|
|
|
|
|
|
|
|
|||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | |||||
First published online 17 February 2004
doi: 10.1242/jcs.00923
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Research Article |
1 Laboratories of Pathology, Dipartimento di Scienze Mediche, Università del Piemonte Orientale `A. Avogadro', via Solaroli 17, 28100 Novara, Italy
2 Molecular Pathology2, Dipartimento di Scienze Mediche, Università del Piemonte Orientale `A. Avogadro', via Solaroli 17, 28100 Novara, Italy
* Author for correspondence (e-mail: isidoro{at}med.unipmn.it)
Accepted 6 October 2003
A short period of hypoxia reduces the cytotoxicity produced by a subsequent prolonged hypoxia in isolated hepatocytes. This phenomenon, termed hypoxic preconditioning, is mediated by the activation of adenosine A2A-receptor and is associated with the attenuation of cellular acidosis and Na+ overload normally occurring during hypoxia. Bafilomycin, an inhibitor of the vacuolar H+/ATPase, reverts the latter effects and abrogates the preconditioning-induced cytoprotection. Here we provide evidence that the acquisition of preconditioning-induced cytoprotection requires the fusion with plasma membrane and exocytosis of endosomal-lysosomal organelles. Poisons of the vesicular traffic, such as wortmannin and 3-methyladenine, which inhibit phosphatydilinositol 3-kinase, or cytochalasin D, which disassembles the actin cytoskeleton, prevented lysosome exocytosis and also abolished the preconditioning-associated protection from acidosis and necrosis provoked by hypoxia. Preconditioning was associated with the phosphatydilinositol 3-kinase-dependent increase of cytosolic [Ca2+]. Chelation of free cytosolic Ca2+ in preconditioned cells prevented lysosome exocytosis and the acquisition of cytoprotection. We conclude that lysosome-plasma membrane fusion is the mechanism through which hypoxic preconditioning allows hepatocytes to preserve the intracellular pH and survive hypoxic stress. This process is under the control of phosphatydilinositol 3-kinase and requires the integrity of the cytoskeleton and the rise of intracellular free calcium ions.
Key words: Cell death, Cathepsin D, Ischemia, Exocytosis, Signal transduction
Related articles in JCS:
This article has been cited by other articles:
|
|
 |
|
  R. Castino, S. Delpal, E. Bouguyon, M. Demoz, C. Isidoro, and M. Ollivier-Bousquet Prolactin Promotes the Secretion of Active Cathepsin D at the Basal Side of Rat Mammary Acini Endocrinology, August 1, 2008; 149(8): 4095 - 4105. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Erdmann, A. Ricken, C. Merkwitz, I. Struman, R. Castino, K. Hummitzsch, F. Gaunitz, C. Isidoro, J. Martial, and K. Spanel-Borowski The expression of prolactin and its cathepsin D-mediated cleavage in the bovine corpus luteum vary with the estrous cycle Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1365 - E1377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Suzuki, Z.-G. Jin, D. F. Meoli, T. Matoba, and B. C. Berk Cyclophilin A Is Secreted by a Vesicular Pathway in Vascular Smooth Muscle Cells Circ. Res., March 31, 2006; 98(6): 811 - 817. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Koch, A. Kanazawa, R. Nishitai, B. E. Knudsen, K. Ogata, T. B. Plummer, K. Butters, and J. L. Platt Intrinsic Resistance of Hepatocytes to Complement-Mediated Injury J. Immunol., June 1, 2005; 174(11): 7302 - 7309. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lkhider, R. Castino, E. Bouguyon, C. Isidoro, and M. Ollivier-Bousquet Cathepsin D released by lactating rat mammary epithelial cells is involved in prolactin cleavage under physiological conditions J. Cell Sci., October 1, 2004; 117(21): 5155 - 5164. [Abstract] [Full Text] [PDF]
|
|
