment is more acidic than normal tissues and the activation of NHE-1, the only system able to regulate pHi homeostasis in this condition , can represent an important event in cell proliferation and malignant transformation. Methods: The ANP effects on pHi were evaluated by fluorescence spectrometry. The effects on p38 MAPK and ROS production were evaluated by immunoblots and analysis of DCF-DA fluorescence, respectively. RT-PCR analysis and Western blotting were used to determine the ANP effect on mRNA NHE-1 expression and protein levels. PLD-catalyzed conversion of phosphatidylcholine to phosphatydilethanol (PetOH), in the presence of ethanol, was monitored by thin layer chromatography. Results: A significant pHi decrease was observed in ANP-treated HepG2 cells and this effect was paralleled by the enhancement of PLD activity and ROS production. The ANP effect on pHi was coupled to an increased p38 MAPK phosphorylation and a down-regulation of mRNA NHE-1 expression and protein levels. Moreover, the relationship between PLD and ROS production was demonstrated by calphostin-c, a potent inhibitor of PLD. At the same time, all assessed ANP-effects were mediated by NPR-C receptors. Conclusion: Our results indicate that ANP recruits a signal pathway associated with p38 MAPK, NHE-1 and PLD responsible for ROS production, suggesting a possible role for ANP as novel modulator of ROS generation in HepG2 cells.

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Section: Discussioncontrasting

confidence: 55%

Atrial Natriuretic Peptide Effects on Intracellular pH Changes and ROS Production in HEPG2 Cells: Role of p38 MAPK and Phospholipase D

Baldini¹,

Vito²,

Vismara³

et al. 2005

Cell Physiol Biochem

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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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“…This is important because the GC-A receptor is widely distributed in many different cell types and mediates the effects of ANP and BNP in many biological functions. In addition to its role in blood pressure control, recent reports have indicated that GC-A might be critical in the regulation of other completely different physiological processes, such as cellular growth in the brain and kidney, 60 angiogenesis, 119 liver regeneration, 120 or even lipolysis in adipose tissue. 121 Second, an important and still unresolved issue is whether cGMP production by different membrane-bound versus soluble GCs is compartmentalized.…”

Section: Future Directionsmentioning

confidence: 99%

Structure, Regulation, and Function of Mammalian Membrane Guanylyl Cyclase Receptors, With a Focus on Guanylyl Cyclase-A

Kühn

2003

Circulation Research

241

161

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Abstract-Besides soluble guanylyl cyclase (GC), the receptor for NO, there are at least seven plasma membrane enzymes that synthesize the second-messenger cGMP. All membrane GCs (GC-A through GC-G) share a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic (GC) region. Although the presence of the extracellular domain suggests that all these enzymes function as receptors, specific ligands have been identified for only three of them (GC-A through GC-C). GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic actions in the heart. GC-B is a specific receptor for C-type natriuretic peptide, having more of a paracrine function in vascular regeneration and endochondral ossification. GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and on epithelial cell growth and differentiation. GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction. Finally, the functions of GC-D (located in the olfactory neuroepithelium) and GC-G (expressed in highest amounts in lung, intestine, and skeletal muscle) are completely unknown. This review discusses the structure and functions of membrane GCs, with special emphasis on the physiological endocrine and cardiac functions of GC-A, the regulation of hormone-dependent GC-A activity, and the relevance of alterations of the atrial natriuretic peptide/GC-A system to cardiovascular diseases. (Circ Res. 2003;93:700-709.)

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Mechanisms of hepatocyte protection against hypoxic injury by atrial natriuretic peptide

Cited by 39 publications

References 36 publications

Atrial Natriuretic Peptide Effects on Intracellular pH Changes and ROS Production in HEPG2 Cells: Role of p38 MAPK and Phospholipase D

Atrial Natriuretic Peptide Effects on Intracellular pH Changes and ROS Production in HEPG2 Cells: Role of p38 MAPK and Phospholipase D

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

Structure, Regulation, and Function of Mammalian Membrane Guanylyl Cyclase Receptors, With a Focus on Guanylyl Cyclase-A

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Mechanisms of hepatocyte protection against hypoxic injury by atrial natriuretic peptide

Cited by 39 publications

References 36 publications

Atrial Natriuretic Peptide Effects on Intracellular pH Changes and ROS Production in HEPG2 Cells: Role of p38 MAPK and Phospholipase D

Atrial Natriuretic Peptide Effects on Intracellular pH Changes and ROS Production in HEPG2 Cells: Role of p38 MAPK and Phospholipase D

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

Structure, Regulation, and Function of Mammalian Membrane Guanylyl Cyclase Receptors, With a Focus on Guanylyl Cyclase-A

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