PI3K-dependent lysosome exocytosis in nitric oxide-preconditioned hepatocytes

被引:18
作者
Carini, Rita
Trincheri, Nicol Francesca
Alchera, Elisa
De Cesaris, Maria Grazia
Castino, Roberta
Splendore, Roberta
Albano, Emanuele
Isidoro, Ciro
机构
[1] Univ Piemonte Orientale, Dipartimento Sci Med, Lab Mol Pathol, I-28100 Novara, Italy
[2] Univ Piemonte Orientale, Dipartimento Sci Med, Pathol Lab, I-28100 Novara, Italy
关键词
preconditioning; PI3-kinase; vacuolar ATPase; cell death; cathepsin D; free radical;
D O I
10.1016/j.freeradbiomed.2006.01.013
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We investigated the signal mediators and the cellular events involved in the nitric oxide (NO)-induced hepatocyte resistance to oxygen deprivation in isolated hepatocytes treated with the NO donor (Z)-1-(N-methyl-N-[6-(N-methylammoniohexyl)amino])diazen-1-ium-1,2-diolate (NOC-9). NOC-9 greatly induced PI3K activation, as tested by phosphorylation of PKB/Akt. This effect was prevented by either 1H-(1,2,4)-oxadiazolo-(4,3)-quinoxalin-1-one, an inhibitor of the soluble guanylate cyclase (sGC), or KT5823, an inhibitor of cGMP-dependent kinase (cGK), as well as by farnesyl protein transferase inhibitor, which blocks the function of Ras GTPase. Bafilomycin A, an inhibitor of the lysosome-type vacuolar H+-ATPase, cytochalasin D, which disrupts the cytoskeleton-dependent organelle traffic, and wortmannin, which inhibits the PI3K-dependent traffic of lysosomes, all abolished the NOC-9-induced hepatocyte protection. The treatment with NOC-9 was associated with the PI3K-dependent peripheral translocation and fusion with the plasma membrane of lysosomes and the appearance at the cell surface of the vacuolar H+-ATPase. Inhibition of sGC, cGK, and Ras, as well as the inhibition of PI3K by wortmannin, prevented the exocytosis of lysosomes and concomitantly abolished the protective effect of NOC-9 on hypoxia-induced pH(i) and [Na+](i) alterations and cell death. These data indicate that NO increases hepatocyte resistance to hypoxic injury by activating a pathway involving Ras, sGC, and cGK that determines PI3K-dependent exocytosis of lysosomes. (c) 2006 Elsevier Inc. All rights reserved.
引用
收藏
页码:1738 / 1748
页数:11
相关论文
共 47 条
[11]   ALTERATION OF NA+ HOMEOSTASIS AS A CRITICAL STEP IN THE DEVELOPMENT OF IRREVERSIBLE HEPATOCYTE INJURY AFTER ADENOSINE-TRIPHOSPHATE DEPLETION [J].
CARINI, R ;
BELLOMO, G ;
BENEDETTI, A ;
FULCERI, R ;
GAMBERUCCI, A ;
PAROLA, M ;
DIANZANI, MU ;
ALBANO, E .
HEPATOLOGY, 1995, 21 (04) :1089-1098
[12]   Ischemic preconditioning reduces Na+ accumulation and cell killing in isolated rat hepatocytes exposed to hypoxia [J].
Carini, R ;
De Cesaris, MG ;
Splendore, R ;
Bagnati, M ;
Albano, E .
HEPATOLOGY, 2000, 31 (01) :166-172
[13]   Regulation of rat hepatocyte protein kinase C β isoenzymes by the lipid peroxidation product 4-hydroxy-2,3-nonenal:: A signaling pathway to modulate vesicular transport of glycoproteins [J].
Chiarpotto, E ;
Domenicotti, C ;
Paola, D ;
Vitali, A ;
Nitti, M ;
Pronzato, MA ;
Biasi, F ;
Cottalasso, D ;
Marinari, UM ;
Dragonetti, A ;
Cesaro, P ;
Isidoro, C ;
Poli, G .
HEPATOLOGY, 1999, 29 (05) :1565-1572
[14]   Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans [J].
Clavien, PA ;
Yadav, S ;
Sindram, D ;
Bentley, RC .
ANNALS OF SURGERY, 2000, 232 (02) :155-162
[15]   Actin filaments and myosin I alpha cooperate with microtubules for the movement of lysosomes [J].
Cordonnier, MN ;
Dauzonne, D ;
Louvard, D ;
Coudrier, E .
MOLECULAR BIOLOGY OF THE CELL, 2001, 12 (12) :4013-4029
[16]   Hepatoprotective effect of endogenous nitric oxide during ischemia-reperfusion in the rat [J].
Cottart, CH ;
Do, L ;
Blanc, MC ;
Vaubourdolle, M ;
Descamps, G ;
Durand, D ;
Galen, FX ;
Clot, JP .
HEPATOLOGY, 1999, 29 (03) :809-813
[17]   Pharmacology of nitric oxide: Molecular mechanisms and therapeutic strategies [J].
Domenico, R .
CURRENT PHARMACEUTICAL DESIGN, 2004, 10 (14) :1667-1676
[18]   PI 3-kinase, Akt and cell survival [J].
Downward, J .
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, 2004, 15 (02) :177-182
[19]  
Dragonetti A, 2000, J CELL SCI, V113, P3289
[20]   An NO derivative of ursodeoxycholic acid protects against Fas-mediated liver injury by inhibiting caspase activity [J].
Fiorucci, S ;
Mencarelli, A ;
Palazzetti, B ;
Del Soldato, P ;
Morelli, A ;
Ignarro, LJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (05) :2652-2657